Female Infertility

Table of Contents

1. Overview and Epidemiology
2. Causes of Female Infertility
3. Ovulatory Dysfunction
4. Tubal and Peritoneal Factors
5. Uterine and Cervical Factors
6. Diminished Ovarian Reserve
7. Initial Diagnostic Workup
8. Treatment by Etiology
9. IVF Success Rates and Fertility Preservation
10. Unexplained Infertility
11. Key Research Papers
12. Connections
13. Featured Videos

1. Overview and Epidemiology

Female infertility is defined as the inability to conceive after 12 months of regular unprotected intercourse (or 6 months if the woman is 35 or older). The World Health Organization states that globally one in six people experience infertility in their lifetime, and female factors contribute to roughly 40% of cases, male factors to another 40%, and combined or unexplained causes account for the remainder.

The global burden is substantial: an older estimate put the number of people affected by infertility at 186 million. In the United States, approximately 12% of women aged 15–44 have difficulty getting pregnant or carrying a pregnancy to term. Fertility declines progressively with age, most sharply after 35, making timely evaluation critical.

In 2025 the World Health Organization issued its first guideline on the prevention, diagnosis and treatment of infertility: 40 recommendations and six good-practice statements, covering among other topics polycystic ovary syndrome, tubal disease, uterine septum, unexplained infertility, sexually transmitted infections, tobacco use and lifestyle. Most of its recommendations are conditional, because the evidence behind them was absent or of low or very low certainty.

Female infertility encompasses a spectrum of conditions affecting ovulation, fallopian tube patency, uterine anatomy, cervical function, and egg quantity and quality. Identifying the underlying cause guides targeted treatment, from simple ovulation induction to advanced assisted reproductive technologies (ART).

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2. Causes of Female Infertility

Female-factor infertility is typically categorized by anatomical or functional origin. The major categories and their approximate prevalences among infertile women are:

• Ovulatory dysfunction: approximately 25% of female infertility cases. Irregular or absent ovulation prevents fertilization.
• Tubal factor: approximately 25% of cases. Blocked or damaged fallopian tubes prevent egg and sperm from meeting or impair embryo transport.
• Uterine/endometrial factors: approximately 10–15%. Fibroids, polyps, adhesions (Asherman's syndrome), or congenital anomalies disrupt implantation.
• Cervical factor: less than 5%. Cervical stenosis or hostile mucus impairs sperm passage.
• Diminished ovarian reserve (DOR): overlaps with ovulatory dysfunction; reduced egg quantity or quality, common in women over 35 or after chemotherapy/surgery.
• Unexplained infertility: approximately 10–20%. Standard workup is normal but conception does not occur; likely reflects subtle defects in egg quality, sperm-egg interaction, or implantation.

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3. Ovulatory Dysfunction

Ovulatory disorders are the most common cause of female infertility and are classified by the World Health Organization into three groups:

• World Health Organization (WHO) Group I (hypothalamic-pituitary failure): low follicle-stimulating hormone (FSH), low estrogen, often caused by extreme weight loss, excessive exercise, or stress. Represents about 10% of ovulatory disorders.
• World Health Organization Group II (hypothalamic-pituitary-ovarian dysfunction): the largest group (70–85%), dominated by polycystic ovary syndrome (PCOS). Polycystic ovary syndrome affects 8–13% of reproductive-age women and is characterized by anovulation, hyperandrogenism, and polycystic ovarian morphology. Insulin resistance drives elevated luteinizing hormone (LH) pulse frequency and androgen excess, suppressing folliculogenesis.
• World Health Organization Group III (ovarian failure): elevated follicle-stimulating hormone, low estrogen. Includes primary ovarian insufficiency (POI) and age-related decline.

Beyond polycystic ovary syndrome, ovulatory disruption arises from:

• Thyroid disorders: both hypothyroidism and hyperthyroidism disrupt the HPO axis. Thyroid-stimulating hormone (TSH) is commonly screened in all infertile women; a commonly used target is thyroid-stimulating hormone <2.5 mIU/L when trying to conceive.
• Hyperprolactinemia: elevated prolactin (from a pituitary adenoma, medications, or hypothyroidism) suppresses GnRH pulsatility. Dopamine agonists (cabergoline, bromocriptine) restore ovulation in >80% of cases.
• Functional hypothalamic amenorrhea (FHA): energy deficit, excessive exercise, or psychosocial stress suppresses GnRH. Treatment is behavioral (weight restoration, reduced exercise intensity).

