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CHARACTERISTICS OF OVULATION

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CHARACTERISTICS OF OVULATION

th
Ovulation. Uploaded on May 15 2012.
Oerjan Why Elias Ebbesen Eikemo.

Medical Research in Biblical Times

Examination of Passages from the Bible,
Exactly as Written

Liubov Ben-Nun

NOT FOR SALE

 Author & Editor: Liubov Ben-Nun, Professor Emeritus

Ben Gurion University of the Negev

Faculty of Health Sciences, Dept. of Family Medicine
Beer-Sheva, Israel.

REMARK:
The small number of pictures and drawings appearing in my books
were checked to the best of my ability regarding publication rights. If I
have made a mistake, I apologize to remove them. In any case on the first
page of all my books, the words: Not for Sale are printed in bold letters.

The Author gains no financial or other benefits.

B. N. Publication House. Israel. 2018.

E-Mail: L-bennun@smile.net.il
Technical Assistance: Carmela Moshe

NOT FOR SALE

The exact time of ovulation within the menstrual cycle is
important for the reproductive function in women. What is
ovulation? How can fertility awareness be described? What is the
appropriate time for intercourse to achieve conception? Its
frequency? What is the span of the fertility window? What are the
features of natural family planning? What are disorders of ovulation?
What are the main principles of anovulation management?
The Biblical verses dealing with the sexual behavior of two women
associated with ovulation were studied from a contemporary
viewpoint.
 CONTENTS
INTRODUCTION 4

DESCRIPTION IN THE BIBLE 5

WHAT IS OVULATION? 6

FERTILITY AWARENESS 9

DESIRED PREGNANCY 21

FERTILITY WINDOW 27

OVULATION DETECTION 32

NATURAL FAMILY PLANNING 64

DISORDERS OF OVULATION 75

MANAGEMENT 89

SUMMARY 102
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INTRODUCTION
Roth (1) mentioned that fertility awareness refers to the
observation and interpretation of cervical mucus, often called vaginal
discharge. A woman's cervical-mucus pattern indicates the time of
ovulation and differentiates the fertile and infertile phases of the
menstrual cycle from each other. Fertility awareness enables a
woman to know when pregnancy can and cannot occur on a daily
basis during each menstrual cycle. There has been, to date, almost
no exploration of the appropriateness of fertility-awareness
instruction for adolescents. A review of the literature on adolescent
cognitive development, sexual activity, knowledge of fertility and
contraceptive risk-taking behavior is presented. Based on the
literature review, a theoretical rationale for fertility-awareness
instruction as a unique sex-education curriculum for adolescents is
proposed. The content and teaching techniques of a fertility-
awareness presentation for teenagers is described. Directions for
future research in fertility-awareness instruction for teenagers, and
the need for long-term follow-up to assess the effects of such
education on teenagers' sexual activity and contraceptive use are
discussed (1).
Ayoola & al. (2) examined women's knowledge of female
reproduction-anatomy, hormones and their functions, ovulation, the
menstrual cycle and its associated reproductive changes, conception,
and signs of pregnancy. A survey was completed by 125 women of
childbearing age as part of a larger "Women's Health Promotion
Program." The women in the study were ages 18-51 years, 52.0
percent were Hispanic, 36.0 percent African American, and 12.0
percent White. The majority, 70.4 percent, had a household income
of less than $20,000, 58.4 percent were not married, 83.2 percent
were not trying to get pregnant at the time, and 37.6 percent had
sexual intercourse that may have put them at risk for pregnancy in
the past month. Less than one-third knew about the reproductive
hormones. Over 80.0 percent knew their reproductive anatomy, 68.8
percent were not keeping any log to track their menstrual flow, 53.6
percent did not know when their next menstruation would be, and
49.6 percent did not know the average number of days for a regular
menstrual cycle. Many did not know what ovulation is (47.2%), the
ovulation timing (67.2%), the number of eggs released from an ovary
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each month (79.2%), and how long an egg or sperm could live in a
woman's body (62.4%). The data show that reproductive knowledge
should be assessed during preconception visits and women should be
taught comprehensive reproductive education-not just selected
topics-to be adequately equipped to make informed reproductive
decisions (2).

The exact time of ovulation within the menstrual cycle is

important for the reproductive function in women. What is
ovulation? How can fertility awareness be described? What is the
appropriate time for intercourse to achieve conception? Its
frequency? What is the span of the fertility window? What are the
features of natural family planning? What are disorders of ovulation?
What are the main principles of anovulation management?
The Biblical verses dealing with the sexual behavior of two women
associated with ovulation were studied from a contemporary
viewpoint.

References
1. Roth B. Fertility awareness as a component of sexuality education.
Preliminary research findings with adolescents. Nurse Pract. 1993;
18(3):40, 43, 47-8 passim.
2. Ayoola AB, Zandee GL, Adams YJ. Women's knowledge of ovulation,
the menstrual cycle, and its associated reproductive changes. Birth.
2016;43(3):255-62.

DESCRIPTION IN THE BIBLE

After the destruction of Sodom and Gomorrah, Lot's two
daughters thought that they were left alone in the world. Awareness
of ovulation days was the underlying factor in the plan of these
daughters to give birth to children and thus prevent the destruction
of the human race: “And the first-born said unto the younger: Our
father is old, and there is not a man on earth to come unto us after
the manner of all the earth. Come let us make our father drink wine
and we will lie with him, that we may preserve seed of our father.
And they made their father drink wine that night. And the first-born
went in and lay with her father; and he knew not when she lay down
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nor when she arose. And it came to pass on the morrow that the
first-born said unto the younger: Behold I lay yesternight with my
father. Let us make him drink wine this night also, and go thou in and
lie with him, that we may preserve seed of our father. And they made
their father drink wine that night also. And the younger arose and lay
with him; and he knew not when she lay down nor when she arose.
Thus were both the daughters of Lot with child by their father. And
the first-born bore a son and called his name Moab – and he is father
of the Moabites to this day. And the younger also bore a son and
called his name Ben-Ami, and he is father of the children of Ammon to
this day” (THE BIBLE: Genesis 19:31-38).
These verses show that Lot's daughters were well aware of their
ovulation dates. They knew when to have sexual relations with their
father and therefore conceived and gave birth to their sons.

WHAT IS OVULATION?
Ovulation is the release of an egg from one of a woman's ovaries.
After the egg is released, it travels down the fallopian tube, where
fertilization by a sperm cell may occur. Ovulation typically lasts one
day and occurs in the middle of a woman's menstrual cycle, about
two weeks before she expects to get her period. But the timing of
the process varies for each woman, and it may even vary from month
to month. If a woman is hoping to become pregnant, she will want to
keep track of when she may be ovulating. Knowing when a woman is
ovulating each month is helpful because she is the most fertile — or
able to become pregnant — around the time of ovulation (1).
Ovulation is the release of an egg from one of a woman's ovaries.
After the egg is released, it travels down the fallopian tube, where
fertilization by a sperm cell may occur. If a woman is hoping to
become pregnant, she will want to keep track of when she may be
ovulating. Knowing when a woman is ovulating each month is helpful
because she is the most fertile — or able to become pregnant —
around the time of ovulation. A couple will be more likely to
conceive if they have sex a day or two before a woman ovulates and
the day of ovulation (1).
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Diagram of the Female Reproductive System.

(Image: © Shutterstock). https://www.livescience.com/54922-what-is-
ovulation.html.

At birth, a female fetus has 1 to 2 million immature eggs called

oocytes inside her ovaries, which are all the eggs she will ever
produce. By the time a girl enters puberty, about 300,000 of these
eggs remain. Approximately 300 to 400 of the remaining eggs will be
ovulated during a woman's reproductive lifetime. A likely sign that a
woman is ovulating is that she is having regular, predictable periods
that occur every 24 to 32 days. With every monthly menstrual cycle,
a woman's body prepares for a potential pregnancy. The cycle is
regulated by hormones, including the sex hormones estrogen and
progesterone, as well as follicle-stimulating hormone and luteinizing
hormone. Hormones play a key role in all stages of the menstrual
cycle, allowing the ovum (egg) to mature and eventually be released
(1).
When a mature egg leaves a woman's ovary and travels into the
fallopian tube, a sperm cell can fertilize the egg. Sperm can live
inside a woman's reproductive tract for about 3 to 5 days after sexual
intercourse. For pregnancy to take place, a sperm cell must fertilize
the egg within 12 to 24 hours of ovulating. The fertilized egg then
travels to the uterus, or womb, where it can attach to the lining of
uterus and develop into a fetus. During ovulation, the walls of the
uterus also thicken to prepare for a fertilized egg. But if the egg is
not fertilized, the uterine lining is shed about two weeks later,
causing menstrual flow to begin. But simply having her period does
not always indicate that a woman is ovulating (1).
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Signs and Symptoms of Ovulation.

Momjunction.

Rosetta & al. (2) stated that assessing menstrual cycle function in
the general population using a non-invasive method is challenging,
both in non-industrialized and industrialized countries. The
Observatory of Fecundity in France (Obseff) recruited on a
nationwide basis a random sample of 943 women aged 18-44 years
with unprotected intercourse. A sub-study was set up to assess the
characteristics of a menstrual cycle by using a non-invasive method
adapted to the general population. Voluntary women were sent a
collection kit by the post and requested to collect urine samples on
pH strips, together with daily recording of reproductive-related
information during a full menstrual cycle. A total of 48 women
collected urine every day, whereas 160 women collected urine every
other day. Immunoassays were used to measure pregnanediol-3-α-
glucuronide, estrone-3-glucuronide and creatinine. Ovulation
occurrence and follicular phase duration were estimated using
ovulation detection algorithms, compared to a gold standard
consisting of three external experts in reproductive medicine. Every
other day urine collection gave consistent results in terms of
ovulation detection with every day collection (intraclass coefficient of
correlation 0.84, 95% confidence interval, 0.76-0.98). The proportion
of anovulatory menstrual cycles was 8%. The characteristics of the
ovulatory cycles were length 28 (26-34), follicular phase 16 (12-23),
luteal phase 13 (10-16) days median (10th-90th percentiles). The
data show that assessing menstrual cycle characteristics based on
urine sample spot only collected every other day in population-based
studies through a non-invasive, well accepted and cost-limited
procedure not requiring any direct contact with the survey team
appears feasible and accurate (2).
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All about ovulation. Conceive baby.

References
1. Cari Nierenberg What is ovulation? 2018.
https://www.livescience.com/54922-what-is-ovulation.html.
2. Rosetta L, Thalabard JC, Tanniou J, et al. Ovulatory status and
menstrual cycle duration assessed by self-collection of urine on pH strips in
a population-based sample of French women not using hormonal
contraception. Eur J Contracept Reprod Health Care. 2017;22(6):450-8.

FERTILITY AWARENESS
Pyper (1) mentioned that information about fertility awareness
helps to fulfill the broader definition of the services many family
planning clinics offer. Although information about natural family
planning is requested by a small number of clients seeking family
planning advice, many more clients benefit from information about
fertility awareness. Fertility awareness is far more than just basic
reproductive anatomy and physiology; fertility awareness involves
understanding basic information about fertility and reproduction,
being able to apply it to oneself, and being able to discuss it with a
partner or with a health professional. Fertility awareness is
fundamental to understanding and making informed decisions about
reproductive health and sexual health. If clients have a better
understanding of fertility awareness, they are in a stronger position
to make informed decisions about how they wish to manage their
reproductive and sexual health, for example: 1] Fertility awareness
information is used to help couples to plan pregnancies as well as to
avoid them. This can be helpful to couples who are having difficulty
conceiving, for the timing of intercourse or for the timing of some of
the sub-fertility investigations. 2] The information is also useful when
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helping couples to understand how each method of family planning

works - how the family planning method interrupts normal fertility,
how the method will fail if not used correctly, and how fertility
returns when the method is discontinued. 3] Women who are fully
breastfeeding value the knowledge about reduced fertility, as do
women during the perimenopausal years who value being given clear
information about their declining fertility. 4] When counseling
couples about the importance of avoiding sexually transmitted
diseases it is important they understand sexually transmitted
diseases may damage their fertility. 5] Couples who choose only to
use a barrier method during the time they think the woman is fertile
are a group who do not readily identify themselves to family planning
providers. These couples often do not have adequate information
about fertility awareness. Advances in technology and the
understanding of ovulation, ovum and sperm survival have confirmed
that the guidelines used to teach fertility awareness and natural
family planning effectively identify the fertile phase of the menstrual
cycle. Serial ultrasound studies on the ovaries during the menstrual
cycle have confirmed the accuracy of the hormonal assays in
pinpointing the likely time of ovulation. Ultrasound studies have also
shown that subjective observations of the alterations in cervical
mucus and the basal body temperature rise are accurate indicators of
the fertile phase. Research on the chances of conception on each
day of the menstrual cycle, using hormonal assays to estimate the
time of ovulation, was carried out in 1994 by Weinberg and Wilcox.
Their results showed that the timing of sexual intercourse, in relation
to ovulation, strongly influences the chance of conception.
Conception only occurred during a 6-day interval that ended on the
estimated day of ovulation. The chances of conception fell to zero 24
hours after ovulation. Several different methods of natural family
planning are taught; some methods depend on only using one of the
indicators of fertility, others are based on two or more indicators.
The main indicators of fertility are: observing the cervical mucus,
recording the basal body temperature, palpating the cervix and a
calculation based on the cycle length. Research studies performed
using a combination of the indicators of fertility show that the failure
rate using a combination is less than most of the studies which use a
single indicator. In each case the method failure is far lower than the
user failure (1).
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Hampton & al. (2) reported a descriptive study of fertility-

awareness knowledge, attitudes, and practice of infertile women
seeking fertility assistance. Previous research has suggested that
poor fertility-awareness may be a contributing cause of infertility
among women seeking fertility assistance at assisted reproductive
technology clinics (ART). The actual practices and attitudes towards
fertility-awareness in this particular group of women are unknown. A
cross-sectional questionnaire-based survey was conducted over 6
months, from 2007-2008, of women on admission to two ART clinics
in a major city in Australia. Two hundred and four of 282 distributed
questionnaires were completed (response rate = 72·3%). Eighty-
three per cent had attempted conception for 1 year or more, 86.8%
actively tried to improve their fertility-awareness from one or more
sources of the information, 68.2% believed they had timed
intercourse mainly within the fertile window of the menstrual cycle in
their attempts at conception, but only 12.7% could accurately
identify this window. Ninety-four per cent believe that a woman
should receive fertility-awareness education when she first reports
trouble conceiving to her doctor. The data show that most women
seeking assistance at ART clinics attempt timed intercourse within
the fertile window of the menstrual cycle. However, few accurately
identify this window, suggesting that poor fertility-awareness may be
a contributing cause of infertility (2).
Hampton & Mazza (3) noticed that most women who attend ART
clinics believe women should receive fertility-awareness education
when they first report trouble conceiving. Interest in fertility
awareness among women who attend general practice is largely
unknown. The aim was to measure fertility-awareness knowledge,
attitudes and practices of women attending general practice. A
cross-sectional survey of women attending three different general
practices was conducted. Of the respondents, 37.1% actively tried to
improve their knowledge of fertility awareness, 9.8% were actively
planning a pregnancy and 4.3% were using fertility awareness as
contraception. Yet, only 2.1% of the overall sample correctly
identified the fertile period of the menstrual cycle. Most
respondents (92.2%) believed women should receive fertility-
awareness education when they first report trouble conceiving. One-
third of women who attend general practice show interest in fertility
awareness, but far fewer can correctly identify the fertile period of
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Ben-Nun Ovulation

the menstrual cycle. All women who report using fertility awareness
as contraception should be counseled on their actual knowledge and
advised accordingly. Concordant with the previous study of women
who experience infertility, most women who attend general practice
believe that women should receive fertility-awareness education
when they first report trouble conceiving. Further research is needed
to determine how best to do this (3).
Thijssen & al. (4) mentioned that fertility awareness based
methods (FABMs) can be used to ameliorate the likelihood to
conceive. A literature search was performed to evaluate the
relationship of cervical mucus monitoring (CMM) and the day-specific
-pregnancy rate, in case of subfertility. A MEDLINE search revealed a
total of 3,331 articles. After excluding Articles based on their
relevance, 10 studies and were selected. The observed studies
demonstrated that the CMM can identify the days with the highest
pregnancy rate. According to the literature, the quality of the vaginal
discharge correlates well with the cycle-specific probability of
pregnancy in normally fertile couples but less in subfertile couples.
The results indicate an urgent need for more prospective randomized
trials and -prospective cohort studies on CMM in a subfertile
population to evaluate the effectiveness of CMM in the subfertile
couple (4).
Blake & al. (5) assessed fertility awareness in a survey of 80
women presenting over a 3-month period to a tertiary referral unit at
the National Women's Hospital in Auckland, New Zealand, for
infertility investigation. It was hypothesized that less than 50% of
menstruating women with a history of at least 2 years of infertility
have an adequate understanding about the fertile time of their
menstrual cycle. 60% of women had been trying to conceive for 2-3
years, 23% for 4-5 years, and 17% for more than 6 years. For 58% of
clients, this was their first visit to a fertility clinic. 13% had attended a
natural family planning (NFP) clinic previously. On the basis of
questionnaire responses, participants were graded from 0 to 2 in
each of the following 3 categories: 1] level of fertility symptom
awareness (cervical mucus and ovulatory pain), 2] level of
understanding of what these symptoms mean, and 3] level of use of
this information to enhance conception. Only 21 women (26%) had a
final score of 4 or greater - a predetermined cut-off considered
indicative of adequate fertility awareness. The largest percentage of
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Ben-Nun Ovulation

women (46%) had scores of 0-1. Of women, 80% of women with

previous NFP instruction had adequate fertility awareness scores.
These finding supported the study hypothesis of a generally poor
level of fertility awareness among women presenting for treatment
of infertility. Greater utilization of NFP clinics by general
practitioners and specialists, as well as incorporation of NFP trained
nurses into tertiary referral clinics, are recommended (5).
Dorairaj (6) studied the efficacy, the ability of Indian women to
use the Billings' Ovulation Method, and its effectiveness in helping
them to control their fertility was studied in a sample of urban poor
living in the Delhi slums. No attempt was made to develop a design
which would rigorously test the acceptability of the method because
the study was concerned with: the question of the ability of poor
women to define fertility and to avoid an unwanted pregnancy by
avoiding sexual relations during the fertility period; and the efficacy
and use-effectiveness of the modified method which had not been
tested. The study, which extended over 36 months, recruited a
sample of 5,752 eligible acceptors of fertility living in the urban
slums. NFP use requires recurrent decision making at 2 stages: in the
beginning of the menstrual cycle to check for signs of fertility; and to
abstain from sexual relations in the fertility period. Age was an
important variable in the use of sexual abstinence oriented methods
and fertility determining methods. Of the acceptors, 192 were below
19 years, 1,545 between 20-24 years, 2,089 between 25-29 years,
1,236 between 30-34 years, 520 between 35-39 years, and 170
between 40-44 years. Of the 5,302 acceptors, 4,380 in Treatment 1
began to use the method after menstruation, 7 (0.16%) had a profuse
discharge and could not distinguish the change in mucus because of
cervicitis which was treated in cycle 2. 663 (5.4%) acceptors did not
see or feel fertile mucus but noticed patches of infertile mucus
throughout the cycle. 419 (69.19%) of them had a family income of
less than Rs300 and 25 (3.77%) were open cases of pulmonary
tuberculosis. 16 acceptors (0.37%) noticed wetness and lubrication
characteristic of fertile type mucus for about 2 hours, 145 (3.31%) for
3-4 hours, and 218 (4.98%) for nearly half a day. 867 (19.79%) had 1
day, 406 (9.27%) 1-1/2 days, 939 (21.44%) for 2 days, 291 (6.64%) 2-
1/2 days, 636 (14.52%) for 3 days and 187 (4.27%) 3-1/2 to 4 days of
fertile mucus. One acceptor had 5 days of fertile mucus. 4 acceptors
failed to check regularly and therefore may have missed the fertile
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Ben-Nun Ovulation

period. In Treatment 2 the initial decision to accept the use of the

method was made by the 450 husbands before instructing their
wives. The continuation rate of 91.86% for 12 months with a
standard error of 0.67% was surprisingly high for a sample with low
literacy and occupational status, low female work participation rates,
small family size and a preference for sons with low motivation to use
other methods. There were 9 unplanned pregnancies classified as
method failures--pregnancies which occurred in acceptors who
followed the method according to the instruction but got pregnant.
The 1 year efficacy rate (life table analysis) was 99.86%. The 1-year
use-effectiveness rate was 97.43% for the 5,752 cohort. The high
efficacy rate of the method can be due to 2 factors: the correct
identification of the fertile mucus; and the ability to clearly
distinguish between infertile and fertile mucus (6).
Mahey & al. (7) evaluated fertility knowledge and awareness
among infertile women attending an Indian assisted fertility clinic
and their understanding of the menstrual cycle, how age affects
fertility and need for assisted fertility treatment. A cross sectional
study was conducted including 205 women seeking fertility
treatment at an assisted reproductive unit between March 2017 to
August 2017. Patients were interviewed with the help of structured
questionnaire by a fertility counselor. The previous studies were
reviewed and a questionnaire was made according to the patient
profile and sociodemographic characteristics. Knowledge and
awareness was stratified according to socioeconomic status (SES).
Most women (59%) were aged between 20 to 30 years indicating
concern about their fertility and need for evaluation. More than half
(63%) women were from the middle socio-economic strata.
Knowledge about fertility and reproduction was low: 85% were not
aware of the ovulatory period in the menstrual cycle, only 8%
considered age more than 35 years as the most significant risk factor
for infertility and most were unaware of when to seek treatment for
infertility after trying for pregnancy. Less than half of women
understood the need for assisted fertility treatment and donor
oocytes in advanced age. The data show that most Indian women
across different SES are unaware of the effect of age on fertility.
Targeted educational interventions are needed to improve
knowledge regarding ideal age of fertility, factors affecting fertility
potential and fertility options available for sub-fertile couples.
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Fertility counseling and information should be provided to young

people at every contact with health care professionals (7).

References
1. Pyper CM. Fertility awareness and natural family planning. Eur J
Contracept Reprod Health Care. 1997;2(2):131-46.
2. Hampton KD, Mazza D, Newton JM. Fertility-awareness knowledge,
attitudes, and practices of women seeking fertility assistance. J Adv Nurs.
2013;69(5):1076-84.
3. Hampton KD, Mazza D. Fertility-awareness knowledge, attitudes
and practices of women attending general practice. Aust Fam Physician.
2015;44(11):840-5.
4. Thijssen A, Meier A, Panis K, Ombelet W. 'Fertility awareness-based
methods' and subfertility: a systematic review. Facts Views Vis Obgyn.
2014;6(3):113-23.
5. Blake D, Smith D, Bargiacchi A, et al. Fertility awareness in women
attending a fertility clinic. Aust N Z J Obstet Gynaecol. 1997;37(3):350-2.
6. Dorairaj K. Use-effectiveness of fertility awareness among the
urban poor. Soc Action. 1984;34(3):286-306.
7. Mahey R, Gupta M, Kandpal S, et al. Fertility awareness and
knowledge among Indian women attending an infertility clinic: a cross-
sectional study. BMC Womens Health. 2018;18(1):177.

