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Causes of female infertility

Authors: Wendy Kuohung, MD, Mark D Hornstein, MD
Section Editor: Robert L Barbieri, MD
Deputy Editor: Kristen Eckler, MD, FACOG

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jun 2021. | This topic last updated: Feb 05, 2020.

INTRODUCTION

Infertility is a complex disorder with significant medical, psychosocial, and economic

aspects. The etiologies of female infertility will be reviewed here. Evaluation and
treatment of female infertility are discussed separately. (See "Evaluation of female
infertility" and "Treatments for female infertility".)

Causes of male infertility are also discussed elsewhere. (See "Causes of male infertility".)

OVERVIEW

In a World Health Organization (WHO) study of 8500 infertile couples, female factor
infertility was reported in 37 percent of infertile couples in developed countries, male
factor infertility in 8 percent, and both male and female factor infertility in 35 percent [1].
The remaining couples had unexplained infertility or became pregnant during the study.
The most common identifiable female factors, which accounted for 81 percent of female
infertility, were:

● Ovulatory disorders (25 percent)

● Endometriosis (15 percent)
● Pelvic adhesions (12 percent)
● Tubal blockage (11 percent)
● Other tubal abnormalities (11 percent)
● Hyperprolactinemia (7 percent)
With advancing female age, there is an increase in the percentage of women with age-
related infertility. In addition, other factors that may reduce fertility, such as leiomyomas,
tubal disease, and endometriosis, also increase. A reduction in coital frequency with
increasing age also impacts fertility [2].

OVARY

Ovulatory disorders — Infrequent ovulation (oligoovulation) or absent ovulation

(anovulation) results in infertility because an oocyte is not available every month for
fertilization. Women who report monthly menses and molimina (breast tenderness,
dysmenorrhea, bloating) are typically ovulatory. If menses and molimina are irregular or
absent, pregnancy or another condition associated with oligoovulation/anovulation is
likely. Potential causes are listed in the table ( table 1) (see individual topic reviews for
more information on each disorder).

The World Health Organization has classified anovulation into three main groups, and
recognizes hyperprolactinemia as additional etiology ( table 2). This system is useful for
defining and treating anovulatory disorders according to the underlying endocrine
dysfunction.

Oocyte aging — Age is an important factor affecting a woman's fertility ( figure 1). The
decrease in fecundability with aging is likely due to a decline in both the quantity and
quality of the oocytes.

The germ cell complement of the ovary reaches its apex of 6 to 7 million follicles in the
mid-gestation female fetus, followed by a steady attrition from 1 to 2 million follicles at
birth to 300,000 follicles at the onset of puberty [3]. The rate of follicle loss accelerates
after the woman reaches her mid-thirties [4,5] (see "Effects of advanced maternal age on
pregnancy"). Other insults to the ovary such as cigarette smoking, radiation,
chemotherapy, and autoimmune disease also accelerate follicular loss [6-8]. Women with
a depleted ovarian follicle pool may continue to ovulate regularly, but have infertility due
to the poor quality of oocytes remaining in the terminal follicular pool. (See "Ovarian
failure due to anticancer drugs and radiation" and "Pathogenesis and causes of
spontaneous primary ovarian insufficiency (premature ovarian failure)".)

The loss of oocyte quality as a woman ages is thought to be due to an increase in meiotic
nondisjunction. Hypothesized mechanisms involve differences between germ cells when
formed during fetal life, damage in germ cells that accumulates over the course of a
woman’s life, or age-related changes in the quality of the granulosa cells surrounding the
oocyte [9].

Ovarian cysts — A review of epidemiologic data, drawn mainly from comparative studies
and cohorts, concluded that it is unclear whether small (<3 to 6 cm) ovarian cysts have a
role in infertility and that the effects of surgical treatment are often more harmful than
the cyst itself to the ovarian reserve [10]. Most of these data involved endometriomas.
(See "Endometriosis: Management of ovarian endometriomas", section on 'Treatment of
subfertility'.)

FALLOPIAN TUBE ABNORMALITIES/PELVIC ADHESIONS

Tubal disease and pelvic adhesions prevent normal transport of the oocyte and sperm
through the fallopian tube. The primary cause of tubal factor infertility is pelvic
inflammatory disease caused by pathogens such as chlamydial or gonorrhea. Other
conditions that may interfere with tubal transport include severe endometriosis (see
'Endometriosis' below), adhesions from previous surgery or nontubal infection (eg,
appendicitis, inflammatory bowel disease), pelvic tuberculosis, and salpingitis isthmica
nodosa (ie, diverticulosis of the fallopian tube). Proximal tubal blockage may result from
plugs of mucus and amorphous debris or spasm of the uterotubal ostium, but does not
reflect true anatomic occlusion [11]. (See "Pelvic inflammatory disease: Treatment in
adults and adolescents" and "Treatment of infertility in females with endometriosis".)