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4. Tubal and Peritoneal Factors

The fallopian tubes must be patent and functional to allow fertilization and embryo transport to the uterus. Tubal damage causes approximately 25% of female infertility and is most often the result of:

• Pelvic inflammatory disease (PID): the leading cause of tubal factor infertility. A single episode of PID carries a 10–12% risk of tubal occlusion; three episodes raise the risk to over 50%. Chlamydia trachomatis and Neisseria gonorrhoeae are the principal pathogens, but anaerobic polymicrobial infection contributes.
• Endometriosis: peritoneal implants create inflammation, adhesions, and hydrosalpinx. Endometriosis-related infertility involves both anatomical distortion and impaired endometrial receptivity.
• Prior ectopic pregnancy: tubal surgery or conservative management (salpingostomy) leaves scarring. Subsequent tubal function is variable; ipsilateral patency on HSG does not guarantee normal ciliary function.
• Prior tubal/pelvic surgery: appendectomy, ovarian cystectomy, or cesarean section can generate peritoneal adhesions affecting tubal mobility.
• Hydrosalpinx: fluid-filled blocked tube. Reduces IVF live birth rates by approximately 50%; salpingectomy or proximal occlusion before IVF restores normal outcomes.

Assessment: hysterosalpingography (HSG) is the standard first-line test for tubal patency. It has a sensitivity of about 65% and specificity of 83% for proximal occlusion, with lower accuracy for distal disease. Laparoscopy with chromopertubation remains the gold standard when clinical suspicion is high despite normal HSG.

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5. Uterine and Cervical Factors

The uterine cavity must allow implantation and support fetal growth. Structural abnormalities are found in 10–15% of infertile women.

Fibroids (Leiomyomata)

Fibroids are benign smooth-muscle tumors present in up to 70% of women by age 50, but fertility impact depends entirely on location. Submucosal fibroids (type 0, 1, 2 — distorting the cavity) clearly reduce implantation and increase miscarriage. Whether hysteroscopic myomectomy restores fertility is uncertain: the 2018 Cochrane review found one small trial (94 women, very low-quality evidence) with a pregnancy result that was not statistically certain (odds ratio 2.44), and no live-birth data. Intramural fibroids (>4 cm, especially those that distort the cavity) likely impair fertility. Subserosal fibroids have minimal impact.

Endometrial Polyps

Endometrial polyps are focal overgrowths of endometrial glands and stroma. Even small (<1 cm) polyps reduce IVF implantation rates. In the 2018 Cochrane review, removing polyps before intrauterine insemination (IUI) raised the clinical pregnancy rate from 28% to an estimated 63% in one trial of 204 women (low-quality evidence); there were no live-birth data, and no randomized trials of polyp removal before IVF or ICSI.

Asherman's Syndrome (Intrauterine Adhesions)

Intrauterine adhesions form after uterine trauma — most commonly post-dilation and curettage (D&C), especially for retained products of conception after missed abortion. Amenorrhea, hypomenorrhea, and recurrent miscarriage are hallmarks. Diagnosis by hysteroscopy (saline infusion sonography is a useful screen). Hysteroscopic adhesiolysis with estrogen add-back restores menstruation in most women, but live birth rates remain below average.

Congenital Uterine Anomalies

Müllerian anomalies (arcuate, septate, bicornuate, unicornuate, didelphic uterus) affect about 5–6% of infertile women. A uterine septum is associated with the highest miscarriage rate (up to 60%). In the only randomized trial of septum surgery (80 women, 2021), live births within a year were 31% after hysteroscopic septum resection and 35% without it (relative risk 0.88), and one womb was perforated during surgery; the trial found that the operation did not improve reproductive outcomes. Other anomalies are managed expectantly or surgically depending on severity.

Cervical Factor

Cervical stenosis (from LEEP/cone biopsy or infection) prevents sperm entry. Hostile cervical mucus is no longer considered a clinically significant barrier to conception given modern IUI bypasses the cervix. Cervical factor alone accounts for <5% of infertility.