HIV SERODISCORDANT COUPLES

Liao & al. (1) mentioned that increased life expectancy of HIV-
positive individuals during recent years has drawn attention to their
quality of life, which includes fulfillment of fertility desires. In
particular, heterosexual HIV serodiscordant couples constitute a
special group for whom the balance between desired pregnancy and
the risk of viral transmission should be carefully considered and
optimized. Although advanced assisted reproductive technologies
are available, such treatments are expensive and are often
unavailable. Standard viral load testing and antiretroviral therapy
may not be accessible due to structural or individual barriers. To
reduce the risk of HIV transmission, a lower cost alternative is timed
condomless sex combined with other risk-reduction strategies.
However, timed condomless sex requires specific knowledge of how
to accurately predict the fertile window in a menstrual cycle. The
aim of this study was to summarize inexpensive fertility awareness
methods (FAMs) that predict the fertile window and may be useful
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for counseling HIV-positive couples on lower cost options to

conceive. Original English-language research articles were identified
by a detailed Medline and Embase search in July 2014. Relevant
citations in the included articles were also retrieved. Calendar
method, basal body temperature and cervicovaginal mucus
secretions are the most accessible and sensitive FAMs, although poor
specificity precludes their independent use in ovulation detection. In
contrast, urinary luteinizing hormone testing is highly specific but less
sensitive, and more expensive. To maximize the chance of
conception per cycle, the likelihood of natural conception needs to
be assessed with a basic fertility evaluation of both partners and a
combination of FAMs should be offered. Adherence to other risk-
reduction strategies should also be advised, and timely referral to
reproductive medicine specialists is necessary when sub/infertility is
suspected. The data show that FAMs provide effective, economical
and accessible options for HIV serodiscordant couples to conceive
while minimizing unnecessary viral exposure. It is important for
health care providers to initiate conversations about fertility desires
in HIV-positive couples and to educate identified couples on safer
conception strategies (1).
Matthews & al. (2) reported that safer conception interventions
reduce HIV incidence while supporting the reproductive goals of
people living with or affected by HIV. A consensus statement was
developed to address demand, summarize science, identify
information gaps, outline research and policy priorities, and advocate
for safer conception services. This statement emerged from a
process incorporating consultation from meetings, literature, and key
stakeholders. Three co-authors developed an outline which was
discussed and modified with co-authors, working group members,
and additional clinical, policy, and community experts in safer
conception, HIV, and fertility. Co-authors and working group
members developed and approved the final manuscript. Consensus
across themes of demand, safer conception strategies, and
implementation were identified. There is demand for safer
conception services. Access is limited by stigma towards PLWH
having children and limits to provider knowledge. Efficacy,
effectiveness, safety, and acceptability data support a range of safer
conception strategies including antiretroviral therapy (ART), pre-
exposure prophylaxis (PrEP), limiting condomless sex to peak fertility,
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home insemination, male circumcision, Sexual Transmitted Infection

(STI) treatment, couples-based HIV testing, semen processing, and
fertility care. Lack of guidelines and training limits implementation.
Key outstanding questions within each theme are identified.
Consumer demand, scientific data, and global goals to reduce HIV
incidence support safer conception service implementation. The
Authors recommend that providers offer services to HIV-affected
men and women, and program administrators integrate safer
conception care into HIV and reproductive health programs. Answers
to outstanding questions will refine services but should not hinder
steps to empower people to adopt safer conception strategies to
meet reproductive goals (2).
Bazzi & al. (3) noticed that antiretroviral pre-exposure prophylaxis
(PrEP) is a promising HIV prevention strategy for HIV serodiscordant
couples (HIV-infected male, uninfected female) seeking safer
conception. However, most research on PrEP for safer conception
has focused on couples in sub-Saharan Africa; little is known about
the perspectives or experiences of heterosexual couples in the U.S.
Qualitative interviews were conducted with six couples (six women
and five of their male partners) receiving PrEP for conception services
at an urban safety net hospital in the U.S. Northeast. In-depth
interview guides explored couple relationships and contextual factors
and attitudes, perceptions, and decision-making processes
surrounding PrEP for safer conception. Thematic analyses focused on
identifying the following emergent themes. Couple relationships
were situated within broader social and cultural contexts of
immigration, family, and community that shaped their experiences
with HIV and serodiscordant relationship status. Despite strong
partner support within relationships, HIV stigma and disapproval of
serodiscordant relationships contributed to couples' feelings of social
isolation and subsequent aspirations to have "normal" families. By
enabling "natural" conception through condomless sex, PrEP for safer
conception provided a sense of enhanced relationship intimacy.
Couples called for increasing public awareness of PrEP through
positive messaging as a way to combat HIV stigma. Findings suggest
that relationship dynamics and broader social contexts appear to
shape HIV serodiscordant couples' fertility desires and motivations to
use PrEP. However, increased public awareness of PrEP for safer
 07

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conception may be needed to combat HIV stigma at the community

level (3).
Thomson & al. (4) mentioned that understanding fertility desires
and preferences for HIV prevention among individuals living with HIV,
including the potential use of PrEP by HIV uninfected partners, can
inform the delivery of safer conception counseling to reduce the risk
of HIV transmission during pregnancy attempts. Men and women,
predominantly heterosexual, engaged in HIV care in Seattle, WA, self-
administered a questionnaire and ART status and HIV viral levels
were abstracted from medical records. Participants' sexual behavior,
fertility desires, and preferences for safer conception strategies and
used log-binomial regression were summarized to identify
demographic, sexual, and behavioral factors associated with
perceived acceptability of PrEP for HIV uninfected partners during
pregnancy attempts. Of the 150 participants, 52% were female and
the mean age was 48 years (range 23-74). 94.7% of participants were
using ART and 79.3% had HIV viral load < 40 copies/mL. Of men,
22.2% and of women 34.6% reported that a healthcare provider had
initiated discussion about fertility desires. Of participants, 28.7%
were reproductive-age and desired children. Among sexually active
reproductive-age participants with fertility desires, 56.3% reported
inconsistent condom use and 62.5% did not report using effective
birth control. 74.4% of reproductive age participants with fertility
desires perceived that PrEP would be acceptable to an HIV uninfected
partner and there were no significant predictors of PrEP
acceptability. Nearly one third of reproductive-aged individuals living
with HIV expressed fertility desires, highlighting a need for safer
conception counseling in this setting. PrEP and ART were favored
safer conception strategies (4).
Hancuch & al. (5) noticed that for HIV-1 serodiscordant couples,
HIV-1 exposure and risk of transmission is heightened during
pregnancy attempts, but safer conception strategies can reduce risk.
As safer conception programs are scaled up, understanding couples'
preferences and experiences can be useful for programmatic
recommendations. Totally, 1,013 high-risk, heterosexual HIV-1
serodiscordant couples from Kenya and Uganda were followed for
two years in an open-label delivery study of integrated PrEP and ART,
the Partners Demonstration Project. Descriptive statistics were used
to describe the cohort and multivariate logistic regression to
 08

Ben-Nun Ovulation

characterize women who reported use of a safer conception strategy

by their first annual visit. 66% (569/859) of women in the study were
HIV-infected and 73% (627/859) desired children in the future. At
the first annual visit, 59% of women recognized PrEP, 58% ART, 50%
timed condomless sex, 23% self-insemination, and fewer than 10%
recognized male circumcision, STI treatment, artificial insemination,
and sperm washing as safer conception strategies. Among those
recognizing these strategies and desiring pregnancy, 37% reported
using PrEP, 14% ART, and 30% timed condomless sex. Women who
reported discussing their fertility desires with their male partners
were more likely to report having used at least one strategy for safer
conception (adjusted odds ratio = 1.91, 95% confidence interval 1.26-
2.89). Recognition of use of safer conception strategies among
women who expressed fertility desires was low, with ARV-based
strategies and self-insemination the more commonly recognized and
used strategies. Programs supporting HIV-1 serodiscordant couples
can provide opportunities for couples to talk about their fertility
desires and foster communication around safer conception practices
(5).
Saleem & al. (6) stated that the recognition and fulfillment of the
sexual and reproductive health and rights (SRHR) of all individuals
and couples affected by HIV, including HIV-serodiscordant couples,
requires intervention strategies aimed at achieving safe and healthy
pregnancies and preventing undesired pregnancies. Reducing risk of
horizontal and vertical transmission and addressing HIV-related
infertility are key components of such interventions. In this
commentary, challenges and opportunities were presented for
achieving safe pregnancies for serodiscordant couples through a
social ecological lens. At the individual level, knowledge (e.g. of HIV
status, assisted reproductive technologies) and skills (e.g. adhering to
ART or PrEP) are important. At the couple level, communication
between partners around HIV status disclosure, fertility desires and
safer pregnancy is required. Within the structural domain, social
norms, stigma and discrimination from families, community and
social networks influence individual and couple experiences. The
availability and quality of safer conception and fertility support
services within the healthcare system remains essential, including
training for healthcare providers and strengthening integration of
SRHR and HIV services. Policies, legislation and funding can improve
 11

Ben-Nun Ovulation

access to SRHR services. A social ecological framework allows us to

examine interactions between levels and how interventions at
multiple levels can better support HIV-serodiscordant couples to
achieve safe pregnancies. Strategies to achieve safer pregnancies
should consider interrelated challenges at different levels of a social
ecological framework. Interventions across multiple levels,
implemented concurrently, have the potential to maximize impact
and ensure the full SRHR of HIV-serodiscordant couples (6).
Heffron & al. (7) mentioned that African HIV serodiscordant
couples often desire pregnancy, despite sexual HIV transmission risk
during pregnancy attempts. PrEP and ART reduce HIV risk and can be
leveraged for safer conception but how well these strategies are used
for safer conception is not known. An open-label demonstration
project of the integrated delivery of PrEP and ART was conducted
among 1013 HIV serodiscordant couples from Kenya and Uganda
followed quarterly for 2 years. Fertility intentions, pregnancy
incidence, the use of PrEP and ART were evaluated during peri-
conception, and peri-conception HIV incidence. At enrollment, 80%
of couples indicated a desire for more children. Pregnancy incidence
rates were 18.5 and 18.7 per 100 person years among HIV-uninfected
and HIV-infected women, and higher among women who recently
reported fertility intention (adjusted odds ratio 3.43, 95% CI 2.38-
4.93) in multivariable GEE models. During the 6 months preceding
pregnancy, 82.9% of couples used PrEP or ART and there were no HIV
seroconversions. In this cohort with high pregnancy rates, integrated
PrEP and ART was readily used by HIV serodiscordant couples,
including during peri-conception periods. Widespread scale-up of
safer conception counseling and services is warranted to respond to
strong desires for pregnancy among HIV-affected men and women
(7).

References
1. Liao C, Wahab M, Anderson J, Coleman JS . Reclaiming fertility
awareness methods to inform timed intercourse for HIV serodiscordant
couples attempting to conceive. J Int AIDS Soc. 2015 Jan 9;18:19447.
2. Matthews LT, Beyeza-Kashesya J, Cooke I, et al. Consensus
statement: supporting safer conception and pregnancy for men and
women living with and affected by HIV. AIDS Behav. 2018;22(6):1713-24.
 10

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3. Bazzi AR, Leech AA, Biancarelli DL, et al. Experiences using pre-
exposure prophylaxis for safer conception among HIV serodiscordant
heterosexual couples in the United States. AIDS Patient Care STDS.
2017;31(8):348-55.
4. Thomson KA, Dhanireddy S, Andrasik M, et al. Fertility desires and
preferences for safer conception strategies among people receiving care
for HIV at a publicly-funded clinic in Seattle, WA. AIDS Care. 2018;
30(1):121-9.
5. Hancuch K, Baeten J, Ngure K, et al. Safer conception among HIV-1
serodiscordant couples in East Africa: understanding knowledge, attitudes,
and experiences. AIDS Care. 2018;30(8):973-981.
6. Saleem HT, Narasimhan M, Denison JA, Kennedy CE. Achieving
pregnancy safely for HIV-serodiscordant couples: a social ecological
approach. J Int AIDS Soc. 2017;20(Suppl 1):21331.
7. Heffron R, Thomson K, Celum C, et al. Fertility intentions,
pregnancy, and use of PrEP and ART for safer conception among East
African HIV serodiscordant couples. AIDS Behav. 2018;22(6):1758-65.

DESIRED PREGNANCY
TIMED INTERCOURSE FOR CONCEPTION
Manders & al. (1) reported that fertility problems are very
common, as subfertility affects about 10% to 15% of couples trying to
conceive. There are many factors that may impact a couple's ability
to conceive and one of these may be incorrect timing of intercourse.
Conception is only possible from approximately five days before up
to several hours after ovulation. Therefore, to be effective,
intercourse must take place during this fertile period. 'Timed
intercourse' is the practice of prospectively identifying ovulation and,
thus, the fertile period to increase the likelihood of conception.
Whilst timed intercourse may increase conception rates and reduce
unnecessary intervention and costs, there may be associated adverse
aspects including time consumption and stress. Ovulation prediction
methods used for timing intercourse include urinary hormone
measurement (luteinizing hormone (LH), estrogen), tracking basal
body temperatures, cervical mucus investigation, calendar charting
and ultrasonography. This review considered the evidence from
randomized controlled trials for the use of timed intercourse on
 11

Ben-Nun Ovulation

positive pregnancy outcomes. The objective of this study was to

assess the benefits and risks of ovulation prediction methods for
timing intercourse on conception in couples trying to conceive. The
following sources were searched to identify relevant randomized
controlled trials, the Menstrual Disorders and Subfertility Group
Specialised Register, the Cochrane Central Register of Controlled
Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, PubMed, LILACS,
Web of Knowledge, the World Health Organization (WHO) Clinical
Trials Register Platform and ClinicalTrials.gov. References of relevant
articles were manually searched. The search was not restricted by
language or publication status. The last search was on 5 August
2014. Randomized controlled trials (RCTs) compared timed
intercourse versus intercourse without ovulation prediction or
comparing different methods of ovulation prediction for timing
intercourse against each other in couples trying to conceive. Two
review authors independently assessed trial eligibility and risk of bias
and extracted the data. The primary review outcomes were
cumulative live birth and adverse events (such as quality of life,
depression and stress). Secondary outcomes were clinical pregnancy,
pregnancy (clinical or self-reported pregnancy, not yet confirmed by
ultrasound) and time to conception. Data were combined to
calculate pooled risk ratios [RRs] and 95% confidence intervals [CIs].
Statistical heterogeneity was assessed using the I(2) statistic. The
overall quality of the evidence was assessed for the main
comparisons using GRADE methods. Five RCTs (2,840 women or
couples) were included comparing timed intercourse versus
intercourse without ovulation prediction. Unfortunately, one large
study (n=1,453) reporting live birth and pregnancy had not published
outcome data by randomized group and therefore could not be
analyzed. Consequently, four RCTs (n=1387) were included in the
meta-analysis. The evidence was of low to very low quality. Main
limitations for downgrading the evidence included imprecision, lack
of reporting clinically relevant outcomes and the high risk of
publication bias. One study reported live birth, but the sample size
was too small to draw any relevant conclusions on the effect of timed
intercourse (RR 0.75, 95% CI 0.16-3.41, 1 RCT, n=17, very low quality).
One study reported stress as an adverse event. There was no
evidence of a difference in levels of stress (mean difference 1.98, 95
CI% -0.87 - 4.83, 1 RCT, n=77, low level evidence). No other studies
 12

Ben-Nun Ovulation

reported adverse events. Two studies reported clinical pregnancy.

There was no evidence of a difference in clinical pregnancy rates (RR
1.10, 95% CI 0.57-2.12, 2 RCTs, n=177, I(2) = 0%, low level evidence).
This suggested that if the chance of a clinical pregnancy following
intercourse without ovulation prediction is assumed to be 16%, the
chance of success following timed intercourse would be between 9%
and 33%. Four studies reported pregnancy rate (clinical or self-
reported pregnancy). Timed intercourse was associated with higher
pregnancy rates compared to intercourse without ovulation
prediction in couples trying to conceive (RR 1.35, 95% CI 1.06-1.71, 4
RCTs, n=1387, I(2) = 0%, very low level evidence). This suggests that
if the chance of a pregnancy following intercourse without ovulation
prediction is assumed to be 13%, the chance following timed
intercourse would be between 14% and 23%. Subgroup analysis by
duration of subfertility showed no difference in effect between
couples trying to conceive for < 12 months versus couples trying for ≥
12 months. One trial reported time to conception data and showed
no evidence of a difference in time to conception. The data show
that there are insufficient data available to draw conclusions on the
effectiveness of timed intercourse for the outcomes of live birth,
adverse events and clinical pregnancy. Timed intercourse may
improve pregnancy rates (clinical or self-reported pregnancy, not yet
confirmed by ultrasound) compared to intercourse without ovulation
prediction. The quality of this evidence is low to very low and
therefore findings should be regarded with caution. There is a high
risk of publication bias, as one large study remains unpublished 8
years after recruitment finished. Further research is required,
reporting clinically relevant outcomes (live birth, clinical pregnancy
rates and adverse effects), to determine if timed intercourse is safe
and effective in couples trying to conceive (1).
Wilcox & al. (2) stated that the timing of sexual intercourse in
relation to ovulation strongly influences the chance of conception,
although the actual number of fertile days in a woman's menstrual
cycle is uncertain. The timing of intercourse may also be associated
with the sex of the baby. Totally, 221 healthy women who were
planning to become pregnant were recruited. At the same time the
women stopped using birth-control methods, they began collecting
daily urine specimens and keeping daily records of whether they had
sexual intercourse. Estrogen and progesterone metabolites were
 13

Ben-Nun Ovulation

measured in urine to estimate the day of ovulation. In a total of 625

menstrual cycles for which the dates of ovulation could be estimated,
192 pregnancies were initiated, as indicated by increases in the
urinary concentration of human chorionic gonadotropin around the
expected time of implantation. Two thirds (n=129) ended in live
births. Conception occurred only when intercourse took place during
a six-day period that ended on the estimated day of ovulation. The
probability of conception ranged from 0.10 when intercourse
occurred five days before ovulation to 0.33 when it occurred on the
day of ovulation itself. There was no evident relation between the
age of sperm and the viability of the conceptus, although only 6
percent of the pregnancies could be firmly attributed to sperm that
were three or more days old. Cycles producing male and female
babies had similar patterns of intercourse in relation to ovulation.
The data indicate that among healthy women trying to conceive,
nearly all pregnancies can be attributed to intercourse during a six-
day period ending on the day of ovulation. For practical purposes,
the timing of sexual intercourse in relation to ovulation has no
influence on the sex of the baby (2).
Ferreira-Poblete (3) reported that several mathematical models
have been developed over the past thirty years to investigate how
the probability of conception changes on the different days of the
cycle with respect to ovulation. A problem general to all models is to
estimate the day of ovulation. Since the most fertile days are those
close to ovulation, less precise estimates of this event will lead to less
accurate estimates of the probability of conception on a given day of
the cycle. Given that a reference point for ovulation is available, the
first model considered conception as dependent only on the timing
of intercourse. Conception was found to be most likely to occur on
only six days in each cycle. However, the model is biologically
unrealistic because it assumes that all ova can be fertilized and lead
to a viable pregnancy. There are other factors that affect the
probability of conception, including whether the ovum is viable or
not. Recent models have extended the idea of cycle viability to allow
for differences between cycles within couples and for the
introduction of couple specific covariates. In a second group of
models the probability of conception depends mainly on the time of
intercourse and the survival times of sperm and ovum. A graphical
summary of the results available in the literature is presented.
 14

Ben-Nun Ovulation

Conception probabilities have been found to be significantly different

from zero from five days before ovulation to the day of ovulation
itself. On average, less than half of the cycles are viable in women,
although recent studies suggest that different cycle viability between
women should be taken into account. Survival times for sperm and
the ovum have been estimated to be 1.4 days and 0.7 days,
respectively. Sperm would have a 5% probability of surviving more
than 4.4 days and a 1% probability of surviving more than 6.8 days
(3).

Ovulation and Fertilization. Sciencephoto.com.

Scarpa & al. (4) conducted multicenter prospective study at four

centers providing services on fertility awareness to find optimal
clinical rules that maximize the probability of conception while
limiting the number of intercourse days required. Women were
followed prospectively while they kept daily records of menstrual
bleeding, intercourse, and mucus symptom characteristics. In some
cycles, women sought to conceive, whereas in other cycles, they
sought to avoid pregnancy. One hundred ninety-one healthy women
used the Billings Ovulation Method. Women were invited to enroll by
their instructors if they satisfied the entry criteria. Cycles in which
mucus was not recorded on a day with intercourse were excluded.
Main outcome measures included clinically identified pregnancies.
There were 161 clinically identified pregnancies in 2,536 menstrual
cycles from 191 women. The approach relies on a statistical model
that relates daily predictors, such as type of mucus symptom, to the
day-specific probabilities of conception. By using Bayesian methods
to search over a large set of possible clinical rules, focusing on rules
based on calendar and mucus, simple rules based on days within the
midcycle calendar interval also have the most fertile-type mucus
 15

Ben-Nun Ovulation

symptom present have high utility. The data show that couples can
shorten their time to pregnancy efficiently by timing intercourse on
days that the most fertile-type mucus symptom is observed at the
vulva (4).

References
1. Manders M, McLindon L, Schulze B, et al. Timed intercourse for
couples trying to conceive. Cochrane Database Syst Rev. 2015 Mar
17;(3):CD011345.
2. Wilcox AJ, Weinberg CR, Baird DD. Timing of sexual intercourse in
relation to ovulation. Effects on the probability of conception, survival of
the pregnancy, and sex of the baby. N Engl J Med. 1995;333(23):1517-21.
3. Ferreira-Poblete A. The probability of conception on different days
of the cycle with respect to ovulation: an overview. Adv Contracept.
1997;13(2-3):83-95.
4. Scarpa B, Dunson DB, Giacchi E. Bayesian selection of optimal rules
for timing intercourse to conceive by using calendar and mucus. Fertil
Steril. 2007;88(4):915-24.

FREQUENCY OF INTERCOURSE
Wilcox & al. (1) mentioned that intercourse in mammals is often
coordinated with ovulation, for example through fluctuations in
libido or by the acceleration of ovulation with intercourse. Such
coordination has not been established in humans. This possibility
was explored by examining patterns of sexual intercourse in relation
to ovulation. Sixty-eight sexually active North Carolina women with
either an intrauterine device or tubal ligation provided data for up to
three menstrual cycles. These women collected daily urine
specimens and kept daily diaries of intercourse and menstrual
bleeding. Major estrogen and progesterone metabolites excreted in
urine were used to identify the day of ovulation. The fertile days of
the cycle were defined as the 6 consecutive days ending with
ovulation. Women contributed a total of 171 ovulatory cycles.
Menstrual bleeding days were excluded from analysis. The frequency
of intercourse rose during the follicular phase, peaking at ovulation
and declining abruptly thereafter. The 6 consecutive days with most
frequent intercourse corresponded with the 6 fertile days of the
menstrual cycle. Intercourse was 24% more frequent during the 6
fertile days than during the remaining non-bleeding days (p<0.001).
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The data indicate that there apparently are biological factors that
promote intercourse during a woman's 6 fertile days (1).
Stanford & Dunson (2) mentioned that time to pregnancy,
typically defined as the number of menstrual cycles required to
achieve a clinical pregnancy, is widely used as a measure of couple
fecundity in epidemiologic studies. Time to pregnancy studies
seldom utilize detailed data on the timing and frequency of sexual
intercourse and the timing of ovulation. However, the simulated
models in this paper illustrate that intercourse behavior can have a
large impact on time to pregnancy and, likewise, on fecundability
ratios, especially under conditions of low intercourse frequency or
low fecundity. Because intercourse patterns in the menstrual cycles
may vary substantially among groups, it is important to consider the
effects of sexual behavior. Where relevant and feasible, an
assessment should be made of the timing and frequency of
intercourse relative to ovulation. Day-specific probabilities of
pregnancy can be used to account for the effects of intercourse
patterns. Depending on the research hypothesis, intercourse
patterns may be considered as a potential confounder, mediator, or
outcome (2).

References
1. Wilcox AJ, Baird DD, Dunson DB, et al. On the frequency of
intercourse around ovulation: evidence for biological influences. Hum
Reprod. 2004;19(7):1539-43.
2. Stanford JB, Dunson DB. Effects of sexual intercourse patterns in
time to pregnancy studies. Am J Epidemiol. 2007;165(9):1088-95.

