Infertility

PGI Ira Mikkaella Genobis

July 12, 2021

 Infertility

• A couple has reduced capacity to conceive after 1 year of trying

• If >35yo, after 6 months of trying

Fecundability
- Monthly ability to get pregnant
- Normal: 20%

Subfertility
• - Decreased capacity for pregnancy but not an impossible feat
Incidence of Subfertility and Infertility
20%

10%

0%
15-44 years old
1982 1988
1995
• Most of this inc occurred among nulliparous women in the oldest age group (35-44)

• 2002 – 7.4% of all women aged 15-44yo in US has infertility

• 2006-2010 – 6% of the population, impaired fecundity occurred in 10.9% of the
reproductive age group
Infertility and age

Married women who are infertile, Pregnancy Rates by Age at 1 Year in Normal
by Age Womenwith Azoospermatic Husbands after
Donor Insemination
Fecundibility: Ability to conceive
Causes of Infertility

Ovulatory disorders
Male factors
Tubal disorders
Endometriosis
others
Unexplained factors
DIAGNOSTIC
EVALUATION
INITIAL INTERVIEW
1. Inform about normal human fecundity

2. tests should be thoroughly explained

3. Available therapies and prognosis for treatment should also be

laid down

4. Inform that after a complete diagnostic infertility evaluation, the

cause for infertility cannot be determined in a large group of
couples
INITIAL INTERVIEW
4. Instruct for the optimal time for conception to occur and have
intercourse which is the day before ovulation

• daily intercourse for 3 consecutive days at midcycle or if

ovulation is more precisely determined, such as if they do LH
monitoring using urinary immunoassays, intercourse should
occur for 2 consecutive days around the LH surge

5. Avoid using various vaginal lubricants and chemical as well as

saliva

6. Intercourse schedule should be less rigorous

Initial Interview
7. Tell the couples that it takes time to become pregnant

8. Stop smoking cigarettes and drinking caffeinated drinks in

excess

9. Vaginal douching reduce the chance of conception by 30%

Diagnostics
Goal of diagnostic tests:

Determine if the woman is ovulating

Determine if the semen sample of male partner is

normal

Patency of fallopian tubes

Documentation of Ovulation
1. History

• Regularity of menstrual cycles

2. Serum Progesterone

• Measured in the mid-luteal phase

• Provide indirect evidence of ovulation and normal luteal

function

• >10ng/ml or higher – atleast 1 day of luteal phase of

normal ovulatory cycle
 Documentation of Ovulation

3. Daily Basal Body Temperature

- provides information about the

approximate day of ovulation and
duration of luteal phase

- Taken shortly after awakening,

only after atleast 6hrs of sleep
and prior to ambulating,
sublingual placement of a
thermometer gradients between
96-100F
Documentation of Ovulation
4. Endometrial Biopsy

• Sometimes considered

• Invasive and painful

• Does not provide accurate information in terms of

“endometrial dating” of the luteal phase
 Semen Analysis
• Evaluates the male partner’s reproductive system
• Reflects the sperm production that occurred
3months earlier
• Abns in semen analysis (male factor) – 20% of
couples as the sole factor
• Abstain from ejaculation 2-3days before collection
of the semen sample
• Entire specimen should be collected because initial
fraction contains greatest density of sperm
• Sperm analysis is a subjective test, there is a fair
degree of variability from test to test in the same
man
Semen Analysis
• It is best to repeat the test
at least once if an
abnormality is found

• If an abnormality persists,
refer for urologic exam

• Comprehensive
evaluation is done
particularly with severe
sperm abns
 Evaluation and Laboratory Tests
History PE Healthy asymptomatic
woman
• Pregnancy complications, • Extremes of body mass,
Previous pelvic surgery,
• CBC, blood type,
skin changes, thyroid Rh factor, rubella
Signigicant dysmenorrhea,
abnormalities, breast status are only
Sexual dysfunction,
Abnormal cervical
secretion, abnormal pain needed
cytology, Use of on abdominal or pelvic
mediations, drugs, exam, assessment of • Pap smear
tobacco, Family history of vagina and cervix obtained within
genetic related illness, 12months
birth defects, age of
menopause in female
• Infectious disease
family members.
screening
Symptoms suggestive of
endocrine disorders –
• Chlamydia,
weight changes, skin
gonorrhoea
changes
Evaluation and Laboratory Tests
Women >35 years old