What is not known. For fibroids, polyps, adhesions and septum, the 2018 Cochrane review of hysteroscopic surgery found no live-birth data from randomized trials, and no randomized trials at all for adhesions, or for any cavity abnormality before IVF or ICSI.

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6. Diminished Ovarian Reserve

Diminished ovarian reserve (DOR) refers to a reduction in the quantity (and sometimes quality) of remaining oocytes below what is expected for a woman's age. It does not preclude natural or assisted conception but reduces success rates and may warrant more urgent treatment planning.

Key markers of ovarian reserve:

• Anti-Müllerian hormone (AMH): secreted by granulosa cells of small antral and preantral follicles; reflects the primordial follicle pool. Can be drawn on any cycle day. AMH <1.0 ng/mL suggests DOR; <0.5 ng/mL indicates severely diminished reserve.
• Antral follicle count (AFC): transvaginal ultrasound count of 2–10 mm follicles on cycle day 2–5. AFC <5–7 is consistent with DOR; <3–4 predicts poor response to ovarian stimulation.
• Day 3 follicle-stimulating hormone: elevated follicle-stimulating hormone (>10–12 international units (IU)/L, lab-dependent) reflects reduced negative feedback from the ovary. Less sensitive and reproducible than AMH; a single normal result does not rule out DOR.
• Day 3 estradiol: elevation above 60–80 pg/mL on day 3, even with normal follicle-stimulating hormone, suggests premature follicular recruitment and poor reserve.

Causes of DOR before age 40 include prior ovarian surgery (endometrioma cystectomy carries the highest risk of reserve loss), gonadotoxic chemotherapy or radiation, genetic causes (FMR1 premutation/fragile X), and autoimmune conditions. For women planning future pregnancy, fertility preservation is arranged before gonadotoxic treatment begins.

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7. Initial Diagnostic Workup

The standard infertility evaluation for a woman (and her partner simultaneously) typically includes:

Ovarian Reserve Testing

• Cycle day 2–3 serum follicle-stimulating hormone, luteinizing hormone, and estradiol
• AMH (any cycle day)
• Antral follicle count by transvaginal ultrasound

Hormonal Screen

• Thyroid-stimulating hormone (thyroid function)
• Prolactin (rule out hyperprolactinemia)
• Androgens (free testosterone, DHEAS) if polycystic ovary syndrome is suspected
• Progesterone on cycle day 21–23 to confirm ovulation (level >3 ng/mL confirms luteal phase; >10 ng/mL suggests adequate corpus luteum)

Uterine Cavity and Tubal Evaluation

• HSG (hysterosalpingography): X-ray with contrast dye injected through the cervix; evaluates tubal patency and uterine cavity contour. Performed cycle day 7–10 (after menses, before ovulation).
• Saline infusion sonohysterography (SIS) or 3D ultrasound: preferred by some centers to assess the uterine cavity for polyps, fibroids, and septa.
• Hysteroscopy: diagnostic gold standard for uterine cavity abnormalities.

Semen Analysis (Male Partner)

A semen analysis is obtained early in the workup, as male factor is responsible for 40–50% of infertility and results directly influence which treatments are recommended. The World Health Organization reference values (2021): concentration ≥16 million/mL, total motility ≥42%, progressive motility ≥30%, normal morphology ≥4% (strict Kruger criteria).

Additional Testing When Indicated

• Karyotype and FMR1 premutation testing for premature ovarian insufficiency
• Laparoscopy when HSG is abnormal or endometriosis/PID is strongly suspected
• Endometrial biopsy for suspected chronic endometritis (CD138 immunostaining)

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8. Treatment by Etiology

Ovulation Induction

For women with World Health Organization Group II anovulation (predominantly polycystic ovary syndrome), first-line oral ovulation induction is highly effective:

• Letrozole (aromatase inhibitor): now preferred over clomifene for polycystic ovary syndrome-related anovulation based on the NEJM PPCOSII trial. Dose: 2.5–7.5 mg/day, cycle days 3–7. In the trial (750 women with polycystic ovary syndrome), 27.5% had a baby over up to five treatment cycles with letrozole versus 19.1% with clomifene; ovulation occurred in 61.7% versus 48.3% of cycles. Twin pregnancies were 3.4% versus 7.4%, a difference that was not statistically significant.
• Clomifene citrate: 50–150 mg/day, cycle days 3–7 or 5–9. Ovulation rate 80%; cumulative pregnancy rate 30–40% over 6 cycles. Anti-estrogenic effects on endometrium and cervical mucus are a disadvantage.
• Metformin + letrozole: for insulin-resistant polycystic ovary syndrome, adding metformin may improve ovulation rates and reduce risk of OHSS.
• Gonadotropins (follicle-stimulating hormone ± luteinizing hormone): injectable, used when oral agents fail. Higher multiple pregnancy risk requires careful monitoring with serial ultrasound and estradiol levels.
• Dopamine agonists (cabergoline): first-line for hyperprolactinemia-driven anovulation; normalizes prolactin and restores ovulation in >80%.

Intrauterine Insemination (IUI)

IUI places washed sperm directly into the uterine cavity at the time of ovulation. It is used for mild male factor, cervical factor, unexplained infertility, and as a step after ovulation induction alone fails. Per-cycle pregnancy rates: approximately 10–20% with ovarian stimulation + IUI. Typically offered for 3–6 cycles before proceeding to IVF.

Tubal Factor: IVF Preferred

For bilateral tubal occlusion or hydrosalpinx, IVF bypasses the tubes entirely and is the treatment of choice. Tubal surgery (salpingoneostomy, fimbrioplasty) is reserved for young women with mild distal disease at experienced centers, given that IVF success rates generally exceed surgical outcomes. For proximal occlusion, selective salpingography/tubal catheterization may be attempted before IVF.

Uterine Factor

• Submucosal fibroids and polyps: hysteroscopic removal before ART
• Asherman's: hysteroscopic adhesiolysis + estrogen therapy
• Uterine septum: hysteroscopic metroplasty (the 2021 randomized trial found it did not improve live births)

Diminished Ovarian Reserve

DOR does not have a proven pharmacological treatment to restore reserve. Management focuses on acting expeditiously:

• IVF with controlled ovarian hyperstimulation (COH) using high-dose gonadotropins; antagonist protocols are preferred for poor responders (Bologna criteria).
• If response is very poor (<3 oocytes retrieved), donor egg IVF is the next option, which achieves live birth rates of 40–50% per cycle regardless of recipient age.
• Oocyte or embryo cryopreservation for women not yet ready to conceive but wishing to preserve fertility.
• DHEA supplementation (75 mg/day for 2–3 months) is used by some centers for DOR; evidence is mixed.

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9. IVF Success Rates and Fertility Preservation

In vitro fertilization (IVF) involves controlled ovarian stimulation, egg retrieval, fertilization in the laboratory, and embryo transfer. Success rates are strongly age-dependent.

According to CDC/SART national data (2021), live birth rates per egg retrieval cycle using the patient's own eggs:

• Under 35: approximately 46–50%
• 35–37: approximately 35–38%
• 38–40: approximately 22–26%
• 41–42: approximately 12–15%
• Over 42: approximately 5–7%

With donor eggs, live birth rates are approximately 40–50% per cycle and are largely independent of recipient age, reflecting that embryo quality is the dominant determinant.

Preimplantation genetic testing for aneuploidy (PGT-A) screens embryos for chromosomal abnormalities before transfer. It reduces miscarriage rates and increases single-embryo transfer success, but adds cost and may reduce the number of transferable embryos in poor-prognosis patients.

Fertility Preservation

Oocyte cryopreservation (egg freezing) allows women to bank eggs before gonadotoxic treatment, age-related decline, or surgery that may compromise ovarian function. Vitrification (rapid freezing) achieves post-thaw survival rates >90% and pregnancy rates comparable to fresh cycles. The American Society for Reproductive Medicine no longer considers egg freezing experimental. Per-egg live birth rates decline significantly with maternal age at freezing; banking before age 35 is most effective.

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10. Unexplained Infertility

Unexplained infertility is diagnosed when standard workup — ovulation confirmation, ovarian reserve testing, tubal patency, semen analysis, and uterine evaluation — is all normal, yet conception does not occur. It affects approximately 10–20% of infertile couples.