FERTILITY WINDOW
Royston (1) stated that the identification of the human fertile
phase as the time during which a woman or a couple may conceive is
elusive. The fertile time depends on many factors in each individual
menstrual cycle and may be said to be more of a statistical than a
physiological entity. This paper reviews the application of statistical
methods to three areas related to conception and the fertile phase.
The first is the prediction and detection of ovulation from serial
measurements, such as hormones, basal body temperature and
 17

Ben-Nun Ovulation

cervical mucus, throughout the menstrual cycle. Typically, such

variables increase from some baseline level to a peak around
ovulation (the most fertile time), then subside to low levels in the
postovulatory phase. The statistical challenge is to detect the rise
(signaling the onset of potential fertility) and subsequent fall.
Analytic methods considered include thresholds, Bayesian change-
point models and particularly the cumulative sum (cusum) technique
which is both simple to apply and understand, and effective. The
second area comprises appropriate methods of analyzing and
interpreting data from clinical studies of the fertile phase, especially
in so-called natural family planning (NFP) where it is usual for women
to observe several indices of potential fertility. Such studies usually
try to establish the temporal relationships between markers of the
fertile phase and examine the success of different combinations of
markers in delineating the fertile time in comparison with a standard
'defined' phase, for example, the interval from three days before to
two days after the peak of luteinizing hormone. The third area is the
assessment of the probability of conception on certain days of the
cycle, which is vital to the understanding of the fertile phase and its
application to NFP. Direct estimation of such probabilities is
impractical; instead, resort must be made to estimation by maximum
likelihood of the parameters of specially constructed models.
Suitable models are described. The need for a new prospective study
of the probability of conception in relation to the markers of the
fertile phase used in the symptothermal method of NFP is discussed
(1).
Lynch & al. (2) noticed that conception, as defined by the
fertilization of an ovum by a sperm, marks the beginning of human
development. Currently, a biomarker of conception is not available;
as conception occurs shortly after ovulation, the latter can be used as
a proxy for the time of conception. In the absence of serial
ultrasound examinations, ovulation cannot be readily visualized
leaving researchers to rely on proxy measures of ovulation that are
subject to error. The most commonly used proxy measures include:
charting basal body temperature, monitoring cervical mucus, and
measuring urinary metabolites of estradiol and luteinizing hormone.
Establishing the timing of the ovulation and the fertile window has
practical utility in that it will assist couples in appropriately timing
intercourse to achieve or avoid pregnancy. Identifying the likely day
 18

Ben-Nun Ovulation

of conception is clinically relevant because it has the potential to

facilitate more accurate pregnancy dating, thereby reducing the
iatrogenic risks associated with uncertain gestation. Using data from
prospective studies of couples attempting to conceive, several
researchers have developed models for estimating the day-specific
probabilities of conception. Elucidating these will allow researchers
to more accurately estimate the day of conception, thus spawning
research initiatives that will expand the current limited knowledge
about the effect of exposures at critical periconceptional windows.
While basal body temperature charting and cervical mucus
monitoring have been used with success in field-based studies for
many years, recent advances in science and technology have made it
possible for women to get instant feedback regarding their daily
fertility status by monitoring urinary metabolites of reproductive
hormones in the privacy of their own homes. Not only are
innovations such as luteinizing hormone test kits and digital fertility
monitors likely to increase study compliance and participation rates,
they provide valuable prospective data that can be used in
epidemiological research. Although great strides were made in
estimating the timing and length of the fertile window, more work is
needed to elucidate the day-specific probabilities of conception using
proxy measures of ovulation that are inherently subject to error.
Modeling approaches that incorporate the use of multiple markers of
ovulation offer great promise to fill these important data gaps (2).
Stirnemann & al. (3) asked: when, within the female cycle, does
conception occur in spontaneously fertile cycles? This study provides
reference values of day-specific probabilities of date of conception in
ongoing pregnancies. The maximum probability of being within a 5-
day fertile window was reached on Day 12 following the last
menstrual period (LMP). The true date of conception is not
observable and may only be estimated. Accuracy of these estimates
impacts on obstetric management of ongoing pregnancies. Timing of
ovulation and fertility has been extensively studied in prospective
studies of non-pregnant fertile women using error-prone proxies,
such as hormonal changes, body-basal temperature and ultrasound,
yielding day-specific probabilities of conception and fertile windows.
In pregnant women, date of conception may be retrospectively
estimated from early pregnancy fetal measurement by ultrasound.
Retrospective analysis of consecutive pregnancies in women referred
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Ben-Nun Ovulation

for routine first-trimester screening, over a 3-year period (2009-

2011) in a single ultrasound center (n=6,323). Within the overall
population, 5,830 cases with a certain date of last menses were
selected for analysis. The date of conception was estimated using a
crown-rump length biometry and an equation derived from IVF/ICSI
pregnancies. Day-specific probabilities of conception were estimated
across several covariates, including age, cycle characteristics and
ethnicity, using deconvolution methods to account for measurement
error. Overall, the day-specific probability of conception sharply rises
at 7 days after the LMP, reaching its maximum at 15 days and
returning to zero by 25 days. Older women tend to conceive earlier
within their cycle, as did women with regular cycles and white and
black women compared with Asian ethnicity. The probability of
being within the fertile window was 2% probability at Day 4, a
maximum probability of 58% at Day 12 and a 5% probability by Day
21 of the cycle. Although conception is believed to occur within
hours following ovulation, a discrepancy is theoretically possible.
However, when comparing the results to those of prospective
studies, no such difference was found. The equation used for
estimating the date of pregnancy was estimated in IVF/ICSI
pregnancies, which could lead to potential bias in spontaneous
pregnancies. However, in this population, the observed bias was
negligible. Non-fertile cycles and early pregnancy losses are
necessarily overlooked because of the nature of the data. Because of
the wider access to retrospective data and the potential bias in
prospective studies of ovulation monitoring, this study should
broaden the perspectives of future epidemiologic research in fertility
and pregnancy monitoring (3).
Frydman & al. (4) noticed predicting ovulation is the basis on
which the fertile period is determined. When observations were
carried out on 60 spontaneous cycles it was possible to detect with
precision the discharge of LH which would produce ovulation by
taking series of plasma levels of LH. The start is defined as the time
when the level of LH becomes 180% greater than the mean level
observed in the previous 24 hours. Ovulation occurs between 37 and
39 hours after this threshold has been crossed. The discharge of LH is
the most constant criterion and the most precise one, and it does
make it possible to work out the chronology of the events that
precede ovulation. Ultrasound and estimation of levels of estradiol in
 20

Ben-Nun Ovulation

the plasma or in the urine do allow one to appreciate how the follicle
is maturing (4).
Albertson & Zinaman (5) revealed that simple and reliable
methods have been sought for both predicting and confirming
ovulation. Application of these methods could include management
of infertile couples to aid in conception and for increasing the
reliability of NFP as a method of birth control. With the advent of
specific hormone assays, serial measurements of estrogens,
progesterone (and metabolites), and luteinizing hormone have been
the gold standard of monitoring ovarian function in women.
However, newer and simpler methodologies have been described
and are currently either in use or being tested. These include the
measurement of basal body temperature (BBT), the evaluation of the
volume, consistency and electro-conductivity of cervicovaginal fluid,
salivary steroid content and cellular enzymatic activity, the use of
enzyme-linked immunosorbent assays applied to solid-phase
formats, and the investigation of new hormonal molecules as
markers of reproductive state and function (5).

References
1. Royston P. Identifying the fertile phase of the human menstrual
cycle. Stat Med. 1991;10(2):221-40.
2. Lynch CD, Jackson LW, Buck Louis GM. Estimation of the day-
specific probabilities of conception: current state of the knowledge and
the relevance for epidemiological research. Paediatr Perinat Epidemiol.
2006;20 Suppl 1:3-12.
3. Stirnemann JJ, Samson A, Bernard JP, Thalabard JC. Day-specific
probabilities of conception in fertile cycles resulting in spontaneous
pregnancies. Hum Reprod. 2013;28(4):1110-6.
4. Frydman R, Testart J, Fernandez H, et al. Prediction of ovulation. J
Gynecol Obstet Biol Reprod (Paris). 1982;11(7):793-9.
5. Albertson BD, Zinaman MJ. The prediction of ovulation and
monitoring of the fertile period. Adv Contracept. 1987;3(4):263-90.
 21

Ben-Nun Ovulation

OVULATION DETECTION
CUES
According to Lobmaier & al. (1), recent research suggests that
men find portraits of ovulatory women more attractive than
photographs of the same women taken during the luteal phase. Only
few studies have investigated whether the same is true for women.
The ovulatory phase matters to men because women around
ovulation are most likely to conceive, and might matter to women
because fertile women might pose a reproductive threat. In an
online study 160 women were shown face pairs, one of which was
assimilated to the shape of a late follicular prototype and the other
to a luteal prototype, and were asked to indicate which face they
found more attractive. A further 60 women were tested in the
laboratory using a similar procedure. In addition to choosing the
more attractive face, these participants were asked which woman
would be more likely to steal their own date. Because gonadal
hormones influence competitive behavior, the Authors also
examined whether estradiol, testosterone and progesterone levels
predict women's choices. The women found neither the late
follicular nor the luteal version more attractive. However, naturally
cycling women with higher estradiol levels were more likely to
choose the ovulatory woman as the one who would entice their date
than women with lower estradiol levels. These results imply a role of
estradiol when evaluating other women who are competing for
reproduction (1).
Burriss & al. (2) mentioned that human ovulation is not
advertised, as it is in several primate species, by conspicuous sexual
swellings. However, there is increasing evidence that the
attractiveness of women's body odor, voice, and facial appearance
peak during the fertile phase of their ovulatory cycle. Cycle effects
on facial attractiveness may be underpinned by changes in facial skin
color, but it is not clear if skin color varies cyclically in humans or if
any changes are detectable. To test these questions women were
photographed daily for at least one cycle. Changes in facial skin
redness and luminance were then quantified by mapping the digital
images to human long, medium, and shortwave visual receptors.
Cyclic variation in skin redness, but not luminance were found
 22

Ben-Nun Ovulation

Redness decreases rapidly after menstrual onset, increases in the

days before ovulation, and remains high through the luteal phase.
However, this variation is unlikely to be detectable by the human
visual system. Changes in skin color are not responsible for the
effects of the ovulatory cycle on women's attractiveness (2).
Roberts & al. (3) mentioned that the lack of obvious visible
manifestations of ovulation in human females, compared with the
prominent sexual swellings of many primates, has led to the idea that
human ovulation is concealed. While human ovulation is clearly not
advertised to the same extent as in some other species, both men
and women judge photographs of women's faces that were taken in
the fertile window of the menstrual cycle as more attractive than
photographs taken during the luteal phase. This indicates the
existence of visible cues to ovulation in the human face, and is
consistent with similar cyclical changes observed for preferences of
female body odor. This heightened allure could be an adaptive
mechanism for raising a female's relative value in the mating market
at the time in the cycle when the probability of conception is at its
highest (3).
Bleske-Rechek & al. (4) investigated women's facial attractiveness
and body shape as a function of menstrual cycle phase, with the
expectation from previous research that both would be enhanced
during the high fertile phase. To control for the effects of women's
daily behaviors on their appearance and waistline, the Authors
visited 37 normally cycling women twice in their dorm, where the
women were photographed and measured at low and high fertile
days of their cycle immediately upon their waking. Seventy-four
judges from a separate institution chose, for each woman, the
picture they thought was more attractive. A subset of 20 women
who, by forward counting, had a High Fertility visit between Days 10-
13 and a Low Fertility visit between Days 20-23 were analyzed; and w
a subsample of 17 women who, by reverse counting, had a High
Fertility visit on the days leading to ovulation and a Low Fertility visit
one week after ovulation was also analyzed. In neither set of
analyses were women's waist- to-hip ratios lower nearer ovulation,
and in neither set were women's high fertile pictures chosen at an
above-chance rate by either male or female judges. Evidence that
facial attractiveness and waist-to-hip ratio are reliable physical cues
of ovulatory status was not found (4).
 23

Ben-Nun Ovulation

According to Larson & al. (5), previous research has documented

shifts in women's attractions to their romantic partner and to men
other than their partner across the ovulation cycle, contingent on the
degree to which her partner displays hypothesized indicators of high-
fitness genes. The current study set out to replicate and extend this
finding. Forty-one couples in which the woman was naturally cycling
participated. Female partners reported their feelings of in-pair
attraction and extra-pair attraction on two occasions, once on a low-
fertility day of the cycle and once on a high-fertility day of the cycle
just prior to ovulation. Ovulation was confirmed using luteinizing
hormone tests. Two measures of male partner sexual attractiveness
were collected. First, the women in the study rated their partner's
sexual attractiveness. Second, the partners were photographed and
had the photos independently rated for attractiveness. Shifts in
women's in-pair attractions across the cycle were significantly
moderated by women's ratings of partner sexual attractiveness, such
that the less sexually attractive women rated their partner, the less
in-pair attraction they reported at high fertility compared with low
fertility (partial r = .37, p(dir) = .01). Shifts in women's extra-pair
attractions across the cycle were significantly moderated by third-
party ratings of partner attractiveness, such that the less attractive
the partner was, the more extra-pair attraction women reported at
high relative to low fertility (partial r = -.33, p(dir) = .03). In line with
previous findings, support for the hypothesis was found that the
degree to which a woman's romantic partner displays indicators of
high-fitness genes affects women's attractions to their own partner
and other men at high fertility (5).
Pillsworth & al. (6) noticed that women's reproductive biology
imposes heavy obligatory costs of parental investment, creating
strong selective forces hypothesized to shape female mating
psychology around critical decisions such as the choice of partner,
the timing of sexual intercourse, and the timing of reproduction. It is
proposed that female sexual desire has evolved as one adaptation
among several designed to regulate these decisions. It is
hypothesized 1] an increase in desire as conception probability
increases, but only among women who are in committed long-term
relationships; and 2] a shift in the desire for a primary partner as
compared with extra-pair partners as ovulation approaches,
dependent upon a woman's evaluation of her primary partner's
 24

Ben-Nun Ovulation

relative quality. Several predictions derived from these hypotheses

were tested in a study of 173 women who were not taking oral
contraceptives. Results confirmed Hypothesis 1: An ovulatory peak in
sexual desire was found only for mated women; for unmated
women, conception probability and sexual desire were uncorrelated.
Hypothesis 2 was partially supported. Among mated women, those
with higher conception probability exhibited higher levels of in-pair
sexual desire relative to those at lower conception probability.
Conception probability and relationship length interacted
significantly to predict extra-pair desires, such that women in longer
relationships were more likely to experience desire for extra-pair
partners during periods of high conception probability. The pursuit
of an in-pair conceptive strategy (as opposed to an extra-pair
conceptive strategy) was also associated with the occurrence of
sexual activity in the relationship (6).

References
1. Lobmaier JS, Bobst C, Probst F. Can women detect cues to ovulation
in other women's faces? Biol Lett. 2016;12(1):20150638.
2. Burriss RP, Troscianko J, Lovell PG, et al. Changes in women's facial
skin color over the ovulatory cycle are not detectable by the human visual
system. PLoS One. 2015;10(7):e0130093.
3. Roberts SC, Havlicek J, Flegr J, et al. Female facial attractiveness
increases during the fertile phase of the menstrual cycle. Proc Biol Sci.
2004;271 Suppl 5:S270-2.
4. Bleske-Rechek A, Harris HD, Denkinger K, et al. Physical cues of
ovulatory status: a failure to replicate enhanced facial attractiveness and
reduced waist-to-hip ratio at high fertility. Evol Psychol. 2011;9(3):336-53.
5. Larson CM, Pillsworth EG, Haselton MG. Ovulatory shifts in
women's attractions to primary partners and other men: further evidence
of the importance of primary partner sexual attractiveness. PLoS One.
2012;7(9):e44456.
6. Pillsworth EG, Haselton MG, Buss DM. Ovulatory shifts in female
sexual desire. J Sex Res. 2004;41(1):55-65.

PREDICTION
Kerin (1) stated that the importance of predicting human
ovulation for either optimizing or avoiding conception has been
considered from an endocrine, morphological and clinical view point.
 25

Ben-Nun Ovulation

Of the biochemical markers in peripheral blood, knowledge of the

luteinizing hormone (LH) peak is the most clearly defined, with a two
to four fold increase above baseline levels for a relatively short 24-30
hour preovulatory period. Ovulation is considered to occur 28-36
hours after the beginning of the LH rise or 8-20 hours after the LH
peak. Daily assessment of the rise in preovular estrogen reflects
Graafian follicle development but the rise is less distinct and spread
over 3-4 days with marked day to day fluctuations. LH induces a
marked reduction in estrogen production some 12 hours prior to
ovulation and at the same time induces a two to three fold increase
in progesterone production above baseline levels. While these
changes in themselves are not great enough for day to day
discrimination, knowledge of their reciprocal relationship may be.
The preovular rise in FSH is relatively small compared to LH and the
radioimmunoassay technique has not generally been refined to be as
rapid and reliable. Monitoring the day to day growth of the
preovular follicle ultrasonically is both linear and potentially
predictable but there is a wide range of its final diameter (17-26 mm)
prior to ovulation making prediction inaccurate. With further
refinements in ultrasonic resolution, detection of intrafollicular
changes of the cumulus oophorus and granulosal cell layer
configuration and thickness may give a closer prediction of the time
of ovulation. At a clinical level knowledge of menstrual cycle length
in association with body messages which herald ovulation are useful
and may forewarn that ovulation in terms of days is approaching.
Such markers as preovulation pain, the detection of periovular
cervical mucus and the change in physical character and position of
the cervix are reliable signs of preovulation for many well motivated
and informed women for either promoting or avoiding conception.
Knowledge of the basal body temperature is not a prospective guide
to ovulation, but once the thermal shift is established in association
with loss of periovular mucus symptoms, the fertile period can be
considered to have passed. Because we do not have a precise and
simple marker of human ovulation, it is necessary that the most
suitable marker of pre- or postovulation is chosen for the particular
need in a given individual (1).
Gnoth & al. (2) mentioned that the symptoms of self-observation
of the menstrual cycle (basal body temperature (BBT), mucus
symptom, autopalpation of the cervix) are often regarded as not
 26

Ben-Nun Ovulation

reliable for ovulation detection. In a prospective study 87 Natural

Family Planning (NFP) cycles are monitored additionally with
ultrasound and LH tests to calculate the correlation of the ovulation-
time with the symptoms of self-observation. The results show that
the symptoms of self-observation allow a reliable detection of the
time of ovulation. Only a short introduction into the method of self-
observation is a necessary precondition. The reliable detection of
ovulation gives the opportunity of cycle analysis of large groups
especially in long time investigations. In this way a large set of
valuable and reliable data on normal and disturbed menstrual cycles
will be available (2).
Sohda & al. (3) noticed that there are many mobile phone apps
aimed at helping women map their ovulation and menstrual cycles
and facilitating successful conception (or avoiding pregnancy). These
apps usually ask users to input various biological features and have
accumulated the menstrual cycle data of a vast number of women.
The purpose of this study was to clarify how the data obtained from a
self-tracking health app for female mobile phone users can be used
to improve the accuracy of prediction of the date of next ovulation.
Using the data of 7,043 women who had reliable menstrual and
ovulation records out of 8,000,000 users of a mobile phone app of a
health care service, the relationship between the menstrual cycle
length, follicular phase length, and luteal phase length was analyzed.
Then a linear function was fitted to the relationship between the
length of the menstrual cycle and timing of ovulation and compared
it with the existing calendar-based methods. The correlation
between the length of the menstrual cycle and the length of the
follicular phase was stronger than the correlation between the length
of the menstrual cycle and the length of the luteal phase, and there
was a positive correlation between the lengths of past and future
menstrual cycles. A strong positive correlation was also found
between the mean length of past cycles and the length of the
follicular phase. The correlation between the mean cycle length and
the luteal phase length was also statistically significant. In most of
the subjects, the method (i.e., the calendar-based method based on
the optimized function) outperformed the Ogino method of
predicting the next ovulation date. The method also outperformed
the ovulation date prediction method that assumes the middle day of
a mean menstrual cycle as the date of the next ovulation. The data
 27

Ben-Nun Ovulation

demonstrate that the large number of subjects allowed us to capture

the relationships between the lengths of the menstrual cycle,
follicular phase, and luteal phase in more detail than previous
studies. Then it was demonstrated how the present calendar
methods could be improved by the better grouping of women. This
study suggested that even without integrating various biological
metrics, the dataset collected by a self-tracking app can be used to
develop formulas that predict the ovulation day when the data are
aggregated. Because the developed method requires data only on
the first day of menstruation, it would be the best option for couples
during the early stages of their attempt to have a baby or for those
who want to avoid the cost associated with other methods. The
result will be the baseline for more advanced methods that integrate
other biological metrics (3).
Owen (4) mentioned that confirmation of ovulation can be
difficult in clinical practice, as gold standard methods including serial
transvaginal ultrasonography, serum LH measurements, or
laparoscopic follicular observation are impractical. Numerous
surrogate markers have been proposed and evaluated in relation to
these gold standards that have more practical clinical applications.
The purpose was to review the evidence on physiological signs of
ovulation timing and fertility in order to determine valid markers that
can be easily identified by women. A literature review of primary
resources in Ovid Medline was undertaken to identify studies
examining physiological signs as they relate to gold standard
assessment of ovulation. Studies examining the
efficacy/effectiveness of different types of natural family planning
were excluded. The most commonly encountered physiological signs
were urine LH, cervical mucus, and BBT. Urine LH as assessed by
home monitoring systems indicated ovulation 91 percent of the time
during the 2 days of peak fertility on the monitor and 97 percent
during the 2 peak days plus 1. Cervical mucus peak characteristics
were identified 78 percent of the time ±1 day, and 91 percent of the
time ±2 days of LH surge indicating ovulation. Further research
supports the importance of cervical mucus in overall fertility, as
conception rates were more closely related to mucus quality than to
timing of intercourse related to ovulation. As a lone indicator of
ovulation, BBT is at best a retrospective marker, and functions best in
conjunction with other signs of ovulation. Additionally, salivary
 28

Ben-Nun Ovulation

ferning, salivary and vaginal fluid electrical potential, finger-finger

electrical potential, and differential skin temperature were
postulated as possible indicators, but were not found to be
temporally related to ovulation. The research on differential skin
temperature is promising, but minimal thus far in number, and has
not been evaluated as an adjunct to BBT as yet. The data show that
home urinary LH monitors are becoming more widely available and
less expensive giving women the potential to assess the ovulatory
status of their cycle in real time. Cervical mucus observation is an
effective and cost-efficient method, but requires some teaching to
increase the confidence of users. In conjunction, LH monitors and
cervical mucus can give the best indication of fertility and ovulation
timing (4).
Su & al. (5) mentioned that the ability to identify the precise time
of ovulation is important for women who want to plan conception or
practice contraception. The current literature was reviewed on
various methods for detecting ovulation including a review of point-
of-care device technology. An examination of methods was
incorporated to detect ovulation that have been developed and
practiced for decades and analyze the indications and limitations of
each-transvaginal ultrasonography, urinary LH detection, serum
progesterone and urinary pregnanediol 3-glucuronide detection,
urinary follicular stimulating hormone detection, BBT monitoring, and
cervical mucus and salivary ferning analysis. Some point-of-care
ovulation detection devices have been developed and
commercialized based on these methods, however previous research
was limited by small sample size and an inconsistent standard
reference to true ovulation (5).
Collins (6) identified and evaluated reference methods for the
prediction and detection of ovulation. The methods currently being
developed or already available are based on 1] calendar calculations,
2] a specific rise in BBT, 3] the presence and type of cervical mucus,
4] changes in the concentration of circulating hormones, 5] the
immunoassay of urinary steroid glucuronides and LH 6] changes in
ovarian morphology, and 7] changes in intrafollicular blood flow.
Some of these methods include an improved algorithm for the day of
shift basal body temperature, an electronic thermometer, a special
syringe for sampling cervicovaginal fluid, and a visual test for
determining the activity of peroxidases. A histologic endpoint has
 31

Ben-Nun Ovulation

been determined for changes in the concentrations of circulating

hormones. Immunotubes are available for measuring urinary estrone
glucuronide and pregnanediol-3 alpha - glucuronide, and an
immunostick for determining urinary luteinizing hormone. The
concentration of plasma hormones and the time of follicular rupture
(ovulation) can be viewed with ultrasonography. In the periovulatory
period, transvaginal ultrasonography with color flow mapping shows
changes in intrafollicular morphology and blood flow and those
changes are described. The requirements of the markers are 1] to
determine whether ovulation occurred, 2] to reveal the day of which
the oocyte was released, 3] the prediction of ovulation, and 4) to
specify the limits of the fertile period, which may be the 4th day
before ovulation to 2 days after ovum release. Information that is
necessary before performance assessment includes 1] the type of
test and reproductive process being monitored, 2] the purpose, 3]
the age and menstrual status of the user, 4] the endpoints for
evaluation, and 5] the number of method failures. Clinical usefulness
requires prospective randomized trials. Signs and reasons for
anovulation are being investigated. Retrospective analysis shows
that motivated and informed women have a low NFP failure rate. For
fully lactating women and those approaching menopause, research is
in progress. False positive and false negative tests are to be expected
at the present level of technology, particularly among subfertile
women (6).

References
1. Kerin J. Ovulation detection in the human. Clin Reprod Fertil.
1982;1(1):27-54.
2. Gnoth C, Frank-Herrmann P, Bremme M, et al. How do self-
observed cycle symptoms correlate with ovulation? Zentralbl Gynakol.
1996;118(12):650-4.
3. Sohda S, Suzuki K, Igari I. Relationship between the menstrual cycle
and timing of ovulation revealed by new protocols: analysis of data from a
self-tracking health app. J Med Internet Res. 2017;19(11):e391.
4. Owen M. Physiological signs of ovulation and fertility readily
observable by women. Linacre Q. 2013;80(1):17-23.
5. Su HW, Yi YC, Wei TY, et al. Detection of ovulation, a review of
currently available methods. Bioeng Transl Med. 2017;2(3):238-46.
6. Collins WP. The evolution of reference methods to monitor
ovulation. Am J Obstet Gynecol. 1991;165(6 Pt 2):1994-6.
 30

Ben-Nun Ovulation

VARIOUS METHODS
SYMPTO-THERMAL METHOD. Parenteau-carreau (1) mentioned
that the symptothermal methods include all those that identify the
woman's fertile period through the basal body temperature and the
periovulatory signs. Research conducted following the discovery
over a century ago of the hyperthermic plateau in the later part of
the menstrual cycle has confirmed that under normal conditions, and
when the daily temperature is taken under comparable conditions,
infertility may be assumed when the high temperature plateau is
confirmed. A reliable temperature curve requires certain conditions:
it should be taken upon awakening with a basal thermometer over a
sufficient time to obtain an accurate measure, at almost the same
time every day, and the graph paper should be appropriately scaled
for recording. Various guidelines of interpretation have been
developed throughout the world. Serena considers infertility assured
from the 3rd consecutive day of elevated temperature as long as
other fertility symptoms have disappeared. Among symptoms of
ovulation that are perceptible to the woman are cyclic changes in the
quantity and consistency of the cervical mucus, which has the
advantage of predating and thus forecasting ovulation and of being
less sensitive than the basal temperature to nongenital infections,
sleepless nights, or other stresses. Use of mucus changes alone as an
indicator of fertility carries the risk that such changes may not be
noticed or may be due to an estrogen surge not related to ovulation.
Other symptoms that are useful for some women in confirming
temperature or mucus changes include 4 different alterations in the
cervix, abdominal pain or mittelschmerz, intramenstrual bleeding,
feeling of heaviness in the breasts, and variations in mood and libido.
Many groups that teach the temperature curve and clyclical
symptoms also provide instructions or mathematical rules for
determining the number of infertile days at the beginning of the
cycle. Some programs state that 6-7 days are usually infertile
provided that the menses were preceded by a hyperthermic plateau.
Many groups recommend the calculation of Ogino or a variant. The
symptothermal method of fertility control combines the basal
temperature curve with the other signs of fertility to serve as a basis
for modification of sexual behavior to enhance or suppress fertility.
Different programs stress different elements or combinations. The
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Ben-Nun Ovulation

efficacy of the symptothermal methods depends on precise

recordkeeping and observation and on competent instruction and
counseling, as well as the willingness of the couple to modify their
sexual behavior. Statistical measures of the method's efficacy are
complex and unsatisfactory as they attempt to apply rigid rules to
actions and decisions that are in fact filled with nuance (1).