FSH Estradiol AMH/MIS

- Reflect the pool of - If elevated on day 2-3 - Reflect the sensitivity of
viable oocytes of mentrual cycle - the ovary to gonadotropic
remaining in the >70pg/mL – do not stimulation
ovary allow for a valid
- >2ng/ml – suggest a larger
interpretation of FSH
- >10mIU/mL – cohort of small available
values
decreased ovarian follicles; <0.5ng/ml –
reserve decreased ovarian reserve
- >20mIU/mL – poor
prognosis
Evaluation and Laboratory Tests
Ultrasound

Pelvic ultrasound

Significant pathologies can be

uncovered

 Fiboroids, endometriosis,
other pathologies,
polycystic ovaries

Antral follicle count can be

obtained on cycle days 2-4
Evaluation and Laboratory Tests

Other blood testing

1. Antibody titers

a. Chlamydia trachomatis – if elevated may signify the possibility of tubal

disease

b. IgG titer >1:32, 35% have evidence of tubal damage

2. TSH

a. N: <4.4uU/ml

b. >2.5mIU/ml – considered abnormal in women presenting with infertility

3. Prolactin
• If an abnormality is found in
one of the first 2 non-invasive
diagnostic procedures
(documentation of ovulation
and semen analysis), it should
be treated prior to proceeding
with the more costly and
invasive procedures UNLESS
there is a history or findings
suggestive of tubal disease
HYSTEROSALPINGOGRAPHY
• Done if these initial diagnostic tests are 1. Better visualization of the tubal
normal mucosal folds and vaginal markings
• performed in the follicular phase of the 2. Evaluate the appearance of
next cycle intratubal architecture to determine
• Avoid HSG if the extent of damage to the tube
3. determine the tube magnitude of the
a. Hx of salpingitis in the disease process and provide
recent past information about lining of the
oviduct and uterine cavity
b. Tenderness on pelvic exam
4. Determine if salpingitis isthmica
• Use water-soluble contrast and
nodosa is present in the interstitial
fluoroscopy
portion of the oviduct
 POST-COITAL TEST
• PCT provides a surrogate for visualizing motile, normal-appearing
sperm.
• Now rarely indicated as a necessary part of the infertility investigation
• Normal: at least 5 motile sperm are visible in normal cervical mucus
obtained from the upper canal just prior to ovulation

LAPAROSCOPY
• performed only provided that the woman is younger than 40yo and having
ovulatory cycles, there is an acceptable semen analysis and an age-appropriate
make of ovarian reserve such as AMH, several cycles of controlled ovarian
stimulation and intrauterine insemination maybe undertaken before doing lap
PROGNOSIS OF VARIOUS DIAGNOSES UNCOVERED BY THE
INFERTILITY INVESTIGATION
Highest probability of
conception with treatment
• Anovulation

Lower probability of
pregnancy
• Tubal disease and sperm
abnormalities
TREATMENT
 • Clomiphene citrate
• Letrozole
Urinary and recombinant
Anovulation
•
gonadotropins
• Dopamine agonists
• Corticosteroids
 Clomiphene citrate
• First – line pharmacologic agent for oligomenorrhea and
amenorrhea
• Given for 5 days, begin 3-5 days after onset of spontaneous menses
or withdrawal bleeding induced with a progesterone

• 5-9days after discontinuation, the rising E2 from the dominant

follicle cause a positive feedback effect on the pituitary or
hypothalamus  LH surg and FSH levels increase  ovulation and
luteinisation of the follicle
• Fecundability increase to 22%; 66->90% - evidence of ovulation

Treatment regimens
1. start with initial dose of 50mg/day x 5 days on the 5th day of
spontaneous or induced menses
2. Increasing dosage regimen
3. Stair-step regimen
Clomiphene citrate
Side effects
• Ovarian cysts - Regress spontaneously without therapy

