Version May 2024
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 "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.
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 "Fragile X syndrome: Prenatal screening and diagnosis".)
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 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 or letrozole (Beyond the Basics)" and "Patient education: Evaluation of infertility in couples (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Common causes – 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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