Reference
1. Parenteau-carreau S. The sympto-thermal methods. Contracept
Fertil Sex (Paris). 1983;11(11):1189-203.

SELF-PALPATION. Parenteau-Carreau & Infante-Rivard (1)

noticed that women experienced in cervical self-palpation recognize
fertile characteristics when the cervix is high, open, soft, and straight;
this happens under estrogenic influence. The cervix is said to show
infertile signs when it is low, closed, firm, and lying against the
vaginal wall; that change occurs quickly under progesterone
influence. The objective of this study was to assess the time
relationship among changes in the cervix observed by self-palpation,
changes in cervical mucus as observed by women, and the shift in
basal body temperature during ordinary cycles. A total of 215
symptothermal charts from natural family planning users were
analyzed. The duration of the change from the maximum fertility
characteristics to the postovulatory return to definite signs of
infertility was measured. This duration ranged from 1 to 7 days, with
a mean of 2.65. The timing of maximum fertility signs in the mucus
was compared with that of maximum fertility signs in the cervix: it
varied from 3 days before to 6 days after, with a mean of 0.48 day.
The timing of the first high temperature was compared with that of
return to definitely infertile characteristics: it varied from 6 days
before to 3 days after, with a mean of -0.69 day. Some of the
variation may be due to the presence of inexperienced users in the
sample. However, a mean difference of half a day between the most
fertile cervix and the most fertile mucus on one hand and between
the first day of infertile cervix and the first high temperature on the
other hand suggest that the cervical changes could be useful
indicators of estrogen and progesterone actions (1).
 32

Ben-Nun Ovulation

Reference
1. Parenteau-Carreau S, Infante-Rivard C. Self-palpation to assess
cervical changes in relation to mucus and temperature. Int J Fertil.
1988;33 Suppl:10-6.

BASAL BODY TEMPERATURE. McCarthy & Rockette (1) reported

that basal body temperature (BBT) is used extensively to monitor
ovulation in the treatment of infertility. There are well-defined
methods of interpreting the BBT graph retrospectively that identify a
presumptive day of ovulation. The prediction of ovulation through
utilization of the BBT graph (strictly concurrent interpretation) is
adversely influenced by temperature fluctuation and cycle length
variability. The BBT graph can be very useful when its interpretation
is well defined and its limitations understood (1).
Davis (2) mentioned that an accurate record of oral basal
temperatures, taken every morning before beginning any activity,
can provide pertinent data on ovarian activity and ovulation. Oral
temperatures are just as reliable as rectal or ovarian temperatures
and are more acceptable to the patient. Basal temperature graphs
collected from 500 patients over a 2-year period show a definite
temperature drop followed by a pronounced rise at time of
ovulation; in many cases vaginal smears, endometrial biopsies, and
operative material confirmed this phenomena. The higher level
continues through the later half of the cycle, dropping sharply just
before menstruation. When pregnancy occurs the basal temperature
remains at the postovulatory level through the 1st few months of
gestation. It then drops but does not return to the preovulatory level
until after delivery. Postpartum basal temperature curves indicate
that the 1st bleeding period is rarely ovulatory while the 2nd
menstrual period is associated with ovulation in about 1/2 the
patients. A basal temperature curve should be part of every sterility
study; it is the simplest device for ascertaining ovarian activity and
dating ovulation. In 75% of sterility cases determining time of
ovulation has resulted in conception. BBTs which continue elevated
provide the most accurate early data concerning pregnancy. During
the 1st week of a missed menstrual period the failure of the
temperature to drop strongly indicates possible pregnancy. Patients
with characteristically irregular periods will not yield as much
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Ben-Nun Ovulation

information through temperature curves. Basal temperatures are

reliable indexes of ovarian activity in at least 3 out of 4 women. In the
4th the curve is so atypical with irregular readings at intervals that no
accurate interpretation of physiological changes can be made. In
addition to fertility studies and indications of pregnancy, basal
temperatures can aid in conception control by pinpointing time of
ovulation. The woman is to refrain from intercourse from the
preovulatory drop until 36-48 hours after the ovulatory rise has
reached a plateau. This system has also helped women avoid
conception in the menopausal period. 1 group followed their basal
temperatures during the climacteric. Fewer and fewer periods were
associated with ovulation and when bleeding ceases entirely the
curve assumes the typical diurnal pattern seen in the male for
ovarian activity is at low ebb (2).
Hilgers & Bailey (3) mentioned that four points on the BBT curve
have been correlated with the estimated time of ovulation (ETO), as
determined by indirect hormonal parameters, in 74 menstrual cycles
from 24 subjects. Only 10 of 66 hormonally normal cycles exhibited a
BBT dip (D), and the ETO ranged from D - 2 through D + 3. In 63 of 66
hormonally normal cycles, a BBT nadir (N), first day of BBT rise (F),
and BBT coverline endpoint (C) were identified. In these 63 cycles,
the ETO ranged from N - 5 through N + 4, F - 6 through F + 3, and C - 5
through C + 4. Biphasic curves were observed in 72 of the cycles
(97.3%) and monophasic curves in 2 cycles (2.7%). In at least 5 of 74
cycles (6.8%) the BBT curve gave incorrect information on the
ovulatory status of the cycle (3).
Matthews & al. (4) analyzed oral BBT recordings of 46 women
that conceived by donor insemination and who had midcycle
monitoring of luteinizing hormone (LH) were analyzed to establish
features associated with an optimal cycle. All cycles exhibited a
biphasic temperature shift associated with the follicular (mean + SD,
36.5 degrees C +/- 0.22) and luteal phases (36.8 degrees C +/- 0.19).
Whilst a mean body temperature rise occurred on Day +1 when all
cycles were analyzed, individual patterns were seen at ovulation
including no change or a decrease in BBT between Day 0 and Day +1.
The BBT of the postovulatory phase was stable and only 4.5% of the
644 observations made showed a change of more than 0.2 degrees C
from day to day. It was concluded that the BBT charting has
limitations when used to recognize the day of ovulation, and that
 34

Ben-Nun Ovulation

some variable patterns of the early luteal phase are consistent with
conception. Optimal luteal phases demonstrated remarkable
stability (4).
Wark & al. (5) stated that the menstrual cycle is a key marker of
health in women of reproductive age. Monitoring ovulation is useful
in health studies involving young women. The upward shift in BBT,
which occurs shortly after ovulation and continues until the next
menses, is a potentially useful marker of ovulation, which has been
exploited in clinical and research settings. The utility of BodyMedia
SenseWear (BMSW) was investigated in monitoring ovulation in
young women by analyzing the correlation and agreement of basal
temperatures measured using BMSW and a digital oral thermometer.
Kappa statistics were used to determine the agreement in ovulation
detection between the two devices, for each participant, under each
form of analysis. Participants also completed an online questionnaire
assessing the acceptability of both devices. Sixteen participants were
recruited with 15 of them providing analyzable data (11 OCP non-
users, 4 OCP users). Weak to moderate correlations were observed
between thermometer and BMSW temperature measurements
averaged over 5 different time intervals. However, no agreement
between methods was observed using Bland-Altman plots. There
was a significant difference in the range of temperatures that each
device recorded (thermometer: 35.3-37.2°C, BMSW: 29.7-36.7°C)
with BMSW temperatures significantly lower than thermometer
temperatures: mean 34.6°C (SD 1.2) versus 36.4°C (SD 0.3)
respectively, p<0.001. Poor agreement was observed between
devices under quantitative analysis of ovulation while fair agreement
was observed under visual analysis. Under both quantitative and
visual analysis, there was 0% agreement for evidence of ovulation.
This study demonstrated the importance of evaluating biomeasures
collected using mobile monitoring devices by comparison with
standard methods. A relatively poor correlation was revealed
between BMSW and oral thermometer temperature readings and
BMSW was unlikely to detect an upward shift in BBT. Participant
behavior suggested poor compliance in the use of BMSW for basal
temperature measurement and that the basal body temperature
method may not be suitable for use in unselected samples of young
women. There is a need for research tools for monitoring ovulation
 35

Ben-Nun Ovulation

that are simple, self-administered, and inexpensive, yet appealing to

young women (5).

References
1. McCarthy JJ Jr, Rockette HE. Prediction of ovulation with basal body
temperature. J Reprod Med. 1986;31(8 Suppl):742-7.
2. Davis ME. The clinical use of oral basal temperatures. J Am Med
Assoc. 1946;130(14):929-32.
3. Hilgers TW, Bailey AJ. Natural family planning. II. Basal body
temperature and estimated time of ovulation. Obstet Gynecol.
1980;55(3):333-9.
4. Matthews CD, Broom TJ, Black T, Tansing J. Optimal features of
basal body temperature recordings associated with conceptional cycles.
Int J Fertil. 1980;25(4):318-20.
5. Wark JD, Henningham L, Gorelik A, et al. Basal temperature
measurement using a multi-Sensor armband in Australian young women: a
comparative observational study. JMIR Mhealth Uhealth. 2015 Oct
5;3(4):e94.

MUCUS OBSERVATION. Bigelow & al. (1) revealed that

intercourse results in a pregnancy essentially only if it occurs during
the 6-day fertile interval ending on the day of ovulation. The strong
association between timing of intercourse within this interval and the
probability of conception typically is attributed to limited sperm and
egg life times. A total of 782 women recruited from natural family
planning centers in Europe contributed prospective data on 7,288
menstrual cycles. Daily records of intercourse, basal body
temperature and vaginal discharge of cervical mucus were collected.
Probabilities of conception were estimated according to the timing of
intercourse relative to ovulation and a 1-4 score of mucus quality.
There was a strong increasing trend in the day-specific probabilities
of pregnancy with increases in the mucus score. Adjusting for the
mucus score, the day-specific probabilities had limited variability
across the fertile interval. Changes in mucus quality across the fertile
interval predict the observed pattern in the day-specific probabilities
of conception. To maximize the likelihood of conception, intercourse
should occur on days with optimal mucus quality, as observed in
vaginal discharge, regardless of the exact timing relative to ovulation
(1).
 36

Ben-Nun Ovulation

Stanford & al. (2) assessed the day-specific and cycle-specific

probabilities of conception leading to clinical pregnancy, in relation
to the timing of intercourse and vulvar mucus observations. This was
a retrospective cohort study of women beginning use of the
Creighton Model Fertility Care System in Missouri, Nebraska, Kansas,
and California. Data were abstracted from Creighton Model Fertility
Care System records, including women's daily standardized vulvar
observations of cervical mucus discharge, days of intercourse, and
clinically evident pregnancy (conception). Established statistical
models were used to estimate day-specific probabilities of
conception. Data were analyzed from 1,681 cycles with 81
conceptions from 309 normally fertile couples (initially seeking to
avoid pregnancy) and from 373 cycles with 30 conceptions from 117
subfertile couples (who were initially trying to achieve pregnancy).
The highest probability of pregnancy occurred on the peak day of
vulvar mucus observation (.38 for normally fertile couples and.14 for
subfertile couples). The probability of pregnancy was greater than.05
for normally fertile couples from 3 days before to 2 days after the
peak, and for subfertile couples from 1 day before to 1 day after the
peak. The cycle-specific probability of conception correlated with the
quality of mucus discharge in normally fertile couples but not in
subfertile couples. The data demonstrate that standardized vulvar
observations of vaginal mucus discharge identify the days with the
greatest likelihood of conception from intercourse in normal fertility
and subfertility and provide an indicator of the overall potential for
conception in a given menstrual cycle in normal fertility (2).
Scarpa & al. (3) provided estimates of the probabilities of
conception according to vulvar mucus observations classified by the
woman on the day of intercourse. Prospective cohort study of 193
outwardly healthy Italian women was conducted using the Billings
Ovulation Method. Outcome measures include 161 conception
cycles and 2,594 non-conception cycles with daily records of the type
of mucus and the occurrences of sexual intercourse. The probability
of conception ranged from 0.003 for days with no noticeable
secretions to 0.29 for days with most fertile-type mucus detected by
the woman. The probability of most fertile type mucus by day of the
menstrual cycle increased from values <20% outside of days 10-17 to
a peak of 59% on day 13. The data show that regardless of the timing
of intercourse in the menstrual cycle, the probability of conception is
 37

Ben-Nun Ovulation

essentially 0 on days with no secretions. This probability increases

dramatically to near 30% on days with most fertile-type mucus, an
association that accurately predicts both the timing of the fertile
interval and the day-specific conception probabilities across the
menstrual cycle (3).

References
1. Bigelow JL, Dunson DB, Stanford JB, et al. Mucus observations in
the fertile window: a better predictor of conception than timing of
intercourse. Hum Reprod. 2004;19(4):889-92.
2. Stanford JB, Smith KR, Dunson DB. Vulvar mucus observations and
the probability of pregnancy. Obstet Gynecol. 2003;101(6):1285-93.
3. Scarpa B, Dunson DB, Colombo B. Cervical mucus secretions on the
day of intercourse: an accurate marker of highly fertile days. Eur J Obstet
Gynecol Reprod Biol. 2006 Mar 1;125(1):72-8.

CERVICO-VAGINAL FLUID. Flynn & al. (1) mentioned that

characteristic changes in cervico-vaginal fluid (CVF) volume which
occur during the menstrual cycle might be used to detect the fertile
phase. Twenty-five normal women were asked to withdraw CVF and
measure its volume at home using a small, disposable, graduated
vaginal aspirator. In 16 cycles day 0 (ovulation) was defined as the
day of maximum follicular diameter according to serial ultrasound
examination. A rise in CVF volume occurred between day -9 and -2
and a peak between day -4 and 0. In these sixteen, and in a further
72 cycles, day 0 (time of maximum fertility) was taken as the day of
peak cervical mucus secretion. CVF volume rose, on the average, on
day -6.2 (range -17 to -2) and peaked on day -0.8 (range -5 to +2). In
two cycles, no rise and peak were identified. Changes in CVF volume
were easy to recognize and could be useful to couples wishing to
achieve pregnancy (1).
Flynn & al. (2) also noticed that recent trends in family planning
demonstrate an increasing interest in natural methods of birth
regulation. In their present form, however, these methods are highly
subjective and individualistic. A further trend in fertility programs
has been a very rapid development of technological methods to
detect fertility in the female cycle, some of which could possibly
benefit natural family planning users. One such technique - that of
changing volumes of CVF, which is a mixture of cervical mucus and
 38

Ben-Nun Ovulation

vaginal transudate - has been tested in a pilot study to ascertain its

reliability to demarcate the fertile phase of the cycle. Results show
that in all cycles tested, it is possible using the Rovumeter aspirator
to detect the beginning of the fertile phase by rapidly increasing
volumes of CVF; this volume reaches a peak approximately 1 day
before ovulation detected by ultrasound and demonstrates an abrupt
fall after ovulation and the onset of the infertile phase. From the
results of this pilot study, the Authors believe that, by the use of
suitable algorithms and larger studies, it should be possible to
develop a CVF volume method which could be offered as an objective
alternative method for users of natural family planning and programs
(2).

References
1. Flynn AM, Docker MF, McCarthy N, Royston JP. Detection of the
fertile phase from changes in cervico-vaginal fluid volume. Int J Fertil.
1988;33 Suppl:17-23.
2. Flynn AM, McCarthy AM, Docker M, Royston JP. The temporal
relationship between vaginal fluid volumes obtained with the Rovumeter
vaginal aspirator and the fertile phase of the cycle. Hum Reprod.
1988;3(2):201-5.

VAGINAL HORMONAL CYTOGRAMS CORRELATION WITH MUCUS

SYMPTOMS. Taylor & al. (1) performed the first study in which
vaginal hormonal cytograms were correlated with cervical mucus
symptoms as charted by women using the ovulation method of
natural family planning. Daily vaginal smears obtained by 67 women
during 78 menstrual cycles provided the basis of the study. The
women had used the ovulation method for at least three cycles and
were not breast-feeding. All vaginal smears examined cytologically
had a microbiologic diagnosis of lactobacilli. All the vaginal hormonal
cytograms revealed ovulatory-type patterns. Karyopyknotic index
(KPI) peak correlated with peak mucus day +/-2 days in 74, or 94.9%,
of the cases, with a mean of peak mucus at +0.14 days. The average
number of mucus days prior to the KPI peak was 6.1. Seven women
also provided daily blood specimens for bioassay of luteinizing
hormone (LH). KPI peaked with a mean of 0.7 days after the LH peak
(1).
 41

Ben-Nun Ovulation

Reference
1. Taylor RS, Woods JB, Guapo M. Correlation of vaginal hormonal
cytograms with cervical mucus symptoms as observed by women using the
ovulation method of natural family planning. J Reprod Med. 1986;
31(3):167-72.

LUTEINIZING HORMONE. Corson (1) compared the accuracy of

self-prediction of ovulation through use of an enzyme immunoassay
for luteinizing hormone (LH) determination was compared to that of
other ovulation-monitoring methods in 45 women who contributed
78 cycles of study. Subjects were instructed to begin testing twice
daily for 3-4 days before the expected day of ovulation and to
continue until a surge was detected. They were further asked to
keep a basal body temperature (BBT) chart and to provide a serum
sample within 18 hours of the urinary surge. The urinary test kit gave
consumer-identified LH surges in 94% of cycles; results were correct,
as confirmed by BBT, in 99% of cycles. The correlation between
urinary and serum LH was good. The mean luteal phase duration
following the urinary LH surge was 15 days. Concomitant use of
clomiphene citrate in 6 subjects did not invalidate urinary LH testing
as long as the testing began after drug administration had been
completed. The detection of the surge of LH occurred in the early
evening in 45 cycles and in the morning in 28 cycles. Urine collected
in the mid-day period was positive in 94% of preovulatory specimens.
Overall, these findings indicate that enzyme immunoassay of urinary
LH is a valid predictor of ovulation as compared with
radioimmunoassay of serum LH and urinary LH, BBT, and ultrasound.
The convenience and accuracy of urinary enzyme immunoassay
testing are important benefits in ovulation prediction in the
treatment of infertility (1).
Seibel (2) noticed that serum LH levels are routinely used in the
treatment of infertility for ovulation assessment and timing of
artificial insemination, in vitro fertilization and endometrial biopsies.
Extensive clinical research has shown the LH surge in serum or
plasma to be the standard for precise ovulation timing. The
relationship of the LH surge to oocyte maturation (preovulatory) and
fresh ovulatory stigmata (postovulatory) enhances the status of LH as
the standard. Within this context, the advantages and disadvantages
 40

Ben-Nun Ovulation

of the method are weighed against broad clinical application for

general ovulation prediction (2).
Chiu & al. (3) determined levels of urinary LH by a rapid,
semiquantitative enzyme immunoassay dipstick test (Ovustick, now
known as OvuKIT) and the results were compared with a standard
serum LH double-antibody radioimmunoassay in 63 cycles of 47
women undergoing stimulated cycles for in vitro fertilization. A good
correlation was found between the two assay methods in 70% of the
cycles. An increase in serum LH was associated with a concurrent rise
in the dipstick measurement. Using the Ovustick method, no false-
positive finding was encountered, but the LH rise was missed in one
case. The number of mature oocytes aspirated was significantly
higher in the stimulated cycles without an endogenous LH surge. The
use of this simple and rapid enzyme immunoassay method makes
possible successful and precise timing of ovulation during artificial
insemination or egg retrieval for IVF in treatments for infertility (3).
Baker & al. (4) tested an enzyme-linked double monoclonal
antibody dipstick for measuring luteinizing hormone in urine for
timing ovulation in thrice daily urine samples collected for several
days around mid-cycle in 24 women undergoing artificial
insemination. The assay produced information comparable to single
daily serum LH measurements. The dipsticks could be used by
untrained people to test their own urine as an aid to the detection of
ovulation for the timing of artificial insemination or of sexual
intercourse to promote or avoid conception (4).
Yong & al. (5) compared a new urine LH kit, First Response
(Tambrands Inc., Palmer, MA) with basal body temperature (BBT),
cervical mucus scoring and abdominal ultrasound follicular scanning
in their ability to predict ovulation to within 2 days of the serum LH
peak. BBT was kept daily. From day 10 daily ultrasound scanning and
cervical mucus examination were performed and serum estradiol, LH,
follicular stimulating hormone and progesterone were assayed. First
Response was significantly more accurate than BBT and cervical
mucus when compared in their ability to predict ovulation to within 2
days of the LH peak (p less than 0.05). First Response pinpointed 93%
(27/29) of the ovulatory cycles compared to 72% (18/25) and 61%
(19/31) for BBT and cervical mucus respectively. It was better but
not significantly so against abdominal ultrasound which predicted
 41

Ben-Nun Ovulation

77% (24/31). The implications of this finding and the value of the
other simple office tests in clinical practice are discussed (5).
Ho & al. (6) compared the results of the cervical mucus score
(CMS), BBT and a LH assay by haemagglutination immunoassay with
plasma LH radioimmunoassay in 28 ovulatory cycles. There was good
correlation of the CMS peak with the plasma LH peak while the urine
LH peak usually occurred one day later. The first day when the CMS
was greater than or equal to 8 occurred within +/- 1 day of the
plasma LH peak in 89.3% of cycles. The first day when the urine LH
was greater than or equal to 100 iu/l occurred within +/- 1 day of the
plasma LH peak in all the cycles. BBT nadir could be identified in only
82% of cycles and it coincided with the plasma LH peak in only 28.6%
of cases. These findings suggest that both the CMS and the rapid
urine LH assay are acceptable methods for determining the time of
ovulation while the BBT is not useful (6).

References
1. Corson SL. Self-prediction of ovulation using a urinary luteinizing
hormone test. J Reprod Med. 1986;31(8 Suppl):760-3.
2. Seibel MM. Luteinizing hormone and ovulation timing. J Reprod
Med. 1986;31(8 Suppl):754-9.
3. Chiu TT, Tam PP, Mao KR. Evaluation of a semiquantitative urinary
LH assay for ovulation detection. Int J Fertil. 1990;35(2):120-4.
4. Baker HW, Bangah ML, Burger HG, et al. Timing of ovulation by
determination of the urinary luteinizing hormone surge with an enzyme-
linked monoclonal antibody dipstick (OvuStick). Aust N Z J Obstet
Gynaecol. 1986;26(1):79-83.
5. Yong EL, Wong PC, Kumar A, et al. Simple office methods to predict
ovulation: the clinical usefulness of a new urine luteinizing hormone kit
compared to basal body temperature, cervical mucus and ultrasound.
Aust N Z J Obstet Gynaecol. 1989;29(2):155-60.
6. Ho PC, Kwan M, Chan SY, et al. Rapid urinary LH assay for prediction
of ovulation. Aust N Z J Obstet Gynaecol. 1985;25(3): 230-2.

URINE PROGESTERONE. Bouchard & al. (1) mentioned that

progesterone rises ~24-36 h after ovulation. Past studies using
ultrasound-confirmed ovulation have shown that three consecutive
tests with a threshold of 5μg/mL of urine progesterone
(pregnanediol-3-glucuronide, PDG), taken after the luteinizing
hormone (LH) surge, confirmed ovulation with 100% specificity. The
 42

Ben-Nun Ovulation

purpose of this study was to evaluate new urine PDG self-test to

retrospectively confirm ovulation in women who were monitoring
ovulation using a hormonal fertility monitor. Thirteen women of
reproductive age were recruited to test urine PDG while using their
home hormonal fertility monitor. The monitor measured the rise in
estrogen (estrone-3-glucuronide, E3G) and LH to estimate the fertile
phase of the menstrual cycle. The women used an online menstrual
cycle charting system to track E3G, LH and PDG levels for four
menstrual cycles. The participants (Mean age 33.6) produced 34
menstrual cycles of data (Mean length 28.4 days), 17 of which used a
PDG test with a threshold of 7μg/mL and 17 with a threshold of
5μg/mL. In the cycles that used the 7μg/mL test strips, 59% had a
positive confirmation of ovulation, and with the 5μg/mL test strips,
82% of them had a positive confirmation of ovulation. The data
indicate that the 5μg/mL PDG test confirmed ovulation in 82% of
cycles and could assist women in the evaluation of the luteal
progesterone rise of their menstrual cycle (1).
Gifford & al. (2) mentioned that urinary concentrations of the
major progesterone (P4) metabolite pregnanediol-3-glucuronide
(PDG) are used to confirm ovulation. The aim was to determine
whether automated immunoassay of urinary P4 was as efficacious as
PDG to confirm ovulation. Daily urine samples from 20 cycles in 14
healthy women in whom ovulation was dated by ultrasound, and
serial weekly samples from 21 women in whom ovulation was
unknown were analysed. Daily samples were assayed by two
automated P4 immunoassays (Roche Cobas and Abbott Architect)
and PDG ELISA. Serial samples were assayed for P4 by Architect and
PDG by ELISA. In women with detailed monitoring of ovulation,
median (95% CI) luteal phase increase was greatest for PDG, 427%
(261-661), 278% (187-354) for P4 Architect and least for P4 Cobas,
146% (130-191), p < 0.0001. Cobas P4 also showed marked
inaccuracy in serial dilution. Similar ROC AUCs were observed for
individual threshold values and two-sample percent rise analyses for
P4 Architect and PDG (both >0.92). In serial samples classified as
(an)ovulatory by PDG, P4 Architect gave ROC AUC 0.95 (95% CI 0.89
to 1.01), with sensitivity and specificity for confirmation of ovulation
of 0.90 and 0.91 at a cutoff of 1.67 μmol/mol. Automated P4 may
potentially be as efficacious as PDG ELISA but research from a range
of clinical settings is required (2).
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Ben-Nun Ovulation

Roos & al. (3) examined relationships and interindividual

variations in urinary and serum reproductive hormone levels relative
to ultrasound-observed ovulation in menstrual cycles of apparently
normally menstruating women. This was a prospective study of
normally menstruating women (no known subfertility), aged 18-40
years (n=40), who collected daily urine samples and attended the
study center for blood samples and transvaginal ultrasound during
one complete menstrual cycle. LH, progesterone, estradiol, urinary
LH, pregnanediol-3- glucuronide (P3G) and estrone-3-glucuronide
were measured. Ultrasound was conducted by two physicians and
interpreted by central expert review. Menstrual cycle length varied
from 22 to 37 days (median 27 days). Ovulation by ultrasound
ranged from day 8 to day 26 (median day 15). Serum and urinary
hormone profiles showed excellent agreement. Estrogen and LH
hormone peaks in urine and serum showed a range of signal
characteristics across the study group before and after ovulation.
The rise in estrogen and LH always occurred before ovulation; the
progesterone rise from baseline always occurred after ovulation. The
data show that urinary and serum reproductive hormones showed
excellent agreement and may be used interchangeably. The
beginning of the surge in serum and urinary LH was an excellent
predictor of ovulation. The rise in progesterone and P3G above
baseline was a consistent marker of luteinization confirming
ovulation. Both LH and progesterone surges delivered clear, sharp
signals in all volunteers, allowing reliable detection and confirmation
of ovulation (3).