• Vasomotor flushes

• Blurring of vision

• Abdominal pain or bloating

• Urticarial

• Slight degree of hair loss

• 10% does not ovulate with the highest dose due to the

lack of ovarian response to raise gonadotropin levels

• Multiples gestations – increased to 8%
 Letrozole
• Aromatase inhibitor

MOA: inhibit E2 production during the 5 days of

administration  negative feedback causing increase in
FSH levels

• Given 2.5 or 5mg x 5 days beginning on cycle day 3 to 5

• Short-acting
• Pregnancy rate is comparable to CC
• Reduced incidence of multiple pregnancies
• has not yet been proven by the US FDA for ovulation
induction
Gonadotropins
Uses:
○ For ovulation induction when
estrogen levels are low and
does not respond to CC or
letrozole
○ E2 <30pg/ml or lack of
withdrawal bleeding after
progesterone administration
○ CC or Letrozole resistant
Non-recombinant Preparation
● from postmenopausal urine
extracts
● SC administration
● Provide 75IU LH and 75IU
FSH/ampule
● Bravelle, metrodin - 75IU
FSH/ampule
Recombinant preparation
● From chinese hamster
ovarian cells
● SC
● Gonal-F, follitin - 75IU FSH
● Luveris – 75IU LH
Gonadotropins
Pregnancy rate
• With sufficient duration of treatment and no other
infertility factors, cumulative pregnancy rates are
excellent
• 77% - cumulative pregnancy rate after 9 cycles of
gonadotropin therapy
• 25-35% - incidence of spontaneous abortion after
gonadotropin therapy
• Overall multiple pregnancy rate – 15%
 Ovarian Hyperstimulation
Syndrome (OHSS)
• 0.5% of women
• large cystic ovaries, high E2 levels, ovarian
elaboration subs such as VEGF (increasing
vascularity and vascular permeability
• HCG triggers this syndrome
• Life-threatening – massive fluid shifts, ascites,
pleural effusion, electrolyte disturbances,
thromboembolism

Treatment
• Largely supportive
• Judicious use of fluids, prevent thrombosis,
correct electrolytes, maintain UO
Gonadotropin-releasing Hormone
• Alternative to HCG
• MOA: continuous administration of GnRH will saturate the receptors thus inhibit
gonadotropin release to induce ovulation, thus GnRH must be administered in a
pulsatile manner at intervals of 1-2hrs
• Given via IV or SC
• Given by means of a small portable pump worn attached to an article of clothing
• Ovulation rate
• 75-85%/cycle

Disadvantage
• Cumbersome, require continous line and a portable pump 24hrs a day
OTHER THERAPEUTIC MODALITIES
Weight And Lifestyle Management
● Weight loss
● Normalize glucose and lipid
metabolism
● Good diet and exercise to improve
overall fitness and metabolic
parameters
Ovarian Electrocauterization
● Reserved for patients who have
difficulties with gonadotropin
stimulation even in the setting of IVF
● Laparoscopic electrical or laser-
generated burn holes ~10 be made
through the ovarian cortex
● Overall term pregnancy rate – 50% after
surgery and a low multiple pregnancy
rate
DEALING WITH A MALE CAUSE OF INFERTILITY

• Refer for evaluation by an andrologist

usually a urologist
• Rule out or treat medical conditions
• Careful urologic exam to check for
testicular abnormalities and infection
• Varicocele repair remains
controversial, variable response to
surgery

• Improving the ejaculate for intrauterine

insemination or carry out IVF with ICSI
Intrauterine Insemination
• a procedure in which processed and concentrated motile sperm are placed directly into the
uterine cavity
• used to treat oligospermia and abnormalities of semen volume or viscosity
• Should take place on the day of or just prior to ovulation and should be scheduled for the
morning after LH is initially detected in an afternoon urine specimen

Indications
• Ejaculatory dysfunction (including sexual dysfunction and impotence)
• Severe vaginismus
• Cervical factor infertility
• Male factor infertility
• Unexplained infertility
• Stage I or II endometriosis

Contraindications
• active cervical, intrauterine, or pelvic infection
IVF/ICSI (Intracytoplasmic Sperm Injection)
• Fertilization rate of oocytes injected with a single normal sperm
obtained from men
• Done when there is low or no sperm ejaculate
• Fertilization rate of oocyte increased above 50%

