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Female infertility: Causes

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: Feb 2023. | This topic last updated: Jul 22, 2021.

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 "Female infertility:
Evaluation" and "Female infertility: Treatments".)

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

In this topic, when discussing study results, we will use the terms "woman/en" or
"patient(s)" as they are used in the studies presented. However, we encourage the
reader to consider the specific counseling and treatment needs of transgender and
gender expansive individuals.

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 'Assess fertility and desire for pregnancy'.)

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
"Endometriosis: Treatment of infertility in females".)

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 "Female infertility: Reproductive surgery", 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.

● (See "Uterine fibroids (leiomyomas): Epidemiology, clinical features, diagnosis,

and natural history", section on 'Infertility or obstetric complications'.)

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 "Endometriosis: Treatment of infertility in
females".)

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 messenger ribonucleoprotein 1) [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
"Natural fertility and impact of lifestyle factors".)

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

th th
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
infertility in couples (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 36.0

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, 2019

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. 2019 Assisted Reproductive Technology: Fertility Clinic and
National Summary Report. Available at: https://www.cdc.gov/art/reports/2019/pdf/2019-Report-ART-Fertility-Clinic-National-
Summary-h.pdf (Accessed on August 29, 2022).

Graphic 50854 Version 5.0