References
1. Bouchard TP, Fehring RJ, Schneider M. Pilot evaluation of a new
urine progesterone test to confirm ovulation in women using a fertility
monitor. Front Public Health. 2019 Jul 2;7:184.
2. Gifford RM, Howie F, Wilson K, et al. Confirmation of ovulation
from urinary progesterone analysis: assessment of two automated assay
platforms. Sci Rep. 2018;8(1):17621.
3. Roos J, Johnson S, Weddell S, et al. Monitoring the menstrual cycle:
Comparison of urinary and serum reproductive hormones referenced to
true ovulation. Eur J Contracept Reprod Health Care. 2015;20(6):438-50.
 44

Ben-Nun Ovulation

URINARY STEROIDS. Cekan & al. (1) mentioned that twenty

normally menstruating women volunteered for a study in which
plasma samples were collected daily during an entire menstrual
cycle. On the same days, samples of morning urine were also
collected, as well as random samples of urine voided at the visit to
the Outpatient Clinic. Progesterone (P), estradiol (E2) and lutropin
(LH) were assayed in plasma, and pregnanediol-3-glucuronide (PdG),
estrone-glucuronide (E1G), estriol-16-glucuronide (E3G), P, and E2
were measured in urine using radioimmunoassays. Progesterone in
urine was assayed both with and without preceding chromatography.
All urinary glucuronides and progesterone exhibited cyclic patterns
similar to those of E2 or P in plasma. Seven-fold increases from early
follicular to luteal phase values (for PdG and urinary P; the latter both
with and without chromatography), or to peak levels (for E1G and
E3G) were observed. The difference between the baseline and peak
levels was less distinct (approximately 5-fold) for E2 in urine. The
day-to-day coefficient of variation of early follicular phase values
decreased from 40% to 25% by calculating the ratios of the
glucuronides or P to creatinine (C). The peaks of estrogen
glucuronides were delayed mostly by 1 day in comparison to the
peaks of E2 in plasma. The urinary peaks of estrogens were in most
cases more closely clustered around the day of the LH-peak when the
measurements were corrected for C. For the determination of the
first significant rise of steroid levels in a cycle, the calculation of a
sustained rise (leading to a significant cumulative sum - CUSUM) was
found superior when compared to other recommended indices, such
as a 50% increase over the mean of 3 preceding values, or the
increase over the baseline level plus 2 standard deviations. Sustained
rises were calculated for all indices studied (including the ratio of
urinary E1G to PdG). The ratio of E1G to C in morning urine gave
consistently the most compact distribution of sustained rises. It is
concluded that daily measurements of urinary PdG (or P) and E1G
(or, possibly, E2) could substitute the serial assays of P and E2 in
peripheral blood in the retrospective assessment of the ovarian
function. The day-to-day variation can be significantly reduced, if
results are expressed per concentration of C. For the prediction of
ovulation or fertile period, the best index of urinary steroids appears
to be the sustained rise in the ratio of E1G to C. However, this "best"
 45

Ben-Nun Ovulation

method is still not good enough in terms of overall reliability and

practicability (1).
Merlo & al. (2) correlated the concentrations of estrone-3-
glucuronide (E(1)3G) and pregnanediol-3-glucuronide (P(2)3G) in
daily samples of early morning urine (EMU) were correlated with the
levels of estradiol (E2), progesterone (P) and LH in respective plasma
samples. Forty-six menstrual cycles were studied, in order to
determine the practical usefulness of the urine assays for detecting:
1] an individualized estrogen concentration threshold value,
announcing the approach of ovulation. 2] an individualized signal
provided by P(2)3G in urine from which it can be assumed that
ovulation has already occurred. The results showed that the
concentration of E2 in plasma, in any day of the cycle, can be
precisely inferred from the respective concentration of E(1)3G in
EMU. The estimation of the plasmatic P values from those of P(2)3G
in EMU had to be based on different factors according to the phase
of the cycle, fact that suggests the presence of a phase-related
variation in the glucuronization of P metabolites. Considering three
consecutive E(1)3G urinary assay results, it was possible to identify a
threshold value termed Estrogen-Peak Initiating Rise (E-PIR), which
anticipated in 3.02 +/- 0.18 days the occurrence of an LH peak. The
attempts to detect the occurrence of ovulation by an individualized
urinary P(2)3G signal proved disappointing. The signal was detected,
either before, simultaneously or after the LH peak (2).

References
1. Cekan SZ, Beksac MS, Wang E, et al. The prediction and/or
detection of ovulation by means of urinary steroid assays. Contraception.
1986;33(4):327-45.
2. Merlo AB, Farinati Z, Quiroga S, et al. Direct assay of urinary steroid
glucuronides for monitoring the approach of ovulation. Int J Fertil.
1984;29(3):189-93.

TEST STRIPS. Ayoola & al. examined whether low-income adult

women will use ovulation test strips, a menstrual calendar chart,
thermometer, temperature graph, and cervical mucus assessment to
monitor their ovulation time and other menstrual changes. Women's
confidence in their ability to detect ovulation time and understand
the menstrual cycle changes were also examined. This was a
 46

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descriptive study. Twenty-two low-income women aged 18 to 39

years living in medically underserved neighborhoods participated in
this study. The women were introduced to and taught how to use a
knowing your body (KB) kit, which consisted of ovulation test strips,
monthly calendars for menstrual logs, digital thermometer for basal
body temperature, and graphs to chart temperature. The women
were interviewed 6 to 8 weeks later to confirm their experiences
with the use of the KB kit. Ninety-one percent of the women used
the ovulation test strips (mean, 3.8 strips); 77.3% were very to
extremely confident that they could properly use the ovulation strip,
54.6% knew when they ovulated, and 31.8% could use the
thermometer to confirm when they were ovulating. Seventy-three
percent of the women were very to extremely comfortable using the
ovulation test strips, 81.8% using the thermometer, 45.5% using the
temperature graph, and 31.8% using the TwoDay Method (cervical
mucus observation). The use of the ovulation test strip and other
content of the KB kit provides a new opportunity for low-income
women to learn about their bodies by monitoring their ovulation
time and other (1).

Reference
1. Ayoola AB, Slager D, Feenstra C, Zandee GL. A feasibility study of
women's confidence and comfort in use of a kit to monitor ovulation. J
Midwifery Womens Health. 2015;60(5):604-9.

HOME BASED OVULATION TESTS. Yeh & al. (1) informed the
WHO Guideline on self-care interventions, a systematic review of the
impact of ovulation predictor kits (OPKs) on time-to-pregnancy,
pregnancy, live birth, stress/anxiety, social harms/adverse events and
values/preferences was conducted. Included studies had to compare
women desiring pregnancy who managed their fertility with and
without OPKs, measure an outcome of interest and be published in a
peer-reviewed journal. PubMed, CINAHL, LILACS and EMBASE were
searched through November 2018. Risk of bias were assessed using
the Cochrane tool for randomized controlled trials (RCTs) and the
Evidence Project tool for observational studies, and conducted meta-
analysis using random effects models to generate pooled estimates
of relative risk (RR). Four studies (three RCTs and one observational
study) including 1,487 participants, all in high-income countries, were
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included. Quality of evidence was low. Two RCTs found no

difference in time-to-pregnancy. All studies reported pregnancy rate,
with mixed results: one RCT from the 1990s among couples with
unexplained or male-factor infertility found no difference in clinical
pregnancy rate (RR 1.09, 95% CI 0.51-2.32); two more recent RCTs
found higher self-reported pregnancy rates among OPK users (pooled
RR: 1.40, 95% CI 1.08-1.80). A small observational study found higher
rates of pregnancy with lab testing versus OPKs among women using
donor insemination services. One RCT found no increase in
stress/anxiety after two menstrual cycles using OPKs, besides a
decline in positive affect. No studies measured live birth or social
harms/adverse events. Six studies presented end-users'
values/preferences, with almost all women reporting feeling
satisfied, comfortable and confident using OPKs. A small evidence
base, from high-income countries and with high risk of bias, suggests
that home-based use of OPKs may improve fertility management
when attempting to become pregnant with no meaningful increase in
stress/anxiety and with high user acceptability (1).
Weddell & al. (2) examined the impact of using ovulation tests on
self-reported levels of stress, psychological well-being, and quality of
life in women with unexplained infertility. The test group used a
home ovulation test to detect the day of ovulation, whereas the
control group was provided with a predicted day of ovulation based
on the average length of menstrual cycle reported during study
recruitment. Volunteers collected their first morning urine samples
to evaluate biochemical levels of stress (urinary cortisol and estrone-
3-glucouronide) and completed questionnaires over two complete
menstrual cycles. Overall, the use of digital ovulation tests by sub-
fertile women under medical care had negligible negative effects and
no detectable positive benefit on psychological well-being, according
to multiple measurements of stress by questionnaire and
biochemical markers. No significant differences were found between
groups for all stress measures at the various study time points,
except in relation to "couple concordance" where the test group
scored much higher than the control group (mean difference at end
of study was 21.25; 95% confidence interval [CI] 9.25-33.25;
p = 0.0015). The maximum difference in log cortisol: creatinine ratio
between the test and control groups was -0.28; 95% CI -0.69-0.13).
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These results do not support propositions that using digital ovulation

tests can cause stress in women trying to conceive (2).
Tiplady & al. (3) asked: does the use of a digital home ovulation
test have any effect on the level of stress in women seeking to
conceive? No difference was found in levels of stress between
women using digital ovulation tests to time intercourse compared
with women who were trying to conceive without any additional
aids: in addition, their use did not negatively impact time to
conception in users but may provide additional benefits, including an
increased understanding of the menstrual cycle, reassurance and
confidence in focusing conception attempts to the correct time in the
cycle. It has been suggested that timing of intercourse in such a way
that it coincides with ovulation by using ovulation tests can lead to
emotional distress; however, no study has been conducted to
investigate this hypothesis specifically, until now. The study was
performed over two complete menstrual cycles as a prospective,
randomized, controlled trial including quantitative and qualitative
methods. The intervention (test) group were given digital ovulation
tests to time intercourse to the most fertile time of the cycle and the
control group were provided with the current National Institute for
Health and Clinical Excellence guidelines for increasing the chances of
conception (intercourse every 2-3 days) and asked not to use any
additional methods to time when ovulation occurs. A total of 210
women who were seeking to conceive were recruited from the
general UK population. A total of 115 women were randomized to
the test group and 95 to the control group through block
randomization. The positive and negative affect schedule (PANAS)
and the Perceived Stress Scale (PSS) were used to measure subjective
stress levels, the Short-Form 12 health survey was used as a measure
of general health and well-being and urine samples were measured
for biochemical markers of stress including urinary cortisol.
Qualitative data were collected in the form of a telephone interview
upon study completion. There was no evidence for a difference
either in total stress as measured using the PSS or in total positive or
negative affect using the PANAS questionnaire between the test and
control groups at any time point for the duration of the study. During
cycle 1, for example, on Day 6, the difference in total stress score
(test-control) was -0.62 [95% confidence interval [CI] -2.47-1.24] and
on the day of the LH surge, it was 0.53 (95% CI -1.38-2.44). In
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Ben-Nun Ovulation

addition, no correlation was observed between time trying to

conceive and levels of stress, or between age and levels of stress, and
no evidence was found to show that stress affected whether or not a
pregnancy was achieved. There is also no evidence that the
biochemistry measurements are related to whether a pregnancy was
achieved or of a difference in biochemistry between the treatment
groups. The use of digital ovulation tests did not negatively affect
time to conception and with an adequately sized study, could
potentially show improvement. To ensure that the results of this
study were not affected by chance, a number of different methods
were used for measuring stress, each of which had been
independently validated. Randomization occurred before the start of
the study because of the need to provide the ovulation tests in
readiness for Day 6 of the first cycle. As a consequence, a number of
women fell pregnant during this period (22 and 13 in the test and
control groups, respectively). A further 15 women were either lost to
follow-up or withdrew consent prior to study start. Pregnancy rate
was higher overall in the test group, so to ensure that there were
sufficient data from women who failed to become pregnant in the
test group, an additional biased recruitment was implemented. This
second cohort may have been different from the first, although no
significant differences were observed between the two phases of
recruitment for any of the information collected upon admission to
the study. Women who seek medical advice while trying to conceive
should not be discouraged by health care professionals from using
digital ovulation tests in order to time intercourse. The cohort of
women recruited to this study initially had no evidence of infertility
and were looking to conceive in a non-medical setting. A separate
study to assess the impact of home ovulation tests in a subfertile
population would be of interest and complementary to the present
study (3).

References
1. Yeh PT, Kennedy CE, Van der Poel S, et al. Should home-based
ovulation predictor kits be offered as an additional approach for fertility
management for women and couples desiring pregnancy? A systematic
review and meta-analysis. BMJ Glob Health. 2019;4(2):e001403.
2. Weddell S, Jones GL, Duffy S, et al. Home ovulation test use and
stress during subfertility evaluation: Subarm of a randomized controlled
trial. Womens Health (Lond). 2019;15:1745506519838363.
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Ben-Nun Ovulation

3. Tiplady S, Jones G, Campbell M, et al. Home ovulation tests and

stress in women trying to conceive: a randomized controlled trial. Hum
Reprod. 2013;28(1):138-51.

ULTRASOUND. Sanchez & al. (1) assessed the correlation

between low levels of progesterone and ovulation by ultrasound
monitoring in infertile patients with regular menstrual cycles. In this
case-control study the sample consisted of 302 women aged 20-40
years, treated from 2000 to 2014 in the Human Reproduction
Laboratory of the University Hospital of the Federal University of
Goiás and in the Department of Gynecology and Obstetrics in
Goiânia, Goiás. Data collection was performed by analysis of physical
records (Medical Records and Health Information Services) and
electronic ones (Sisfert©, 2004) after approval by a Human Research
Ethics Committee. Patients were classified according to their
ovulatory status, evaluated by progesterone levels and ultrasound
monitoring and divided into two groups: Group I (anovulatory cycle
patients, n=74) and Group II (ovulatory patients, n=228). In both
groups associations were made between the percentage of patients
with normal progesterone (≥ 10 ng/ml) and percentage of patients
with low progesterone (5.65 - 9.9 ng/ml). The groups were paired for
comparisons related to age, body mass index, duration of infertility,
follicle stimulating hormone (FSH), thyroid stimulating hormone
(TSH), luteinizing hormone (LH) and estradiol (E2). There was a
significant association between the percentage of ovulation by
ultrasound monitoring and the percentages of patients who
presented low levels of progesterone. The study suggests that low
serum levels of progesterone are associated with low percentage of
ovulation in infertile women with regular menstrual cycles and
women with unexplained infertility (1).
Petsos & al. (2) examined for the presence of subtle hormonal
abnormalities in women with long-standing unexplained infertility.
For a full cycle serum LH, FSH, progesterone and estradiol levels were
measured about three times a week, and serial ultrasound scans of
the ovaries made until the time of apparent ovulation. The results on
45 cycles in 35 women with unexplained infertility and in three
normal volunteers are presented. Normal ovulatory cycles were
defined by a length of 26-32 d, and progressive follicular maturation
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Ben-Nun Ovulation

followed by disappearance or abrupt reduction in size of a follicle

within 48 h of the recorded LH peak, followed by progressive and
sustained rise in serum progesterone levels to more than 25 nmol/l
and a luteal phase length of greater than or equal to 13 d. Thirty
spontaneous cycles (28 women) were clearly normal while 15
spontaneous cycles (12 women) were abnormal. Abnormalities
included luteinization of an unruptured follicle (eight cycles), absence
of follicular development (two cycles), poor follicular development
(two cycles), persistence of a large ovarian cyst from the preceeding
cycle (two cycles) and one aluteal cycle. Six of the abnormal cycles
were characterized hormonally by inappropriate elevation of serum
LH levels throughout. If this study had been based only on serial
ultrasound scans, all results on abnormal cycles might have been
misinterpreted. If it had been conducted only with (multiple)
progesterone determinations and the level of greater than 25 nmol/l
had been taken as indicative of ovulation nine clearly abnormal
cycles would have been considered as normal. The data show that
the combination of the hormonal and ultrasound assessment of
ovulation increases the confidence for confirmation of normality and
reveals various ovulatory disorders which are possibly due to an
endocrinological defect or defects (2).

References
1. Sanchez EG, Giviziez CR, Sanchez HM, et al. Low progesterone levels
and ovulation by ultrasound assessment in infertile patients. JBRA Assist
Reprod. 2016;20(1):13-6.
2. Petsos P, Chandler C, Oak M, et al. The assessment of ovulation by a
combination of ultrasound and detailed serial hormone profiles in 35
women with long-standing unexplained infertility. Clin Endocrinol (Oxf).
1985;22(6):739-51.

VARIOUS DEVICES. Potluri & al. (1) mentioned that the ability to
accurately predict ovulation at-home using low-cost point-of-care
diagnostics can be of significant help for couples who prefer natural
family planning. Detecting ovulation-specific hormones in urine
samples and monitoring basal body temperature (BBT) are the
current commonly home-based methods used for ovulation
detection; however, these methods, relatively, are expensive for
prolonged use and the results are difficult to comprehend. Here, a
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Ben-Nun Ovulation

smartphone-based point-of-care device for automated ovulation

testing using artificial intelligence (AI) is reported by detecting fern
patterns in a small volume (<100 μL) of saliva that is air-dried on a
microfluidic device. The performance of the device was evaluated
using artificial saliva and human saliva samples and observed that the
device showed >99% accuracy in effectively predicting ovulation (1).
Jellonek & al. (2) described studies for evolving of modern
methods for determination of the ovulation time in women. After an
analysis of literature reports three methods were chosen based on
differences in body temperature measurements and a measuring
device for these experiments was designed. The results are
presented of preliminary experiments with this method of
"measurements of changes in the reactivity of blood vessels".
Further studies can be conducted only by physicians, and the paper
contains proposals of using this device as well as the literature data
(2).
Shilaih & al. (3) mentioned that core and peripheral body
temperatures are affected by changes in reproductive hormones
during the menstrual cycle. Women worldwide use the BBT method
to aid and prevent conception. However, prior research suggests
that taking one's daily temperature can prove inconvenient and
subject to environmental factors. This study investigated whether a
more automatic, non-invasive temperature measurement system can
detect changes in temperature across the menstrual cycle. The
examined how wrist skin temperature (WST), measured with
wearable sensors, correlates with urinary tests of ovulation and may
serve as a new method of fertility tracking. One hundred and thirty-
six eumenorrheic, non-pregnant women participated in an
observational study. Participants wore WST biosensors during sleep
and reported their daily activities. An at-home luteinizing hormone
(LH) test was used to confirm ovulation. WST was recorded across
437 cycles (mean cycles/participant = 3.21, S.D. = 2.25). The
relationship between the fertile window and WST temperature shifts
were tested, using the BBT three-over-six rule. A sustained 3-day
temperature shift was observed in 357/437 cycles (82%), with the
lowest cycle temperature occurring in the fertile window 41% of the
time. Most temporal shifts (307/357, 86%) occurred on ovulation
day (OV) or later. The average early-luteal phase temperature was
0.33°C higher than in the fertile window. Menstrual cycle changes in
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Ben-Nun Ovulation

WST were impervious to lifestyle factors, like having sex, alcohol, or

eating prior to bed, that, in prior work, have been shown to
obfuscate BBT readings. Although currently costlier than BBT, the
present study suggests that WST could be a promising, convenient
parameter for future multiparameter fertility awareness methods (3).

This chapter (1-3) shows that there are numerous methods

related to ovulation detection.

References
1. Potluri V, Kathiresan PS, Kandula H, et al. An inexpensive
smartphone-based device for point-of-care ovulation testing. Lab Chip.
2018;19(1):59-67.
2. Jellonek K, Kozimor K, Kozimor K, Musial Z. Elaboration of a device
for detection of the ovulation period in women. Wiad Lek. 1992;45(9-
10):339-42.
3. Shilaih M, Goodale BM, Falco L, et al. Modern fertility awareness
methods: wrist wearables capture the changes in temperature associated
with the menstrual cycle. Biosci Rep. 2018;38(6).

NATURAL FAMILY PLANNING

Davis (1) mentioned that fertility-aware couples can use natural
family planning (NFP) to prevent pregnancy or to time intercourse so
conception occurs. Fertility awareness also helps in diagnosing and
treating premenstrual syndrome, infertility, and abnormal patterns.
NFP can be 89% effective (comparable to that of barrier methods)
when couples are properly trained and strictly follow NFP techniques.
The rhythm or calendar method consists of numerical calculations
based on previous menstrual cycles. Menstrual cycle charting
involves keeping records of the last 6-12 cycles to predict future
cycles. It is undependable during postpartum, lactation, and at the
end of the childbearing years, however. The basal body temperature
(BBT) method includes women measuring their temperature every
morning before rising. A fall in BBT usually comes 12-24 hours before
ovulation. Examination of the cervical mucus also helps to identify
fertile days. Mucus during fertile days is clear, plentiful, elastic, thin,
and slippery and forms a thin strand at least 6 cm long when placed
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Ben-Nun Ovulation

between 2 fingers. These qualities facilitate sperm mobility through

the cervix. The sympto-thermal method is a combination of the
previous methods. It also takes into consideration other signs and
symptoms of fertility such as intermenstrual pain. Breast feeding
also provides some protection against pregnancy but can be
unreliable. A major disadvantage of NFP is other methods are more
effective. Some advantages include it being immediately reversible,
safe, and increases fertility and infertility awareness. If a couple is
interested in using NFP to prevent pregnancy, health providers or
counselors must make the time to conduct the extensive training.
NFP success hinges on user's motivation and their ability to interpret
signs and symptoms of fertility (1).
Gross (2) mentioned that indirect evidence of the occurrence of
ovulation, which is generally accepted, is an increase in plasma or
serum progesterone. Pelvic ultrasonography can estimate the
probable time of ovulation within 12 h. There is a close association
between the rise in progesterone, luteinizing hormone (LH) and
estrogen peaks and ovulation. A WHO study reported that ovulation
occurred at a median time of 8 h after the rise in plasma
progesterone, 15 h after the LH peak and 24 h after the estrogen
peak. The BBT method is the most effective in determining the
premenstrual infertile period, but it is unreliable for an accurate
determination of ovulation and the postmenstrual infertile period.
Nor is BBT an effective method of predicting ovulation during
postpartum lactational amenorrhea. Therefore, BBT is usually used
as a secondary indicator of ovulation and is combined with more
reliable indicators. Observed changes in cervical mucus patterns can
be used to define the probable fertile period, although this method
produces a wide range of days. The peak mucus symptom is closely
correlated with ovulation. Mucus symptoms can be used as a guide
for the timing of blood or urine samples for estimation of LH,
estrogen and progesterone or their metabolites. Symptothermal
methods incorporate other symptoms such as cervical changes,
intermenstrual pain, breast tenderness and backaches, but these are
secondary signs of ovulation and are recommended to be used in
conjunction with mucus and BBT (2).
Gallagher (3) stated that the discussion of NFP reviews the basis
of natural planning and discusses recognizing ovluation, determining
the fertile phase, achieving pregnancy, the Billings method and
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Ben-Nun Ovulation

symptothermal methods, the last early "safe" day, cervical palpation,

application of natural methods, premenopause, the post
contraceptive pill, effectiveness, continuity, and achieving autonomy.
NFP for contraception appeals to those with a strong commitment to
the ideals of marriage, who regard sexual intercourse as 1 of many
ways to express love, and who have esthetic, health, or moral
objections to other methods or found them unsuitable. NFP requires
abstinence from sexual intercourse and genital contact during
ovulation and on days before it when conditions at the cervix provide
for sperm support and migration. The art of NFP lies in the ability to
recognize the beginning and end of this fertile phase. Two signs
associated with ovulation have practical value in delineating the
fertility phase. Two signs associated with ovulation have practical
value in delineating the fertile phase of the cycle: mucus detectable
at the vulva which serves as a predictor of ovulation; and the
sustained rise in BBT after ovulation, serving as an indicator of the
occurrence of ovulation. The onset of cervical mucus is detectable at
the vulva by most women 4-7 days ahead of ovulation. The Billings
and symptothermal methods require women to observe and record
the subjective and objective features typical of estrogenic and
progestogenic mucus appearing at the vulva. Using the Billings
method the woman observes the conditions and observed by touch
or on folded toilet paper when wiping the area before and after
urinating. Rules of the method include abstinence while the woman
becomes familiar with her mucus symptom, abstinence during
menses, and restriction of intercourse to alternate nights in the
preovulatory phase. The symptothermal method employs at least 2
of the major indicators of ovulation and fertility, using the mucus
symptom and temperature shift to demarcate the fertile phase of the
cycle. Breastfeeding does not guarantee infertility but usually
provides an extended period of amenorrhea, especially when the
only source of the baby's nourishment is breast milk. Results of the
effectiveness phase of the World Health Organization 5 nation study
of the Billings ovulation method, published in 1981, included an
overall pregnancy rate of 22.6/100 woman years. The method
related pregnancy rate was 2.8%; user related rate was 19.3%; and
0.5% were in the uncertain category. The overall pregnancy rate was
7.47 with the symptothermal method. The method related
pregnancy rate was 0.93% and user rate was 6.54% (3).
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Klaus (4) focuses on the components of the fertile phase; sympto-

thermal methods; the history and methodology of NFP (calendar
rhythm, BBT, cervical mucus - the Billings Ovulation method); special
circumstances - periods of erratic ovulation (puberty, lactation,
premenopause, discontinuation of ovulation suppression, cervicitis
and vaginitis, ovulation suppression by stress and pharmaceuticals);
effectiveness of NFP; achieving pregnancy; achieving couple
autonomy (confidence in the method, periodic abstinence, dynamics
of the learning process, and support systems); problem areas; and
delivery systems. The number of users of NFP methods increased
from 2.8% of currently married couples in 1973 to 3.4% in 1976. In
1979, 75,000 new clients received training in contemporary NFP,
while the number increased to over 100,000 in 1980. NFP is planning
for achieving or preventing a pregnancy by the timing of intercourse.
A couple can, by observing and recording certain natural symptoms
and bodily changes that occur in a woman's menstrual cycle and
using the information as a guide, learn to identify fertile and infertile
phases in the menstrual cycle. Precise prediction of ovulation forms
one of the components of delineation of the fertile phase. Billings
pioneered the use of cervical mucus as a single parameter for the
prediction of ovulation and its application to NFP. Women are
instructed to observe their mucus patterns at the vulva, relying
primarily on the sensation of wetness and lubrication, the use of the
Kegel exercise, palpation with the finger, a "wipe-through" with toilet
paper, or a combination of these observations. In the absence of
ovulation, the usual changing mucus pattern is also absent. NFP can
be used either to achieve or to avoid pregnancy. When NFP is used
to avoid pregnancy, one will encounter method-related pregnancies,
teaching-related pregnancies due either to poor teaching or poor
learning or both. The major use effectiveness studies are listed in
table form, and the results are shown under new headings. To
achieve pregnancy, it is the general practice of NFP instructors to
teach women to recognize and record their fertility signs and to
suggest some months of merely concentrating coitus at the time of
maximum fertility. Mastery of NFP calls for both identification of the
fertile phase and integration of that knowledge into the couple's
sexual decision making and behaviors. Studies are reviewed in terms
of the specter of genetically damaged offspring. NFP instruction is
available in nearly every country outside the Soviet bloc (4).
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Ben-Nun Ovulation