Women with distal tubal obstruction may develop hydrosalpinges, which decrease the
success rate of in vitro fertilization (IVF). In addition to obstruction to sperm migration,
hydrosalpinges appear to reduce fertility by retrograde flow of tubal contents into the
endometrial cavity, which creates a hostile environment to implantation of an embryo.
Removal of the hydrosalpinges increases the success of IVF. (See "Reproductive surgery
for female infertility", section on 'Salpingectomy before in vitro fertilization'.)

UTERUS

Impaired implantation, either mechanical or due to reduced endometrial receptivity, are

the basis of uterine causes of infertility.

Uterine fibroids (leiomyomata) — Uterine fibroids are common benign smooth muscle
monoclonal tumors. Although conflicting data exist, it appears that fibroids with a
submucosal or intracavitary component can lower pregnancy and implantation rates, as
shown by improved pregnancy rates following removal of such lesions, although
supporting data conflict [12,13]. However, the impact of fibroid presence or removal on
live birth rate is unclear. The impact of fibroids on fertility and treatment in individuals
who desire pregnancy is discussed in related content.

Uterine anomalies — Uterine abnormalities are thought to cause infertility by interfering

with normal implantation. Müllerian anomalies are a significant cause of recurrent
pregnancy loss (RPL), with the septate uterus associated with the poorest reproductive
outcome [14]. Other structural abnormalities associated with infertility include
endometrial polyps, and synechiae from prior pregnancy-related curettage. However, data
establishing a causal link between these uterine abnormalities and infertility are lacking.
(See "Congenital uterine anomalies: Clinical manifestations and diagnosis" and
"Endometrial polyps" and "Intrauterine adhesions: Clinical manifestation and diagnosis".)

Intrauterine adhesions — Intrauterine adhesions as a cause of infertility are reviewed

separately. (See "Intrauterine adhesions: Clinical manifestation and diagnosis", section on
'Clinical presentation'.)

Luteal phase defect — Luteal phase defect (LPD) refers to abnormalities of the corpus
luteum that result in inadequate production of progesterone, which is necessary for
making the endometrium receptive to implantation. A 2015 committee opinion from the
American Society of Reproductive Medicine concluded that "although progesterone is
important for the process of implantation and early embryonic development, luteal phase
defect (LPD) as an independent entity causing infertility has not been proven" [15]. There
are no agreed upon definitions, diagnostic tests, or treatments for LPD [15]. We agree that
endometrial dating is not useful for evaluating or guiding treatment of infertile women
[16,17].

ENDOMETRIOSIS

Mechanisms which decrease fertility in women with endometriosis include anatomic

distortion from pelvic adhesions, damage to ovarian tissue by endometrioma formation
and surgical resection, and the production of substances such as cytokines and growth
factors which impair the normal processes of ovulation, fertilization, and implantation.
(See "Treatment of infertility in females with endometriosis".)

CERVICAL FACTORS
Normal midcycle cervical mucus facilitates the transport of sperm. Congenital
malformations and trauma to the cervix (including surgery) may result in stenosis and
inability of the cervix to produce normal mucus, thereby impairing fertility. (See "Benign
cervical lesions and congenital anomalies of the cervix".)

INHERITED THROMBOPHILIA

Inherited thrombophilias do not appear to be related to unexplained infertility [18,19]. A

large retrospective study reported no significant association with common
thrombophilias, including factor V Leiden and lupus anticoagulant, and diminished in vitro
fertilization success [20]. Thus, neither screening for thrombophilias nor treating them is
advised in cases of repeated infertility treatment failure.

IMMUNE FACTORS

Autoantibodies — An increased frequency of abnormal immune test results in women

with early reproductive failure has been reported repeatedly; however, the most rigorous
studies have not proven a cause and effect between these phenomena [21]. Immune
testing of infertile couples in clinical practice is not supported by existing data, and
treatments administered to address abnormal results on immunologic testing solely for
the purpose of improving fertility have not been proven to be beneficial and may cause
harm.

Women with some autoimmune diseases are at increased risk of infertility unrelated to
direct effects of these antibodies on fertilization and implantation. For example,
premature ovarian failure has also been described in women with systemic lupus
erythematosus and myasthenia gravis. Autoimmune oophoritis may occur as part of type
I and type II syndromes of polyglandular autoimmune failure, which are associated with
autoantibodies to multiple endocrine and other organs.

Celiac disease — Women with untreated celiac disease may have an increased frequency
of reproductive abnormalities, including infertility, miscarriage, and intrauterine growth
restriction [22]. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac
disease in adults", section on 'Menstrual and reproductive issues'.)

GENETIC CAUSES
Infertile couples have been shown to have a higher prevalence of karyotype abnormalities
(trisomies, mosaics, translocations, etc) than the general population [23]. The frequency
varies according to the cause of infertility and clinical history. The most common
aneuploidies associated with infertility are 45, X (Turner syndrome) in women and 47, XXY
(Klinefelter syndrome) in men. (See "Clinical manifestations and diagnosis of Turner
syndrome" and "Causes of primary hypogonadism in males", section on 'Klinefelter
syndrome'.)