Donor Sperm Insemination

• Azoospermic partners
• The attitude of both partners regarding the use of donor semen and
stability of marriage must be discussed before the procedure is
performed
• Preg rate - 50%, monthly fecundity 9% after 6 months of treatment
Uterine Causes Of
Infertility
 Intrauterine adhesions

• Most common risk Treatment Prognosis

factor: previous
• hysteroscopic • good, 75%
curettage of the
uterine cavity lysis of the conceived
adhesions after
• Can cause menstrual hysterocopic
abnormalities, recurrent
treatment
abortions, decreased ability
to conceive
 Leiomyoma
• Difficult to assess its effect
on conception
• many women have no
difficulty conceiving
despite with myomas
• Submucous fibroids and
larger intramural fibroids
>4cm decreased rate of
pregnancy
Treatment Prognosis
• Myomectomy is Retrospective studies:
justified if no other • overall preg rate after
cause of infertility is myomectomy in women
found and myomas with no other causes of
of moderate size infertility has been found to
and position are be significantly improved
present prospective studies
• No data showing a benefit
of myomectomy
 Genital Tuberculosis

Diagnosis Treatment Prognosis

• Endometrial • Anti-tuberculosis • pregnancy after therapy is

biopsy and medications rare
culture • If TB is present in the tube
but not in the uterus,
pregnancies have been
reported following IVF
• Calcified lymph nodes or granulomas in the
pelvis

Tubal obstruction in the distal isthmus or

proximal ampulla – pipe stem configuration of
the tube proximal to the obstruction

Multiple strictures along the course of the tube

Irregularity to the contour of the ampulla

Deformity of obliteration of the endometrial

cavity without a previous curettage
Tubal causes of infertility
Distal tubal obstruction or proximal tubal obstruction
Distal obstruction is more common than proximal
Distal obstruction leads to hydrosalpinx
Prognosis after surgical tubal reconstruction depends on the amount of
damage to the tube and the location of the obstruction
Extensive damage leads to unlikely chances of conception after tubal
reconstruction but have greater chances of conceiving with an IVF
procedure
If both proximal and distal obstruction exists, subsequent intrauterine
pregnancy is uncommon and surgical reconstruction should not be
performed in such cases
ENDOMETRIOSIS
• 40% of cases
• Diagnosis may be subtle and may only be realized if a laparoscopy is carried out unless there
is a strong component of pain as a presenting complaint or a large endometrioma is seen
on US
• Tx:
• Initial tx: COS with IUI –if pregnancy does not occur in 3-6 cycles, IVF is offered

Indications for surgery

a. Patients with pain and presence of large endometriomas

b. 2-4cm endometriomas may be observed because of the concern of

compromising ovarian reserve

• Pregnancy rate ~50% with operative laparoscopy

UNEXLPAINED INFERTILITY
• Couples with normal ovulation and pelvic evaluation with a normal uterus and patent tubes
on HSG as well as normal semen analysis
• Laparoscopy is no longer carried out routinely

Routine empirical treatment

• Ovarian stimulation with CC or gonadotropins coupled with IUI
• CC or gonadotropins alone is not efficacious
 Counselling
• Infertility and its treatment can affect a woman and
emotional
and her spouse or partner medically, financially,
socially, emotionally, and psychologically

• Address the emotional and social needs of

couples undergoing treatment
support
• Individual counselling and support groups should
be part of every infertility practice.
References:
● Lobo, R. A., Gershenson, D. M., Lentz, G. M., & Valea, F. A. (2016). Comprehensive gynecology E-book. Elsevier
Health Sciences.

● Middleton, MD, N. R., & Ginsburg, MD, E. S. (2011, May 26). Procedure for intrauterine insemination.
UpToDate. https://www.uptodate.com/contents/procedure-for-intrauterine-insemination-iui-
using-processed-sperm

● Physiology, prolactin - StatPearls - NCBI bookshelf. (2021, May 9). National Center for Biotechnology
Information. https://www.ncbi.nlm.nih.gov/books/NBK507829/