Hume (5) mentioned early methods of NFP (calendar rhythm,

basal body temperature, and symptothermal) and dismissed as
unsatisfactory for fertility regulation at the present state of
knowledge of female reproductive physiology. Cervical mucus
patterns, which reflect ovarian hormone levels, are shown to be
accurate markers of the fertile and infertile phases of a woman's
menstrual cycle. Interpretation of these patterns forms the basis of
the Billings Ovulation Method of natural family planning. Extensive
laboratory and clinical studies have shown this method to be on a
sound scientific footing that it is applicable to all phases of a woman's
reproductive life, and that women readily understand and are able to
teach other women the meaning of these patterns as experienced by
changing sensations at the vulva and changing characteristics of any
visible mucus. The simple rules which have been formulated for
postponing and achieving pregnancy are given. Field trials of this
non-invasive method for fertility regulation in both developing and
developed countries show that the rules are readily understood by
participants. In the most recent trials, it has been shown that the
method-related pregnancy rate is less than 1 per 100 woman years,
which compares more than favorably with other contraceptive
techniques (5).
Fehring (6) noticed that calendar-based methods are not usually
considered effective or useful methods of family planning among
health professionals. However, new "high-" and "low"-tech calendar
methods have been developed, which are easy to teach, to use, and
may be useful in helping couples avoid pregnancy. The low-tech
models are based on a fixed-day calendar system. The high-tech
models are based on monitoring urinary metabolites of female
reproductive hormones. Both systems have high levels of
satisfaction. This article describes these new models of family
planning and the research on their effectiveness. The author
proposes a new algorithm for determining the fertile phase of the
menstrual cycle for either achieving or avoiding pregnancy (6).
Lolarga (7) mentioned that there is renewed interest in NFP as the
Philippine Population Program enters the 1980s. Much of this
interest is due to the realization that, properly practiced, NFP can be
a highly effective means of birth spacing. In 1978 the Special
Committee to Review the Philippine Population Program
recommended that more efforts be made to promote NFP. The
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Ben-Nun Ovulation

different methods of NFP are reviewed. Sex without intercourse,

coitus interruptus, and prolonged nursing are not officially
recognized as NFP methods by the Program. The rhythm method
was first described independently by Drs. Hermann Knaus of Austria
and Kyusaku Ogino of Japan in the 1930s. Ogino's method of
calculating a woman's fertile period is based on the lengths of the last
12 menstrual cycles which she recorded on a calendar. The
advantages of rhythm are that it is inexpensive, it requires only the
cost of charts which may be homemade, there are no physical side
effects, control is in the woman's hands, and it is acceptable to
people who consider it their duty to follow religious teachings.
Disadvantages include: keeping constant, accurate records of cycles
for long periods of time; the need for perseverance and correct
interpretation of the chart; the possible need for medical advice and
help; and the fear that something might upset a woman's cycle and
change the time of ovulation. The continuation rates of rhythm
acceptors in the Philippines are unimpressive. A study of 142 women
revealed a high pregnancy/failure rate--25% for a 12-month period
compared to 0 with oral contraception (OC) and the IUD's 2%. The
BBT method helps determine the unsafe period with some accuracy.
Its premise is that there are slight but detectable changes in a
woman's body temperature during her cycle. These changes herald
ovulation. A special thermometer must record temperature changes
of 0.1 degree Farenheit. This instrument and the charts are the only
expenses involved. The reviewers of the Philippine Population
Program noted that since the end of the unsafe period can be
indicated only by the temperature, the total period of abstinence
becomes long, although the BBT method gives more or less 10
successive days for intercourse. The cervical mucus method, also
known as the Billings method, takes into account the cervical
secretions during the menstrual cycle. Appearance of this mucus is an
indication of fertility. All that is required of a practitioner is to learn
to distinguish the different sensations of wetness and dryness. The
disadvantage is that the method becomes ineffective in areas where
there is cervicitis or infection of the cervix. The symptom thermal
method is the BBT method combined with other NFP techniques and
is widely used. With this method an accurate record of the 6
immediately preceding menstrual cycles is established. The start of
the fertile period is set by substracting 20 days plus 1. The woman
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watches for symptoms like pelvic heaviness, breast softness, and

mucus discharge (7).
Hilgers & al. (8) correlated the ovulation method of natural family
planning the "Peak" mucus symptom with the estimated time of
ovulation (ETO) and to note cyclic variations within a group of 24
women as well as in individual women. Criteria for entry into the
study were: the recording of mucus observations and oral BBTs for at
least 3 cycles, a documentation of at least 3 cycles in which biphasic
temperature curves were obtaining showing a luteal phase of at least
12 days. Serum samples were assayed for luteinizing hormone,
estradiol-17 beta, and progesterone by radioimmunoassay. ETO was
considered to have occurred during the time when the progesterone
level was between 1 ng/ml and 2.3 ng/ml. Scores characterizing the
mucus discharge were kept by the women and used for plotting the
mucus cycle in correlation with hormone levels. Of the 73 cycles
studied 65 were considered ovulatory. 64 cycles displayed a "Peak"
symptom; ovulation in these was found to occur from 3 days before
to 3 days after the "Peak" symptom; on average 0.31 days before the
"Peak" symptom. In 95.4% of the 64 cycles it was estimated to occur
from 2 days before to 2 days after the "Peak" symptom. The number
of mucus days preceding the ETO averaged 5.9 days. The cyclic
variation in correlation between the ETO and the "Peak" symptom in
the individual woman averaged 1.8 days. In 63 of the 65 normal
ovulatory cycles ETO coincided with the time of fertility as defined by
the ovulation method. The findings of this study are in agreement
with those of previous studies and would, it seems, justify future
work to further clarify the method's application and the role of
cervical mucus (8).
Spieler & Shuler (9) reviewed the current status of NFP. There is
renewed interest in NFP, and many couples who find other methods
unacceptable for medical, safety, or personal reasons are turning to
NFP methods. The percent of contraceptive users who rely on
behavioral methods in developing countries in 35% in Peru, 20%-25%
in Haiti, Philippines, and Sri Lanka, and average 7.5% for the
remaining 23 developing countries. In the U.S. about 4.7% of all
contraceptive users rely on behavioral methods. Worldwide, rhythm
is the most commonly used form of behavior fertility control, but this
method is not promoted by most NFP programs. The 3 modern
methods of NFP are 1) the BBT method, 2) the cervical mucus, or
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Ben-Nun Ovulation

Billings method, and 3) the sympto-thermal method. All these

methods rely on physical signs and symptoms to detect ovulation and
require sexual abstinence during the fertile phase of the menstrual
cycle. The BBT method requires women to detect the slight rise in
temperature which occurs at the time of ovulation. The method is
94%-97% effective if intercourse is restricted to the postovulatory
phase of the cycle. Disadvantages of the method are that intercourse
must be restricted to only 7-13 days of the cycle, women must take
their temperature daily, the method cannot be used during fever
episodes, and the method is inappropriate for use during lactation or
near menopause. The cervical mucus method is based on observing
cervical mucus changes during the cycle. These changes signal the
fertile and infertile phases of the cycle. According to a World Health
Organization study, 93% of the women instructed in the method
were able to detect mucus changes, and illiterate women were as
adept at identifying these changes as university graduates. Findings
also indicated that the method was 97% effective if abstinence was
practiced during 15 days of the cycle, but use-effectiveness was only
about 80%. This method has the advantage of not requiring
ovulatory regularity. The sympto-thermal method uses a
combination of symptoms including temperature shifts and mucus
changes to detect ovulation. Some studies indicate that the
combined method is more effective than those methods based on
only 1 symptom, but many individuals find the combined method
difficult and confusing. The advantages of NFP methods are that they
require no medical supervision and that they have no side effects.
Family planning providers often have negative attitudes toward NFP
and many programs do not provide NFP services. Many providers
maintain that the methods are ineffective and difficult to apply and
that there is little demand for NFP. Research should be undertaken
to determine if these opinions are valid. The major source of funding
for NFP programs and projects is the U.S. Agency for International
Development (USAID). The agency is currently supporting 22 NFP
projects under USAID grants and another 16 bilateral NFP programs.
The research undertaken in connection with these projects should
provide needed information on NFP advantages, disadvantages,
effectiveness, and demand (9).
Zufferey (10) compared risks of 5 NFP methods. The main risk of
these methods is the risk of pregnancy stemming from method
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failure, errors in instruction, error in application of the method, and

failure to observe abstinence during the entire fertile period. The
calendar rhythm method, the oldest NFP method, is based on
calculation of likely fertile days in the preceding 6-12 menstrual
cycles. The method is seldom taught at present because of its high
failure rate, but it continues to be used, often by individuals with an
incomplete understanding of the calculations. The principle of the
BBT method is well known. The thermal shift affirms the beginning
of the infertile period but does not allow prediction of ovulation.
Instructions provided by different organizations to identify the third
day of the hyperthermal plateau are not standardized; the various
interpretations applied to the same cycle do not necessarily lead to
identification of the same day as the start of the infertile period.
Comparisons of efficacy between methods are therefore difficult.
Well-conducted prospective studies have demonstrated high
theoretical efficacy, but failure rates in practice appear to be higher.
Women often do not know how to interpret a temperature curve
correctly, and the curve may be influenced by illness, sleeping late, a
change of life style or thermometer. Some authors have reported
that 3-20% of ovulatory cycles have monophasic temperature curves.
The temperature method requires lengthy abstinence lasting until
the third day of higher temperature, which may create conflicts in
some couples. To ease the difficulties of interpretation of the
temperature method, a Swiss architect developed an electronic
thermometer programmed according to rules of the calendar rhythm
method for cycles of 19-39 days. The woman's 6 most recent cycle
lengths remain in the memory to indicate probable infertile days.
Although no formal evaluations have appeared in the literature on
the Bioself thermometer, the method appears to entail risks
including registration of incorrect temperature due to humidity or
rundown batteries, and inadequate programming to identify the safe
period. The Billings or cervical mucus method is based on
observation by the woman of the thickness, wetness, and other
characteristics of mucus secretions in the vulva to predict ovulation.
Various studies have shown high theoretical efficacy but practical
efficacy is lower. Vaginal infections, some ovarian pathologies, and
postpartum hormonal changes are among factors that can alter
mucus patterns. The method does not confirm ovulation, and false
"peak days" may occur. The symptothermal method is based on all
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the principles of the cervical mucus and temperature methods as well

as autopalpation of the cervix and any other signs of ovulation.
Effectiveness rates are high. In general pregnancy risks are the same
as those for the cervical mucus and temperature methods. A
theoretical heightened risk of abortion or fetal malformation
common to all the methods due to fertilization of aging gametes has
not been definitively evaluated. Another possible risk results from
timing of abstinence at the phase of the menstrual cycle when the
woman's sexual desire is likely to be greatest (10).
Germano & Jennings (11) noticed that helping clients select and
use appropriate family planning methods is a basic component of
midwifery care. Many women prefer nonhormonal, nondevice
methods, and may be interested in methods that involve
understanding their natural fertility. Two new fertility awareness-
based methods, the Standard Days Method and the TwoDay Method,
meet the need for effective, easy-to-provide, easy-to-use
approaches. The Standard Days Method is appropriate for women
with most menstrual cycles between 26 and 32 days long. Women
using this method are taught to avoid unprotected intercourse on
potentially fertile days 8 through 19 of their cycles to prevent
pregnancy. They use CycleBeads, a color-coded string of beads
representing the menstrual cycle, to monitor their cycle days and
cycle lengths. The Standard Days Method is more than 95% effective
with correct use. The TwoDay Method is based on the presence or
absence of cervical secretions to identify fertile days. To use this
method, women are taught to note everyday whether they have
secretions. If they had secretions on the current day or the previous
day, they consider themselves fertile. The TwoDay Method is 96%
effective with correct use. Both methods fit well into midwifery
practice (11).
Chao (12) discussed the effect of lactation on ovulation and
fertility in relation to 7 factors: the duration of postpartum
amenorrhea, the return of ovulation in the postpartum woman, the
effect of breastfeeding on fertility, the physiologic basis for infecunity
during lactation, contraceptive use during lactation (barrier methods,
IUDs, and steroidal contraceptives), breastfeeding while pregnant,
and tandem nursing. Women who breastfeed their children have a
longer period of amenorrea and infertility following delivery than
women who do not breastfeed. The length of postpartum
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amenorrhea varies greatly and depends on several factors, including

maternal age and parity and the duration and frequency of
breastfeeding. Due to the fact that there exists such individual
variability in the duration of daily suckling, as well as the duration of
the breastfeeding period, it is not possible to define within narrow
limits the expected period of postpartum amenorrhea in lactating
women. The return of menstruation is not necessarily the result of
preceding ovulation in the postpartum woman. There is a wide range
in the reports as to the occurrence of ovulation before 1st
menstruation, ranging from 12-78%. In general, ovulation precedes
1st menstruation more frequently in those who do not nurse when
compared to those who nurse. Breastfeeding has a demonstrable
influence in inhibiting ovulation; it is not surprising that it has an
inhibiting effect on fertility. According to Perez, during the first 3
months when a woman is nursing, there is higher security provided
against conception than most contraceptives. After that time, the
effect on fertility becomes uncertain and is determined by the
frequency and duration of suckling and the time interval from
delivery, and possibly maternal age, parity, nutrition. The physiologic
basis for lactation infertility is not completely understood. During
pregnancy, the level of circulating prolactin is greatly elevated. The
elevated blood levels of prolactin begin at 8 weeks and rise to levels
of 200 ng per ml at term. In lactating women, prolactin levels stay
elevated, with spikes of increased secretion during and following
suckling. The evidence points strongly to the fact that persistent
hyperprolactinemia caused by breastfeeding postpartum results in an
anovulatory or oligo-ovulatory state, and this results in relative
infertility. It is appropriate to suggest other contraceptive methods
to women who want to delay subsequent pregnancy because
lactation alone is unreliable in preventing conception after the 9th
week postpartum. There appears to be no contraindications to the
use of the vaginal diaphragm or condom while breastfeeding. A
report of added risk of uterine perforation in lactating women
requires confirmation. The use of steroidal contraceptives while
breastfeeding remains controversial (12).

This chapter (1-12) demonstrates various strategies of the natural

family planning methods.
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References
1. Davis MS. Natural family planning. NAACOGS Clin Issu Perinat
Womens Health Nurs. 1992;3(2):280-90.
2. Gross BA. Natural family planning indicators of ovulation. Clin
Reprod Fertil. 1987;5(3):91-117.
3. Gallagher J. More about natural family planning. Aust Fam
Physician. 1983;12(11):786-92.
4. Klaus H. Natural family planning: a review. Obstet Gynecol Surv.
1982;37(2):128-50.
5. Hume K. Fertility awareness in the 1990s - the Billings Ovulation
Method of natural family planning, its scientific basis, practical application
and effectiveness. Adv Contracept. 1991;7(2-3):301-11.
6. Fehring RJ. New low- and high-tech calendar methods of family
planning. J Midwifery Womens Health. 2005;50(1):31-8.
7. Lolarga E. A second look at natural family planning. Initiatives
Popul. 1983;7(1):2-12.
8. Hilgers TW, Abraham GE, Cavanagh D. Natural family planning. I.
The peak symptom and estimated time of ovulation. Obstet Gynecol.
1978;52(5):575-82.
9. Spieler J, Shuler A. Natural family planning in 1985: a status report.
Popul Today. 1985;13(5):3, 9.
10. Zufferey MM. The risks of the natural family planning methods.
Ther Umsch. 1986;43(5):417-24.
11. Germano E, Jennings V. New approaches to fertility awareness-
based methods: incorporating the standard days and twoday methods into
practice. J Midwifery Womens Health. 2006;51(6):471-7. Erratum in:J
Midwifery Womens Health. 2017.
12. Chao S. The effect of lactation on ovulation and fertility. Clin
Perinatol. 1987;14(1):39-50.

DISORDERS OF OVULATION
INSUFFICIENCY/FAILURE
Laven (1) mentioned that primary ovarian insufficiency (POI), also
known as premature ovarian failure or premature menopause, is
defined as cessation of menstruation before the expected age of
menopause. Potential etiologies for POI can be divided into genetic,
autoimmune, and iatrogenic categories. This review will try to
summarize the genetic basis of POI focusing on recent data that are
available using newer genetic techniques such as genome-wide
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association studies, whole-exome sequencing (WES), or next-

generation sequencing techniques. By using these techniques, many
genes have arisen that play some role in the pathophysiology of POI.
Some of them have been replicated in other studies; however, the
majority has not been proven yet to be unequivocally causative
through functional validation studies. Elucidating the genetic and
molecular basis of POI is of paramount importance not only in
understanding ovarian physiology but also in providing genetic
counseling and fertility guidance. Once additional variants are
detected, it might become possible to predict the age of (premature)
menopause in women at risk for POI. Women having certain
perturbations of POI can be offered the option of oocyte
cryopreservation, with later thawing and use in assisted reproductive
technology at an appropriate age (1).
Rebar (2) noticed that amenorrhea with hypergonadotropinism
consists of several distinct disorders. Affected individuals should be
investigated thoroughly and not merely told they have ovarian
failure. Accumulating evidence suggests that some women with
"premature ovarian failure" do indeed ovulate again and even
conceive. Thus, elevated levels of circulating gonadotropins can no
longer be regarded as establishing that the ovaries are devoid of all
oocytes. Delineation of all of the causes of hypergonadotropic
amenorrhea and the establishment of rational means of inducing
ovulation in women with follicles remaining are clearly tasks for
present and future investigations (2).
Aiman & Smentek (3) reported that the diagnosis of premature
ovarian failure was made in 35 women (ages 17 to 40) with increased
concentrations of follicle-stimulating hormone and luteinizing
hormone. Three had primary amenorrhea, 29 had secondary
amenorrhea (less than one to 15 years), and three had irregular
menstrual intervals of less than six months. Symptoms and signs of
estrogen deficiency were present in fewer than 50% of these women
and were not helpful in distinguishing the different causes of ovarian
failure. Six of these women had an autoimmune disorder associated
with ovarian failure. Thirteen of 16 women had a normal 46,XX
karyotype, and five of 14 women who had an ovarian biopsy had a
specimen that contained follicles with oocytes. Two women
conceived after they developed ovarian failure and while taking cyclic
estrogen and progestin (3).
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Christin-Maitre & Braham (4) mentioned that premature ovarian

failure (POF) is defined as the cessation of ovarian function under the
age of 40 years. It is characterized by primary or secondary
amenorrhea for at least four months, sex steroid deficiency and
elevated serum gonadotropin concentrations. The diagnosis is
confirmed by the detection of menopausal Follicle Stimulating
Hormone (FSH) levels on at least two occasions a few weeks apart in
a woman before the age of 40. It occurs in 1/10,000 in women below
the age of 20, 1/1,000 below 30 and 1% in women before the age of
40. The classic etiologies are Turner syndrome, pelvic surgery,
radiotherapy or chemotherapy. Although new genetic etiologies
have been found in the past 10 years, the cause of POF is unknown in
more than 75% of cases. Hormone replacement therapy should be
administered in order to avoid vascular diseases and osteoporosis.
For infertility, the most successful treatment remains assisted
conception with donated oocytes (4).
Goswami & Conway (5) revealed that the diagnosis of POF is
based on the finding of amenorrhea before age 40 associated with
follicle-stimulating hormone levels in the menopausal range.
Screening for associated autoimmune disorders and karyotyping,
particularly in early onset disease, constitute part of the diagnostic
work up. There is no role for ovarian biopsy or ultrasound in making
the diagnosis. Management essentially involves hormone
replacement and infertility treatment, the most successful being
assisted conception with donated oocytes. Embryo cryopreservation,
ovarian tissue or oocyte cryopreservation and in vitro maturation of
oocytes hold promise in cases where ovarian failure is foreseeable as
in women undergoing cancer treatments (5).
Kalu & Panay (6) noticed that POF generally describes a syndrome
consisting of amenorrhea, sex steroid deficiency, and
elevated/menopausal levels of gonadotropins in a woman aged more
than two standard deviations below the mean age at menopause
estimated for the reference population. Numerous questions
relating to this condition remain unanswered, and several important
management issues are yet to be addressed. The challenges posed by
this important condition range from difficulties with nomenclature to
the absence of standardized diagnostic criteria and management
guidelines. In the present paper the management of spontaneous
premature ovarian failure was discussed, the challenging issues were
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highlighted, the current literature was reviewed and a practical

management outline based on the local practice was proposed.
Women with POF have unique needs that require special attention.
There is an urgent need for a more suitable terminology and
evidence-based guidelines on which to establish the diagnosis and
manage this difficult condition (6).
Vilodre (7) reported that POF occurs in approximately 1:1000
women before 30 years, 1:250 by 35 years and 1:100 by the age of
40. It is characterized by primary or secondary amenorrhea and
cannot be considered as definitive because spontaneous conception
may occur in 5 to 10% of cases. In 95% of cases, POF is sporadic. The
known causes of POF include chromosomal defects, autoimmune
diseases, exposure to radiation or chemotherapy, surgical
procedures, and certain drugs. Frequently, however, the etiology is
not clear and these cases are considered to be idiopathic. POF is
defined by gonadal failure and high serum FSH levels. Clinical
approach includes emotional support, hormonal therapy with
estrogens and progesterone or progestogens, infertility treatment,
and prevention of osteoporosis and potential cardiovascular risk (7).
Rudnicka & al. (8) mentioned that premature ovarian
insufficiency (POI) is defined as a cessation of ovarian function before
the age of 40 years. It is associated with hypoestrogenism and loss of
residual follicles, both of which lead to menstrual abnormalities,
pregnancy failures, and decreased health-related quality of life. The
prevalence of POI is estimated at 1% in the general population.
Current European Society of Human Reproduction and Embryology
(ESHRE) diagnostic criteria include: amenorrhoea or oligomenorrhoea
for at least four months and increased follicle-stimulating hormone
(FSH) levels > 25 IU/l measured twice (with a four-week interval).
The aetiopathogenesis of the disease in most cases remains
unexplained. Nevertheless, in some patients with POI, genetic
abnormalities, metabolic disorders, autoimmunity, iatrogenic
procedures, infections, or environmental factors have been
established as underlying causes of the syndrome (8).
Kodaman (9) noticed that early menopause, whether a
consequence of primary ovarian insufficiency or resulting from
surgical removal of gonads in a premenopausal woman, offers unique
health-related challenges. Premature deprivation of sex steroids sets
into motion a cascade of events that preferentially target urogenital,
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skeletal, cardiovascular, and neurocognitive systems, and culminate

in global health deterioration in a chronologically younger population
of women compared with those undergoing age-appropriate,
NATURAL menopause. Overtly, menopausal symptoms may be
shared between those experiencing early menopause versus those
undergoing a natural attrition of their reproductive physiology.
Extrapolation of concerns emanating from recent randomized trials
of menopausal hormone therapy may not be applicable to young
women experiencing early menopause, however, and estrogen
replacement remains a mainstay in the clinical management of this
population (9).