Individual genes that affect fecundity have been identified, including KAL1 (Kallmann's
syndrome) [24], GnRH receptor [25,26], FSH receptor [27], beta subunit of FSH [28], LH
receptor [29], FMR1 (fragile X syndrome) [30], SF1, DAX1 [31], LEP (leptin) [32], LEP receptor
[33], GPR54 [34,35], FGFR1 [36], and TUBB8 [37]. TUBB8 mutations are unique in that they
impact only oocytes. TUBB8 mutations disrupt microtubule function during oocyte division
and thereby arrest human oocyte maturation and prevent fertilization [37]. Of these
genes, clinical testing is available for abnormalities of FMR1, which causes fragile X
syndrome. (See "Prenatal screening and diagnosis for fragile X syndrome".)

LIFESTYLE FACTORS

Lifestyle factors which may contribute to subfertility are reviewed separately. (See
"Optimizing natural fertility in couples planning pregnancy".)

UNEXPLAINED

Unexplained infertility is the diagnosis given to couples after a thorough evaluation has
not revealed a cause. Many cases of unexplained infertility may be due to small
contributions from multiple factors. (See "Unexplained infertility".)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and

regions around the world are provided separately. (See "Society guideline links: Female
infertility".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces
are longer, more sophisticated, and more detailed. These articles are written at the 10th to
12th grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Female infertility (The Basics)" and "Patient
education: Infertility in couples (The Basics)")

● Beyond the Basics topics (see "Patient education: Ovulation induction with
clomiphene (Beyond the Basics)" and "Patient education: Evaluation of the infertile
couple (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● The most common causes of female infertility include: ovulatory dysfunction (age or
non-age related), fallopian tube abnormalities (related to pelvic adhesions and
infection), endometriosis, uterine abnormalities (congenital or acquired), and cervical
factors. (See 'Overview' above.)

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Topic 5408 Version 33.0

GRAPHICS

Causes of ovulatory dysfunction

Primary hypothalamic-pituitary dysfunction

Immaturity at onset of menarche or perimenopausal decline

Intense exercise

Eating disorders

Stress

Idiopathic hypogonadotropic hypogonadism

Hyperprolactinemia

Lactational amenorrhea

Pituitary adenoma or other pituitary tumors

Kallman syndrome

Tumors, trauma, or radiation of the hypothalamic or pituitary area

Sheehan's syndrome

Empty sella syndrome

Lymphocytic hypophysitis (autoimmune diseases)

Other disorders
Polycystic ovary syndrome

Hyperthyroidism or hypothyroidism

Hormone-producing tumors (adrenal, ovarian)

Chronic liver or renal disease

Cushing's disease

Congenital adrenal hyperplasia

Premature ovarian failure, which may be autoimmune, genetic, surgical idiopathic, or related to drugs or radiation

Turner syndrome

Androgen insensitivity syndrome

Medications
Estrogen-progestin contraceptives

Progestins

Antidepressant and antipsychotic drugs

Corticosteroids

Chemotherapeutic agents

Graphic 79628 Version 6.0

World Health Organization classification of anovulation

WHO class 1: Hypogonadotropic hypogonadal anovulation (hypothalamic amenorrhea)

These women have low or low-normal serum follicle-stimulating hormone (FSH) concentrations and low serum
estradiol concentrations due to decreased hypothalamic secretion of gonadotropin-releasing hormone (GnRH) or
pituitary unresponsiveness to GnRH.

WHO class 2: Normogonadotropic normoestrogenic anovulation

These women may secrete normal amounts of gonadotropins and estrogens. However, FSH secretion during the
follicular phase of the cycle is subnormal. This group includes women with polycystic ovary syndrome (PCOS). Some
ovulate occasionally, especially those with oligomenorrhea.

WHO class 3: Hypergonadotropic hypoestrogenic anovulation

The primary causes are premature ovarian failure (absence of ovarian follicles due to early menopause) and ovarian
resistance (follicular form).

Hyperprolactinemic anovulation
These women are anovulatory because hyperprolactinemia inhibits gonadotropin and therefore estrogen secretion;
they may have regular anovulatory cycles, but most have oligomenorrhea or amenorrhea. Their serum gonadotropin
concentrations are usually normal.

WHO: World Health Organization.

Graphic 69734 Version 5.0

Percentages of transfers using fresh embryos from fresh donor or fresh nondonor eggs that
resulted in live births, by age of woman, 2016

The above figure compares percentages of transfers resulting in live births for ART cycles using fresh embryos from
donor eggs with those for ART cycles using a woman's own eggs, among women of different ages. The likelihood of a
fertilized egg implanting is related to the age of the woman who produced the egg. Thus, the percentage of transfers
resulting in live births for cycles using embryos from women's own eggs declines as women get older. By contrast,
since egg donors are typically in their 20s or early 30s, the percentage of transfers resulting in live births for cycles
using embryos from donor eggs remained consistently high at above 40%.

ART: assisted reproductive technology.

Reproduced from: Centers for Disease Control and Prevention. 2016 Assisted Reproductive Technology: National Summary Report.
Available at: https://www.cdc.gov/art/reports/2016/national-summary.html (Accessed on January 28, 2020).

Graphic 50854 Version 4.0