References
1. Laven JS. Primary Ovarian Insufficiency. Semin Reprod Med. 2016;
34(4):230-4.
2. Rebar RW. Hypergonadotropic amenorrhea and premature ovarian
failure: a review. J Reprod Med. 1982;27(4):179-86.
3. Aiman J, Smentek C. Premature ovarian failure. Obstet Gynecol.
1985;66(1):9-14.
4. Christin-Maitre S, Braham R. General mechanisms of premature
ovarian failure and clinical check-up. Gynecol Obstet Fertil. 2008;
36(9):857-61.
5. Goswami D, Conway GS. Premature ovarian failure. Horm Res.
2007;68(4):196-202.
6. Kalu E, Panay N. Spontaneous premature ovarian failure:
management challenges. Gynecol Endocrinol. 2008;24(5):273-9.
7. Vilodre LC, Moretto M, Kohek MB, Spritzer PM. Premature ovarian
failure: present aspects. Arq Bras Endocrinol Metabol. 2007; 51(6):920-9.
8. Rudnicka E, Kruszewska J, Klicka K, et al. Premature ovarian
insufficiency - aetiopathology, epidemiology, and diagnostic evaluation.
Prz Menopauzalny. 2018;17(3):105-8.
9. Kodaman PH. Early menopause: primary ovarian insufficiency and
surgical menopause. Semin Reprod Med. 2010;28(5):360-9.

AGING OVARY
Szafarowska & Jerzak (1) mentioned that the biological state of
the ovum remains the key element in normal reproduction. Age-
related decrease in the number of oocytes, as well as disturbed
neuroendocrine function of the ovary and lesions in the uterus,
contribute to reduced fertility. Decreasing number of ovarian
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follicles is accompanied by reduction of their quality including mainly

abnormalities of the nucleus (dispersed chromatin, decondensation
of chromosomes and abnormalities connected with the spindle
apparatus). This results in failed reproduction due to abnormal
gametogenesis, fertilization process, early development of the
embryo and abnormal implantation. This work describes age-related
biochemical mechanisms conditioning molecular changes occurring
due to abnormal microenvironment of the ovary; their accumulation
leads to aging and to a more rapid apoptosis of the oocyte. There are
many theories explaining the causes of oocyte destruction, including
abnormal vascularization, oxidative stress, imbalance of free radicals,
influence of toxic compounds and genetic changes. Decreased blood
perfusion in the microenvironment of a maturating ovum leads to
hypoxia and thus to a chain of reactions of oxidative stress. Oxidative
imbalance leads to abnormalities of cellular biomolecules. it is
suggested that glycation processes in a cell, leading to the formation
of compounds called AGEs (Advanced Glycation End Products), are
also responsible for aging of the cells. They contribute directly to
protein damage, induce a chain of reactions of oxidative stress, and
increase the inflammatory reactions. The role of mitochondria and
telomeres in the aging process and loss of reproductive functions has
been especially underscored. This work stresses the prognostic value
of clinically used markers evaluating the ovarian reserve. The role of
Anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH),
estradiol, inhibin B and antral follicle count (AFC) was presented in
this paper (1).
Pertynska-Marczewska & Diamanti-Kandarakis (2) mentioned
that the hypothalamic gonadotropin-releasing hormone pulse
generator, the pituitary gonadotropes, the ovaries, and the uterus
play a crucial role in female fertility. A decline in reproductive
performance represents a complex interplay of actions at all levels of
the hypothalamic-pituitary-ovarian axis. Recently, in the field of
female reproductive aging attention is drawn to the carbonyl stress
theory. Advanced glycation end products (AGEs) contribute directly
to protein damage, induce a chain of oxidative stress (OS) reactions,
and increase inflammatory reactions. Here, some of the mechanisms
underlying glycation damage in the ovary were highlighted. Searches
of electronic databases were performed. Articles relevant to possible
role of OS, AGEs, and receptor for AGE (RAGE) in aging ovary were
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summarized in this interpretive literature review. Follicular

microenvironment undergoes an increase in OS with aging. Data
support the role of OS in ovulatory dysfunction because AGEs are
well-recognized mediators of increased OS. RAGE and AGE-modified
proteins with activated nuclear factor-kappa B are expressed in
human ovarian tissue. It was suggested that accumulation of AGEs
products at the level of the ovarian follicle might trigger early ovarian
aging or could be responsible for reduced glucose uptake by
granulosa cells, potentially altering follicular growth. Impaired
methylglyoxal detoxification causing relevant damage to the ovarian
proteome might be one of the mechanisms underlying reproductive
aging. Further investigation of the role for the AGE-RAGE axis in the
ovarian follicular environment is needed, and results could relate to
assisted reproduction technology outcomes and new measures of
ovarian reserve (2).

References
1. Szafarowska M, Jerzak M. Ovarian aging and infertility. Ginekol Pol.
2013;84(4):298-304.
2. Pertynska-Marczewska M, Diamanti-Kandarakis E. Aging ovary and
the role for advanced glycation end products. Menopause.
2017;24(3):345-51.

OVERWEIGHT WOMEN
Sasaki & al. (1) revealed that obesity is one of the extra
hypothalamic-pituitary-ovarian axis factors that can influence
ovulation. The isolated impact of obesity on ovulation without other
comorbidities needs to be further studied. The goal is to evaluate the
association between the anovulation in the ultrasonographic
monitoring of the ovulation cycle and the body mass increase of
infertile patients without polycystic ovaries of a university service.
Case-control study performed at the Human Reproduction
Laboratory of the University Hospital. Totally, 1,356 ultrasound
monitoring reports of ovulation were evaluated between January
2011 and December 2015. Those patients who ovulated on the
monitored cycle were named case. After applying the exclusion
criteria, a total of 110 cases and 118 controls were consolidated. The
exposure variables were normal BMI or patients classified with a BMI
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above normal. The groups were comparable in age, age at

menarche, number of pregnancies, deliveries, cesarean sections and
abortions, number of antral follicles, FSH, prolactin and TSH values.
Among the anovulatory patients, 57 (51.82%) were overweight, while
among ovulatory patients, 44 (37.29%) were in this same BMI
category. The odds ratio was 1.8655, with a significant p value
(p<0.05). The data show that there was an association between
anovulation and increase in the Body Mass Index, with an increased
risk of anovulation in patients with BMI above normal (1).

Reference
1. Sasaki RSA, Approbato MS, Maia MCS, et al. Ovulatory status of
overweight women without polycystic ovary syndrome. JBRA Assist
Reprod. 2019;23(1):2-6.

POLYCYSTIC OVARY SYNDROME

Marciniak & al. (1) reported that Polycystic Ovary Syndrome
(PCOS) is a complex endocrine disorder, affecting 5-10% women of
reproductive age. It is one of the most common causes of functional
infertility and a clinical problem that can be faced by doctors of many
specialities. PCOS is characterized by hyperandrogenism,
oligoovulations and metabolic disorders. ESHRE/ASRM (2003) or AES
(2006) criteria are used to diagnose a patient with polycystic ovary
syndrome. Although a lot of studies are carried out, ethiology and
pathogenesis of PCOS is still not clear. The treatment must be long-
term, causal and depending on the patient's expectations. The
fundamental part of the therapy are lifestyle modifications and
weight loss. Losing as little as 5% of body mass increases frequency of
ovulations, chances of pregnancy and improves hormonal profile.
First-line therapy is clomiphene citrate and for hyperandrogenism
reduction combined oral contraceptive pill is frequently used.
Metformin, not only improves carbohydrate metabolism, but also
increases ovulations' frequency and chances of pregnancy.
Metabolic syndrome, diabetes mellitus type 2, hypertension and
higher risk of endometrial cancer are characteristic for patients with
PCOS (1).
Azziz & al. (2) mentioned that PCOS affects 5-20% of women of
reproductive age worldwide. The condition is characterized by
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hyperandrogenism, ovulatory dysfunction and polycystic ovarian

morphology (PCOM) - with excessive androgen production by the
ovaries being a key feature of PCOS. Metabolic dysfunction
characterized by insulin resistance and compensatory
hyperinsulinaemia is evident in the vast majority of affected
individuals. PCOS increases the risk for type 2 diabetes mellitus,
gestational diabetes and other pregnancy-related complications,
venous thromboembolism, cerebrovascular and cardiovascular
events and endometrial cancer. PCOS is a diagnosis of exclusion,
based primarily on the presence of hyperandrogenism, ovulatory
dysfunction and PCOM. Treatment should be tailored to the
complaints and needs of the patient and involves targeting metabolic
abnormalities through lifestyle changes, medication and potentially
surgery for the prevention and management of excess weight,
androgen suppression and/or blockade, endometrial protection,
reproductive therapy and the detection and treatment of
psychological features. This Primer summarizes the current state of
knowledge regarding the epidemiology, mechanisms and
pathophysiology, diagnosis, screening and prevention, management
and future investigational directions of the disorder (2).
Franks & al. (3) found that with the use of pelvic ultrasound
imaging more than half of the women presenting to the clinic with
ovulatory disturbances have polycystic ovaries. As a group hirsutism
is common, the serum LH, the LH:FSH ratio and serum androgen
levels are higher than in other groups of patients with anovulation,
but many of the women studied were non-hirsute and had normal
levels of these hormones. The etiology of PCOS remains obscure and
there is probably more than one cause. Disturbance of
hypothalamic/pituitary, ovarian or adrenal function could all result in
the development of polycystic ovaries. The own data, based on
pelvic ultrasound and measurement of serum androgen levels,
suggest that an ovarian abnormality, other than the obvious
morphological one, may be identified in most women although this
does not prove (except perhaps in those women with unilateral
PCOS) that the ovary is the primary site of the disturbance.
Management of ovulatory disturbances includes symptomatic
treatment of dysfunctional uterine bleeding and induction of
ovulation. Although the ovulation rate following clomiphene is
quoted as about 75%, this is probably an overestimate; less than half
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the 'ovulators' become pregnant and in those who do there is a high

risk of early pregnancy loss. Induction of ovulation in clomiphene
non-responders remains a difficult problem. The results of ovarian
wedge resection are variable and any beneficial effect is short-lived
with the risk of long-term infertility due to pelvic adhesions.
Laparoscopic electrocautery may be a useful alternative, but it is too
early to assess this form of treatment. Of the medical methods of
ovulation induction in clomiphene non-responders, two methods
have emerged as being highly promising: the first is administration of
HMG following suppression of the pituitary by an LH-RH analogue; so
far only a very small number of patients have been treated. The
second is low-dose (3).

References
1. Marciniak A, Lejman-Larysz K, Nawrocka-Rutkowska J, et al.
Polycystic ovary syndrome - current state of knowledge. Pol Merkur
Lekarski. 2018;44(264):296-301.
2. Azziz R, Carmina E, Chen Z, et al. Polycystic ovary syndrome. Nat
Rev Dis Primers. 2016 Aug 11;2:16057.
3. Franks S, Adams J, Mason H, Polson D. Ovulatory disorders in
women with polycystic ovary syndrome. Clin Obstet Gynaecol.
1985;12(3):605-32.

AUTOIMMUNE OVARY
Tatarchuk & al. (1) ascertained the influence of AІТ on the
formation of autoimmune damage to ovaries by determining the
connections between the levels of AOAB, ATPO, gonadotropic and
sex hormone levels, and the functional state of the ovaries and
thyroid gland. Totally, 198 girls age 10-18 were studied: 166 with AIT
(AIT+ Group), и 32- without AIT (the AIT- Group). A defined
difference between TTH and ATPO was revealed, which is explained
by the presence of thyroid pathology in the AIT+ Group. Prolactin
levels and ovarian volume were notably higher, while Progesterone
levels were lower in the AIT+ Group. No discernable differences
among levels of AOAB, sex hormones, Estrogen, Testosterone or
antral follicules were observed. A direct correlation was revealed
between AOAB levels and the girls' age both in the AIT+ and AIT-
groups. AOAB data was divided into three tertials in order to study
links with various hormonal homeostasis. Analysis of data obtained
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showed numerous correlative links between ATPO, AOAB,

gonadotropins, sex hormones, TTH and ovarian volume in all tertials
of both the AIT+ and AIT- groups; correlative links were found, too,
between AOAB and ATPO in the III tertial groups AIT+ and AIT-. In
adolescents with AIT disbalance occurs at all levels of hormonal
homeostasis as well as in ovarian structure. Such changes and the
presence of ATPO and AOAB may be associated with emerging
autoimmune ovary damage (1).

Reference
1. Tatarchuk T, Zakharenko N, Bachynska I, Kosey N. On the issue of
autoimmune ovary damage during puberty. Georgian Med News.
2018;(279):49-56.

PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

Mayorga & al. (1) estimated the prevalence of premature ovarian
failure (POF) and its associated factors in patients with systemic lupus
erythematosus (SLE). Cross-sectional study including consecutive SLE
women <60 years of age attending a rheumatology clinic. A face-to-
face interview was undertaken to obtain demographic, gynecological
and lupus characteristics. Additional rheumatologic and endocrine
data were retrieved from patients' medical records. POF prevalence
was estimated in the study sample and in a subgroup of patients
aged <40 years at interview. Associations between POF and selected
variables were assessed by logistic regression analyses. A total of 961
patients were analyzed. Prevalence of POF, secondary amenorrhea
of known cause, menopause and hysterectomy were 5.4%, 0.8%,
7.8% and 4.4%, respectively. In 674 (70%) patients who had not been
exposed to cyclophosphamide (CYC) the prevalence of POF was 0.6%.
Disease activity over time (OR 1.4; 95% CI 1.0-1.8, p < 0.05)) and CYC
treatment (OR 5.9 (95%; CI 1.8-18.8, p < 0.01)) were associated with
higher prevalence. Association between POF and endocrine
autoimmune diseases was not found. In the absence of CYC
treatment, the prevalence of POF in lupus patients is consistent with
that reported in the general population. The existence of
autoimmune processes at the ovary seems unlikely in most lupus
patients (1).
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Reference
1. Mayorga J, Alpízar-Rodríguez D, Prieto-Padilla J, et al. Prevalence of
premature ovarian failure in patients with systemic lupus erythematosus.
Lupus. 2016;25(7):675-83.

CHEMOTHERAPY
Cui & al. (1) mentioned that alkylating chemotherapy is often
used to treat pre-menopausal women for various malignancies and
autoimmune diseases. Chemotherapy-associated ovarian failure is a
potential consequence of this treatment which can cause infertility,
and increases the risk of other long term adverse health sequelae.
Randomized trials, predominantly of women undergoing alkylating
chemotherapy for breast cancer, have shown evidence for the
efficacy of gonadotropin-releasing hormone agonists (GnRHa) in
preventing chemotherapy-associated ovarian failure. The European
St Gallen and United States National Comprehensive Cancer Network
guidelines recommend the use of concurrent GnRHa to reduce the
risk of ovarian failure for pre-menopausal women undergoing
chemotherapy for breast cancer. The GnRHa goserelin, a monthly 3.6
mg depot subcutaneous injection, has recently been listed on the
Australian Pharmaceutical Benefits Scheme to reduce risk of ovarian
failure for pre-menopausal women receiving alkylating therapies for
malignancy or autoimmune disease. The first dose of goserelin
should ideally be administered at least 1 week before
commencement of alkylating treatment and continued 4-weekly
during chemotherapy. Concurrent goserelin use should now be
considered for all pre-menopausal women due to commence
alkylating chemotherapy (except those with incurable cancer),
regardless of their childbearing status, in an effort to preserve their
ovarian function. For women who have not completed childbearing,
consideration of other fertility preservation options, such as
cryopreservation of embryos or oocytes, is also important (1).

Reference
1. Cui W, Stern C, Hickey M, et al. Preventing ovarian failure associated
with chemotherapy. Med J Aust. 2018;209(9):412-416.
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GENETIC ASPECTS
Cordts & al. (1) mentioned that the diagnosis of premature
ovarian failure (POF) is based on the finding of amenorrhea before
the age of 40 years associated with follicle-stimulating hormone
levels in the menopausal range. It is a heterogeneous disorder
affecting approximately 1% of women <40 years, 1:10,000 women by
age 20 years and 1:1,000 women by age 30 years. POF is generally
characterized by low levels of gonadal hormones (estrogens and
inhibins) and high levels of gonadotropins (Luteinizing hormone [LH]
and Follicle Stimulating Hormone [FSH] (hypergonadotropic
amenorrhea). Review of significant articles regarding genetic causes
that are associated with POF was conducted. Heterogeneity of POF is
reflected by a variety of possible causes, including autoimmunity,
toxics, drugs, as well as genetic defects. Changes at a single
autosomal locus and many X-linked loci have been implicated in
women with POF. X chromosome abnormalities (e.g., Turner
syndrome) represent the major cause of primary amenorrhea
associated with ovarian dysgenesis. Many genes have been involved
in POF development, among them BMP15, FMR1, FMR2, LHR, FSHR,
INHA, FOXL2, FOXO3, ERα, SF1, ERβ and CYP19A1 genes. The data
show that despite the description of several candidate genes, the
cause of POF remains undetermined in the vast majority of cases (1).
Meczekalski & Podfigurna-Stopa (2) defined POF as a primary
ovarian insufficiency before the age of 40 years. It is characterized by
a cessation of menstruation for at least 4 months associated with the
elevation of serum FSH concentration (FSH>40 IU/L). It affects
approximately 1% of women under 40. Known causes of premature
ovarian failure can be classified as genetic, autoimmune,
environmental, iatrogenic (after chemotherapy, radiations, surgery)
and idiopathic. It is estimated that up to 40% of POF can be
attributed to genetic causes. Classification of genetic causes can be
different. Review of genetic causes of POF based on classification is
presented: non-syndromic POF and syndromic causes of POF. The list
of the candidate genes related to POF is still increasing. Elucidation
of genetic determination of POF has a critical significance for
identification the possible marker of POF or possible new kind of POF
therapy (2).
Ledig & al. (3) mentioned POF is a heterogeneous group of
disorders with amenorrhea and high serum gonadotropins in women
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of less than 40 years. Ovarian dysgenesis (OD) which is characterised

by the loss of follicles before puberty describes the most severe POF
outcome. Although a multitude of different factors including non-
genetic as well as genetic causes are known to play a role in the
development of POF and OD, the underlying etiology remains
unsolved in the majority of cases. In the last years, array-CGH was
found to be a very useful tool in the identification of candidate genes
in different conditions. Therefore, array-CGH analysis was performed
by using high-resolution Agilent oligonucleotide arrays in a total of 74
POF and OD patients and identified 44 private losses and gains
potentially causative for POF. It is striking to note that a lot of the
genes involved in these rearrangements can be classified in 1] genes
involved in meiosis (e.g. PLCB1, RB1CC1, MAP4K4), 2] genes involved
in DNA repair (e.g. RBBP8) and 3] genes involved in folliculogenesis or
male fertility in homologs of model organisms (e.g. IMMP2L, FER1L6,
MEIG1) (3).
Orlandini & al. (4) defined premature ovarian insufficiency (POI)
by the presence of primary or secondary amenorrhea, for at least 4
months, before the age of 40 years associated with follicle
stimulating homone levels in menopausal range, exciding 40 UI/L.
The diagnosis is confirmed by two blood sample at least 1 month to
measure the level of FSH (over 40 UI/L) and level of estradiol (below
50 pmol/L). Ovarian follicular dysfunction and/or depletion of
functional primordial follicles characterized this pathology. Abnormal
bleeding patterns also include oligomenrrhea and polimenorrhea;
because of these irregular menstrual cycles during adolescence,
diagnosis could be difficult in young women. Excluding the cases in
which an etiopathogenetic agent could be identified, such as in case
of chemio- and radiotherapy or extensive surgery, women with
autoimmune diseases and/or infections, the etiology of POI remains
idiopathic. An important genetic component exists, supported by
both a frequent recurring familiar event (20-30%) and the association
with other different genetic disorders in particular the X chromosome
defects and the implication of some different genes with significant
functions in ovarian development. For most of the women the
diagnosis of POI is unexpected because of there are no obvious signs
or symptoms that precede the cessation of periods with a normal
menstrual history, age of menarche and fertility prior to the onset of
menopause. The diagnosis of POI has a deleterious psychological
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impact on the emotional sphere of the women affected: anger,

depression, anxiety and sadness are common and the fact that the
diagnosis coincides with infertility needs a psychological support.
Oral hormonal replacement therapy (HRT) administration is not
recommended as first choice of treatment because of the higher
hormones concentration with respect to the real hormones necessity
of the patients and transdermal HRT may be preferred in women
with coagulation disturbances to relief symptoms and to improve to
quality of life and the sexuality of these women until the age of 50
years old which is the median age of physiological menopause.
Moreover it should be considered the associate comorbidities of POI
such as bone loss, cardiovascular disease and endocrine disease (4).

This chapter (1-4) describes disorders of ovulation including

insufficiency or ovary failure, aging ovary, autoimmune diseases,
chemotherapy and genetic aspects.
In the Bible, Lot's daughters successfully conceived so there is no
reason to suspect they suffered from any kind of ovulatory disorder.

References
1. Cordts EB, Christofolini DM, Dos Santos AA, et al. Genetic aspects of
premature ovarian failure: a literature review. Arch Gynecol Obstet.
2011;283(3):635-43.
2. Meczekalski B, Podfigurna-Stopa A. Genetics of premature ovarian
failure. Minerva Endocrinol. 2010;35(4):195-209.
3. Ledig S, Röpke A, Wieacker P. Copy number variants in premature
ovarian failure and ovarian dysgenesis. Sex Dev. 2010; 4(4-5):225-32.
4. Orlandini C, Regini C, Vellucci FL, et al. Genes involved in the
pathogenesis of premature ovarian insufficiency. Minerva Ginecol.
2015;67(5):421-30.

MANAGEMENT
Torrealday & al. (1) mentioned that premature ovarian
insufficiency (POI) is a complex and relatively poorly understood
entity with a myriad of etiologies and multisystem sequelae that
stem from premature deprivation of ovarian sex hormones. Timely
diagnosis with a clear understanding of the various comorbidities
that can arise from estrogen deficiency is vital to appropriately
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counsel and treat these patients. Prompt initiation of hormone

therapy is critical to control the unsolicited menopausal symptoms
that many women experience and to prevent long-term health
complications. Despite ongoing efforts at improving the
understanding of the mechanisms involved, any advancement in the
field in recent decades has been modest at best and researchers
remain thwarted by the complexity and heterogeneity of the
underpinnings of this entity. In contrast, the practice of clinical
medicine has made meaningful strides in providing assurance to the
women with POI that their quality of life as well as long-term health
can be optimized through timely intervention. Ongoing research is
clearly needed to allow pre-emptive identification of the at-risk
population and to identify mechanisms that if addressed in a timely
manner, can prolong ovarian function and physiology (1).
Luisi & al. (2) reported that POI represents a condition
characterized by the absence of normal ovarian function due to an
incipient (by 3-10 years) ovarian aging. In most of the women
affected there are no signs or symptoms that precede the
interruption of menstruation and the onset of POI and the majority
of women have a normal history of menarche, regular menstrual
cycles and normal fertility. The possible genetic role in the
development of POI has been largely demonstrated and many genes
have been involved; on the other hand, ovary is not protected
immunologically and the detection of autoantibodies directed against
various ovarian targets strongly support the hypothesis of an
autoimmune etiology. In approximately 5-10% of women with a
diagnosis of POI with a normal karyotype, a spontaneous pregnancy
could occur even if the recovery of ovarian function is temporary and
poorly predictable. Embryo donation and adoption are other
alternatives that should be considered. POI and subsequent loss of
reproductive capacity is a devastating condition and a difficult
diagnosis for women to accept so it requires an individualized and a
multidisciplinary approach. Hormonal replacement therapy (HRT)
should be commenced as soon as possible to prevent and to contrast
the onset of the symptoms related to hypoestrogenism and to
improve the quality of life for these women (2).
Hakimi & Cameron (3) mentioned that infertility has been
described as a devastating life crisis for couples, and has a
particularly severe effect on women, in terms of anxiety and
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depression. Anovulation accounts for around 30% of female

infertility, and while lifestyle factors such as physical activity are
known to be important, the relationship between exercise and
ovulation is multi-factorial and complex, and to date there are no
clear recommendations concerning exercise regimes. The objective
of this review was to systematically assess the effect of physical
activity on ovulation and to discuss the possible mechanisms by
which exercise acts to modulate ovulation in reproductive-age
women. This was done with a view to improve existing guidelines for
women wishing to conceive, as well as women suffering from
anovulatory infertility. The published literature was searched up to
April 2016 using the search terms ovulation, anovulatory, fertility,
sport, physical activity and exercise. Both observational and
interventional studies were considered, as well as studies that
combined exercise with diet. Case studies and articles that did not
report anovulation/ovulation or ovarian morphology as outcomes
were excluded. Studies involving administered drugs in addition to
exercise were excluded. In total, ten interventions and four
observational cohort studies were deemed relevant. Cohort studies
showed that there is an increased risk of anovulation in extremely
heavy exercisers (>60 min/day), but vigorous exercise of 30-60
min/day was associated with reduced risk of anovulatory infertility.
Ten interventions were identified, and of these three have studied
the effect of vigorous exercise on ovulation in healthy, ovulating
women, but only one showed a significant disruption of ovulation as
a result. Seven studies have investigated the effect of exercise on
overweight/obese women suffering from polycystic ovary syndrome
(PCOS) or anovulatory infertility, showing that exercise, with or
without diet, can lead to resumption of ovulation. The mechanism by
which exercise affects ovulation is most probably via modulation of
the hypothalamic-pituitary-gonadal (HPG) axis due to increased
activity of the hypothalamic-pituitary-adrenal (HPA) axis. In heavy
exercisers and/or underweight women, an energy drain, low leptin
and fluctuating opioids caused by excess exercise have been
implicated in HPA dysfunction. In overweight and obese women
(with or without PCOS), exercise contributed to lower insulin and free
androgen levels, leading to the restoration of HPA regulation of
ovulation. Several clear gaps have been identified in the existing
literature. Short-term studies of over-training have not always
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produced the disturbance to ovulation identified in the observational

studies, bringing up the question of the roles of longer term training
and chronic energy deficit. This merits further investigation in
specific cohorts, such as professional athletes. Another gap is the
complete absence of exercise-based interventions in anovulatory
women with a normal body mass index (BMI). The possibly
unjustified focus on weight loss rather than the exercise program
means there is also a lack of studies comparing types of physical
activity, intensity and settings. These gaps are delaying an efficient
and effective use of exercise as a therapeutic modality to treat
anovulatory infertility (3).
Chae-Kim & Gavrilova-Jordan (4) stated that POI is the loss of
normal hormonal and reproductive function of ovaries in women
before age 40 as the result of premature depletion of oocytes. The
incidence of POI increases with age in reproductive-aged women, and
it is highest in women by the age of 40 years. Reproductive function
and the ability to have children is a defining factor in quality of life for
many women. There are several methods of fertility preservation
available to women with POI. Procreative management and
preventive strategies for women with or at risk for POI are reviewed
(4).
Huang & al. (5) noticed that POI is a difficult-to-treat
gynecological disorder with complex etiologies. Although
acupuncture has gained increased popularity for the management of
POI, evidence regarding its efficacy is lacking. This systematic review
protocol aims to describe a meta-analysis to assess the effectiveness
and safety of acupuncture for patients with POI. The following 10
databases will be searched from the publishment to July 2019:
PubMed, Embase, the Web of Science, the Cochrane Central Register
of Controlled Trials, 4 Chinese databases (China National Knowledge
Infrastructure, Wanfang Digital Periodicals, Chinese Biomedical
Literature Database, Chinese Scientific Journal Database database), 1
Korean medical database (KoreaMed), 1 Japanese medical database
(National Institute of Informatics). The primary outcomes will be the
resumption of menstruation and the serum FSH levels, and the
secondary outcomes include the serum Estradiol levels, anti-
Mullerian hormone levels, antral follicle count, follicular growth,
endometrial thickness, and adverse events. RevMan V.5.3 will be
used to conduct the meta-analysis, if possible. If it is not allowed, a
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descriptive analysis or a subgroup analysis will be conducted. Risk

ratio for dichotomous data and mean differences or standardized
mean differences for continuous data will be calculated with 95%
confidence intervals using a random effects model or a fixed effects
model. This study will provide the latest analysis of the currently
available evidence for the efficacy of acupuncture in treating POI (5).
Meldrum (6) mentioned that Ovulation induction protocols for
oocyte retrieval have evolved from clomiphene citrate/human
menopausal gonadotropins (menotropins) to human menopausal
gonadotropins alone and, finally, to a combination of human
menopausal gonadotropins and an agonist of gonadotropin-releasing
hormone (GnRH-a). The almost abandonment of clomiphene use is
due to findings from studies that showed reduced implantation due
to the antiestrogen effect of clomiphene. The use of GnRH-a was
introduced to maintain low levels of luteinizing hormone late in
follicular development to prevent premature ovulation or premature
senescence of the oocyte. The GnRH-a increases oocyte yield in poor
responders, decreases cycle cancellations, improves the rate of
pregnancy, and allows some control over the timing of retrieval.
Attempts to use the GnRH-a to stimulate follicle maturation in a
"short protocol" have resulted in variable and sometimes poor
results. Therefore, the long GnRH-a/human menopausal
gonadotropin protocol is currently used for most patients to prepare
for oocyte retrieval (6).
D'Amato & al. (7) evaluated the efficacy of a novel protocol of
ovulation induction for poor responders. This prospective,
controlled, clinical study was conducted at research institute's
reproductive unit. Patients included 145 infertile women, aged 27-39
years, candidates for assisted reproductive techniques (ART). Before
undergoing ART, 85 patients received clomiphene citrate, high-dose
recombinant human FSH, and a delayed, multidose GnRH antagonist,
whereas 60 patients underwent a standard long protocol. Main
outcome measures included estradiol levels (pg/mL), cancellation
rate, oocyte retrieval, embryo score, and fertilization and pregnancy
rates. Patients undergoing the study protocol obtained lower
cancellation rates (4.7% vs. 34%) and higher E(2) levels (945.88 +/-
173.2 pg/mL vs. 169.55 +/- 45.07 pg/mL), oocyte retrieval (5.56 +/-
1.13 vs. 3.36 +/- 1.3), and pregnancy (22.2% vs. 15.3%) and
implantation rates (13.5% vs. 7.6%) compared with those receiving
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the long protocol. Age negatively correlated with ovarian response in

the latter, whereas the ovarian outcome results were comparable in
younger (<35 years) and older (>35 years) women treated with the
study protocol. The proposed protocol of ovulation induction can be
usefully administered in poor responders as well as in aged woman,
probably because the delayed administration of GnRH antagonist
prevents its adverse effects on ovarian paracrine activity and on
oocyte maturation (7).
Oduola & al. (8) mentioned that the management of patients with
sub-fertility, particularly unexplained sub-fertility, is a sensitive and
complex matter. This was a prospective observational study
conducted from October 2016 to March 2017 in Galway, Ireland, the
aim of which was to identify the clinical pregnancy rates (CPR) in
women undergoing ovulation induction (OI) with timed sexual
intercourse (TSI) or intrauterine insemination (IUI) and to compare
them across two groups: 1] Anovulatory women and 2] ovulatory
women with unexplained subfertility. Patients undergoing OI were
recruited consecutively and OI regimens were prescribed as per local
clinical protocol. The main observation was a higher CPR in the
anovulatory group (18%) compared with the ovulatory group (CPR =
10%) (p < 0.05). No difference was observed in the CPR between the
TSI and IUI groups. There are many studies to support the use of OI
in the treatment of women with anovulatory subfertility, though the
use of OI in ovulatory women is a more controversial issue. The
treatment options offered to these patients need to be individualized
to each couple and should consider their length of infertility, age, and
financial means. Due to the lower cost and the less invasive nature
of OI-treatment it was concluded that a short treatment course could
be offered as an acceptable alternative prior to IVF (8).
Sullivan & al. (9) revealed that POI is a rare but important cause
of ovarian hormone deficiency and infertility in women. In addition to
causing infertility, POI is associated with multiple health risks,
including bothersome menopausal symptoms, decreased bone
density and increased risk of fractures, early progression of
cardiovascular disease, psychological impact that may include
depression, anxiety, and decreased perceived psychosocial support,
potential early decline in cognition, and dry eye syndrome.
Appropriate hormone replacement therapy (HRT) to replace
premenopausal levels of ovarian sex steroids is paramount to
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increasing quality of life for women with POI and ameliorating

associated health risks. In this review, POI and complications
associated with this disorder, as well as safe and effective HRT
options are discuss. To decrease morbidity associated with POI, the
Authors recommend using HRT formulations that most closely mimic
normal ovarian hormone production and continuing HRT until the
normal age of natural menopause, ∼50 years. Special populations of
women with POI, including women with Turner syndrome, women
with increased risk of breast or ovarian cancer, women approaching
the age of natural menopause, and breastfeeding women were
address (9).
Hammarbäck & al. (10) noticed that in the premenstrual
syndrome the negative symptoms appear during the luteal phase of
the menstrual cycle. Ovulation and the formation of a corpus luteum
seem to be of great importance in precipitating the syndrome. In a
large group of women with premenstrual syndrome investigated
daily with symptom ratings and weekly plasma estradiol and
progesterone assays, 8 were found to have one ovulatory and one
spontaneously occurring anovulatory menstrual cycle. In both these
cycles, the post- and premenstrual phases were compared by testing
for recurrence of symptoms. All patients showed a highly significant
cyclical worsening of negative premenstrual symptoms during the
ovulatory cycles, whereas in the anovulatory cycles the cyclical
symptoms disappeared, resulting in relief of the premenstrual
syndrome. These results support earlier hypotheses, suggesting that
the premenstrual syndrome appears as a result of provoking factors
produced by the corpus luteum. This view is in line with earlier
therapeutic findings showing that induced anovulation can relieve
the premenstrual syndrome (10).
Weiss & al. (11) reported that ovulation induction with follicle
stimulating hormone (FSH) is a second-line treatment in women with
polycystic ovary syndrome (PCOS) who do not ovulate or conceive on
clomiphene citrate. The objective was to compare the effectiveness
and safety of gonadotrophins as a second-line treatment for
ovulation induction in women with clomiphene citrate-resistant
PCOS, and women who do not ovulate or conceive after clomiphene
citrate. In January 2018, the Cochrane Gynaecology and Fertility
Group Specialised Register of Controlled Trials, CENTRAL, MEDLINE,
Embase, PsycINFO, CINAHL, the World Health Organization clinical
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trials register, Clinicaltrials.gov, LILACs, and PubMed databases, and

Google Scholar were searched. References of in all obtained studies
were checked. There were no language restrictions. All randomized
controlled trials reporting data on clinical outcomes in women with
PCOS who did not ovulate or conceive on clomiphene citrate, and
undergoing ovulation induction with urinary-derived gonadotrophins,
including urofollitropin (uFSH) in purified FSH (FSH-P) or highly
purified FSH (FSH-HP) form, human menopausal gonadotropin (HMG)
and highly purified human menopausal gonadotrophin (HP-HMG), or
recombinant FSH (rFSH), or continuing clomiphene citrate. Trials
reporting on ovulation induction followed by intercourse or
intrauterine insemination were included. Studies that described co-
treatment with clomiphene citrate, metformin, luteinizing hormone,
or letrozole were excluded. Three review authors (NW, EK, and
MvW) independently selected studies for inclusion, assessed risk of
bias, and extracted study data. Primary outcomes were live birth
rate per woman and multiple pregnancies per woman. Secondary
outcomes were clinical pregnancy, miscarriage, incidence of ovarian
hyperstimulation syndrome (OHSS) per woman, total gonadotrophin
dose, and total duration of stimulation per woman. Data were
combined using a fixed-effect model to calculate the risk ratio (RR).
The overall quality of evidence was summarized for the main
outcomes using GRADE criteria. The review included 15 trials with
2,387 women. Ten trials compared rFSH with urinary-derived
gonadotrophins (three compared rFSH with human menopausal
gonadotrophin, and seven compared rFSH with FSH-HP), four trials
compared FSH-P with HMG. No trials that compared FSH-HP with
FSH-P were found. One trial compared FSH with continued
clomiphene citrate. Recombinant FSH (rFSH) versus urinary-derived
gonadotrophins. There may be little or no difference in the birth rate
between rFSH and urinary-derived gonadotrophins (RR 1.21, 95%
confidence interval (CI) 0.83-1.78; five trials, n=505; I² = 9%; low-
quality evidence). This suggests that for the observed average live
birth per woman who used urinary-derived FSH of 16%, the chance of
live birth with rFSH is between 13% and 28%. There may also be little
or no difference between groups in incidence of multiple pregnancy
(RR 0.86, 95% CI 0.46 to 1.61; eight trials, n=1368; I² = 0%; low-quality
evidence), clinical pregnancy rate (RR 1.05, 95% CI 0.88-1.27; eight
trials, n=1330; I² = 0; low-quality evidence), or miscarriage rate (RR
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1.20, 95% CI 0.71-2.04; seven trials, n=970; I² = 0; low-quality

evidence). The Authors are uncertain whether rFSH reduces the
incidence of OHSS (RR 1.48, 95% CI 0.82-2.65, ten trials, n=1565, I² =
0%, very low-quality evidence). Human menopausal gonadotrophin
(HMG) or HP-HMG versus uFSH when compared to uFSH, the Authors
are uncertain whether HMG or HP-HMG improves live birth rate (RR
1.28, 95% CI 0.65-2.52; three trials, n=138; I² = 0%; very low quality
evidence), or reduces multiple pregnancy rate (RR 2.13, 95% CI 0.51-
8.91; four trials, n = 161; I² = 0%; very low quality evidence). The
Authors are also uncertain whether HMG or HP-HMG improves
clinical pregnancy rate (RR 1.31, 95% CI 0.66-2.59; three trials, n=102;
I² = 0; very low quality evidence), reduces miscarriage rate (RR 0.33,
95% CI 0.06-1.97; two trials, n=98; I² = 0%; very low quality evidence),
or reduces the incidence of OHSS (RR 7.07, 95% CI 0.42-117.81; two
trials, n= 53; very low quality evidence) when compared to uFSH.
Gonadotrophins versus continued clomiphene citrateGonadotrophins
resulted in more live births than continued clomiphene citrate (RR
1.24, 95% CI 1.05-1.46; one trial, n= 661; I² = 0%; moderate-quality
evidence). This suggests that for a woman with a live birth rate of
41% with continued clomiphene citrate, the live birth rate with FSH
was between 43% and 60%. There is probably little or no difference
in the incidence of multiple pregnancy between treatments (RR 0.89,
95% CI 0.33-2.44; one trial, n=661; I² = 0%; moderate-quality
evidence). Gonadotrophins resulted in more clinical pregnancies
than continued clomiphene citrate (RR 1.31, 95% CI 1.13-1.52; one
trial, n= 661; I² = 0%; moderate-quality evidence), and more
miscarriages (RR 2.23, 95% CI 1.11-4.47; one trial, n=661; I² = 0%;
moderate-quality evidence). None of the women developed OHSS.
There may be little or no difference in live birth, incidence of multiple
pregnancy, clinical pregnancy rate, or miscarriage rate between
urinary-derived gonadotrophins and recombinant follicle stimulating
hormone in women with polycystic ovary syndrome. For human
menopausal gonadotropin or highly purified human menopausal
gonadotrophin versus urinary follicle stimulating hormone the
Authorsare uncertain whether one or the other improves or lowers
live birth, incidence of multiple pregnancy, clinical pregnancy rate, or
miscarriage rate. The Authors are uncertain whether any of the
interventions reduce the incidence of ovarian hyperstimulation
syndrome. It is suggested weighing costs and convenience in the
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decision to use one or the other gonadotrophin. In women with

clomiphene citrate failure, gonadotrophins resulted in more live
births than continued clomiphene citrate without increasing multiple
pregnancies (11).
Cheng & al. (12) evaluated the effects of coadministration of
metformin with clomiphene citrate (CC) and HMG in women with CC-
resistant polycystic ovary syndrome (PCOS). Sixty women with PCOS
were randomly assigned to receive 3 months' treatment with
metformin or placebo together with CC and HMG. Transvaginal
ultrasound was used to monitor follicular development and ovulation
was induced by human chorionic gonadotropin (HCG). The number
of dominant follicles, the estradiol level on the day HCG was given
and the amount of HMG required were significantly lower in the
metformin group than in the placebo group, whereas the mono-
ovulatory rate and pregnancy rate in the third cycle were significantly
higher. The cumulative pregnancy rate in the metformin group
(43.3%) was higher than in the placebo group (20.0%), but this
difference did not reach statistical significance. In conclusion,
coadministration of metformin with CC and HMG reduced the
amount of HMG required and increased the mono-ovulatory rate and
pregnancy rate (12).
Wang & al. (13) compared the effectiveness of alternative first
line treatment options for women with WHO group II anovulation
wishing to conceive. Systematic review and network meta-analysis
were conducted. Data sources included Cochrane Central Register of
Controlled Trials, Medline, and Embase, up to 11 April 2016. Study
selection included randomized controlled trials comparing eight
ovulation induction treatments in women with WHO group II
anovulation: clomiphene, letrozole, metformin, clomiphene and
metformin combined, tamoxifen, gonadotropins, laparoscopic
ovarian drilling, and placebo or no treatment. Study quality was
measured on the basis of the methodology and categories described
in the Cochrane Collaboration Handbook. Pregnancy, defined
preferably as clinical pregnancy, was the primary outcome; live birth,
ovulation, miscarriage, and multiple pregnancy were secondary
outcomes. Of 2,631 titles and abstracts initially identified, 57 trials
reporting on 8,082 women were included. All pharmacological
treatments were superior to placebo or no intervention in terms of
pregnancy and ovulation. Compared with clomiphene alone, both
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letrozole and the combination of clomiphene and metformin showed

higher pregnancy rates (odds ratio 1.58, 95% CI 1.25-2.00; 1.81, 1.35-
2.42; respectively) and ovulation rates (1.99, 1.38-2.87; 1.55, 1.02-
2.36; respectively). Letrozole led to higher live birth rates when
compared with clomiphene alone (1.67, 1.11-2.49). Both letrozole
and metformin led to lower multiple pregnancy rates compared with
clomiphene alone (0.46, 0.23-0.92; 0.22, 0.05-0.92; respectively).
The data show that in women with WHO group II anovulation,
letrozole and the combination of clomiphene and metformin are
superior to clomiphene alone in terms of ovulation and pregnancy.
Compared with clomiphene alone, letrozole is the only treatment
showing a significantly higher rate of live birth (13).
Cutler & al. (14) reported that PCOS affects between 8 and 18% of
women and is the leading cause of female anovulatory infertility.
Unfortunately, common treatments for women trying to conceive
can be ineffective as well as disruptive or harmful to patients' quality
of life. Despite evidence that women with PCOS have expressed the
need for alternative fertility treatments, lifestyle interventions
incorporating a nutritional plan with supplementation, increased
physical activity, and techniques for stress management have not
been combined as a program and studied in this population.
Literature suggests that each of these individual components can
positively influence reproductive hormones and metabolic health.
This is a randomized controlled trial which will include 240 women
diagnosed with PCOS, according to the Rotterdam criteria, who are
trying to conceive. Participants will be randomized to either a
comprehensive lifestyle intervention program or prescribed an oral
fertility medication, letrozole. These two groups will be further
randomized to consume either myo-inositol or a placebo.
Participants will be between the ages of 18 and 37 years. Exclusion
criteria include women who have already begun fertility treatment,
who are currently using myo-inositol or have taken it within the past
3 months, or who are being treated for, or have a history of, an
eating disorder. The primary outcome will be the ovulation rate, the
secondary outcome will be conception. Other outcomes include
miscarriage rates, validated rating measures of overall quality of life
(including social, relational, mind/body and emotional sub-
categories) and mental health scores (depression, anxiety, and
stress). This trial will determine the effectiveness of a structured
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lifestyle-based comprehensive intervention program for women with

PCOS experiencing infertility. In addition, it will determine whether
supplementing with myo-inositol provides any further benefit. The
objective of this study is to assess a possible non-pharmacological
solution to ovulatory dysfunction in these patients and perhaps
improve other associated features of PCOS (14).
Kamenov & al. (15) noticed that insulin resistance plays a key role
in the pathogenesis of PCOS. One of the methods for correcting
insulin resistance is using myo-inositol. The aim of the present study
is to evaluate the effectiveness of myo-inositol alone or in
combination with clomiphene citrate for 1] induction of ovulation
and 2] pregnancy rate in anovulatory women with PCOS and proven
insulin resistance. This study included 50 anovulatory PCOS patients
with insulin resistance. All of them received myo-inositolduring three
spontaneous cycles. If patients remained anovulatory and/or no
pregnancy was achieved, combination of myo-inositol and
clomiphene citrate was used in the next three cycles. Ovulation and
pregnancy rate, changes in body mass index (BMI) and homeostatic
model assessment (HOMA) index and the rate of adverse events
were assessed. After myo-inositol treatment, ovulation was present
in 29 women (61.7%) and 18 (38.3%) were resistant. Of the ovulatory
women, 11 became pregnant (37.9%). Of the 18 myo-inositol
resistant patients after clomiphene treatment, 13 (72.2%) ovulated.
Of the 13 ovulatory women, 6 (42.6%) became pregnant. During
follow-up, a reduction of body mass index and HOMA index was also
observed. The data show that Myo-inositol treatment ameliorates
insulin resistance and body weight, and improves ovarian activity in
PCOS patients (15).

This chapter (1-15) demonstrates different strategies for

ovulation induction.

References
1. Torrealday S, Kodaman P, Pal L. Premature ovarian insufficiency - an
update on recent advances in understanding and management. F1000Res.
2017 Nov 29;6:2069.
2. Luisi S, Orlandini C, Regini C, et al. Premature ovarian insufficiency:
from pathogenesis to clinical management. J Endocrinol Invest.
2015;38(6):597-603.
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3. Hakimi O, Cameron LC. Effect of exercise on ovulation: a systematic

review. Sports Med. 2017;47(8):1555-1567.
4. Chae-Kim JJ, Gavrilova-Jordan L. Premature ovarian insufficiency:
procreative management and preventive strategies. Biomedicines. 2018
Dec 28;7(1). pii: E2.
5. Huang L, Chen Y, Luo M, et al. Acupuncture for patients with
premature ovarian insufficiency: A systematic review protocol. Medicine
(Baltimore). 2019;98(18):e15444.
6. Meldrum DR. Ovulation induction protocols. Arch Pathol Lab Med.
1992;116(4):406-9.
7. D'Amato G, Caroppo E, Pasquadibisceglie A, et al. A novel protocol
of ovulation induction with delayed gonadotropin-releasing hormone
antagonist administration combined with high-dose recombinant follicle-
stimulating hormone and clomiphene citrate for poor responders and
women over 35 years. Fertil Steril. 2004;81(6):1572-7.
8. Oduola OO, Ryan GA, Umana E, et al. Ovulation induction:
comparing success rates between anovulatory and ovulatory cycles using
different treatment protocols. Gynecol Endocrinol. 2019 May 14:1-3.
9. Sullivan SD, Sarrel PM, Nelson LM. Hormone replacement therapy
in young women with primary ovarian insufficiency and early menopause.
Fertil Steril. 2016;106(7):1588-99.
10. Hammarbäck S, Ekholm UB, Bäckström T. Spontaneous
anovulation causing disappearance of cyclical symptoms in women with
the premenstrual syndrome. Acta Endocrinol (Copenh). 1991;125(2):132-7.
11. Weiss NS, Kostova E, Nahuis M, et al. Gonadotrophins for
ovulation induction in women with polycystic ovary syndrome. Cochrane
Database Syst Rev. 2019 Jan 16;1:CD010290.
12. Cheng J, Lv J, Li CY, et al. Clinical outcomes of ovulation induction
with metformin, clomiphene citrate and human menopausal
gonadotrophin in polycystic ovary syndrome. J Int Med Res. 2010;
38(4):1250-8.
13. Wang R, Kim BV, van Wely M, et al. Treatment strategies for
women with WHO group II anovulation: systematic review and network
meta-analysis. BMJ. 2017 Jan 31;356:j138.
14. Cutler DA, Shaw AK, Pride SM, et al. A randomized controlled trial
comparing lifestyle intervention to letrozole for ovulation in women with
polycystic ovary syndrome: a study protocol. Trials. 2018;19(1):632.
15. Kamenov Z, Kolarov G, Gateva A, et al. Ovulation induction with
myo-inositol alone and in combination with clomiphene citrate in
polycystic ovarian syndrome patients with insulin resistance. Gynecol
Endocrinol. 2015;31(2):131-5.
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SUMMARY
Fertility awareness is fundamental to understanding and making
informed decisions about reproductive health and sexual health.
Conception is only possible from approximately five days before
up to several hours after ovulation. Therefore, to be effective,
intercourse must take place during this fertile period. Overall, the
day-specific probability of conception sharply rises at 7 days after the
last menstrual period, reaching its maximum at 15 days and returning
to zero by 25 days. The exact time of ovulation within the menstrual
cycle is important for the reproductive function of women.
In the Bible, awareness of ovulation days was the underlying
factor in the plan of the two women to conceive and give birth to
children. Lot's daughters successfully conceived so there is no reason
to suspect they suffered from any kind of ovulatory disorder.
Thus, the Bible shows that even in these remote times women
were aware of their precise ovulation date. What method did they
use to time their ovulation date? Although there are numerous
contemporary strategies, it seems likely that one of the simplest
family planning methods was used.
This research expands our knowledge and gives important
information on awareness of ovulation in Biblical times

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