Likely contributing mechanisms include subtle defects in egg quality (particularly in older women), impaired sperm-egg recognition, embryo arrest at the cleavage stage, and subclinical implantation failure. Chronic endometritis (detectable only by endometrial biopsy with CD138 staining) has emerged as a treatable cause found in up to 30% of women with repeated implantation failure.

Management follows a stepwise approach based on the woman's age and duration of infertility:

1. Expectant management: for women under 35 with <2 years of infertility; monthly fecundability approximately 2–4%.
2. Clomifene/letrozole + IUI (3–6 cycles): adds approximately 8–15% per-cycle pregnancy rate.
3. Gonadotropins + IUI: higher success but increased multiple pregnancy risk.
4. IVF: for women ≥35, after failed IUI, or when time is limited; per-cycle success far exceeds IUI and provides diagnostic information (fertilization, embryo quality) unavailable from IUI.

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Key Research Papers

Key Research Papers

1. Zegers-Hochschild F, Adamson GD, de Mouzon J, et al. International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology, 2009. Fertility and Sterility. 2009;92(5):1520–1524. — PubMed PMID: 19828144
2. Legro RS, Brzyski RG, Diamond MP, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. New England Journal of Medicine. 2014;371(2):119–129. — PubMed PMID: 25006718
3. Broeze KA, Opmeer BC, Van Geloven N, et al. Are patient characteristics associated with the accuracy of hysterosalpingography in diagnosing tubal pathology? An individual patient data meta-analysis. Human Reproduction Update. 2011;17(3):293–300. — PubMed PMID: 21147835
4. Pritts EA, Parker WH, Olive DL. Fibroids and infertility: an updated systematic review of the evidence. Fertility and Sterility. 2009;91(4):1215–1223. — PubMed PMID: 18339376
5. Bosteels J, van Wessel S, Weyers S, et al. Hysteroscopy for treating subfertility associated with suspected major uterine cavity abnormalities. Cochrane Database of Systematic Reviews. 2018;12(12):CD009461. — PubMed PMID: 30521679
6. La Marca A, Sunkara SK. Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice. Human Reproduction Update. 2014;20(1):124–140. — PubMed PMID: 24077980
7. Centers for Disease Control and Prevention. 2021 Assisted Reproductive Technology National Summary and Fertility Clinic Reports. Atlanta (GA): U.S. Department of Health and Human Services, 2023.
8. Practice Committee of the American Society for Reproductive Medicine. Testing and interpreting measures of ovarian reserve: a committee opinion. Fertility and Sterility. 2020;114(6):1151–1157. — PubMed PMID: 33280722
9. Polyzos NP, Devroey P. A systematic review of randomized trials for the treatment of poor ovarian responders: is there any light at the end of the tunnel? Fertility and Sterility. 2011;96(5):1058–1061.e7. — PubMed PMID: 22036048
10. Cobo A, García-Velasco JA, Coello A, et al. Oocyte vitrification as an efficient option for elective fertility preservation. Fertility and Sterility. 2016;105(3):755–764.e8. — PubMed PMID: 26688429
11. Rikken JFW, Kowalik CR, Emanuel MH, et al. Septum resection versus expectant management in women with a septate uterus: an international multicentre open-label randomized controlled trial. Human Reproduction. 2021;36(5):1260–1267. — PubMed PMID: 33793794
12. World Health Organisation Guideline Development Group for Infertility, Mburu G, Santesso N, et al. Recommendations from the WHO guideline for the prevention, diagnosis, and treatment of infertility. Fertility and Sterility. 2026;125(5):880–894. — PubMed PMID: 41387135

PubMed Topic Searches

1. PubMed: Female infertility
2. PubMed: Ovulatory dysfunction infertility
3. PubMed: Tubal factor infertility
4. PubMed: Diminished ovarian reserve
5. PubMed: IVF live birth rate age
6. PubMed: Letrozole ovulation induction
7. PubMed: Unexplained infertility treatment
8. PubMed: Oocyte cryopreservation outcomes

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12. Connections

• Fertilization: How Sperm Meets Egg — interactive animation
• Infertility (General)
• Endometriosis
• Polycystic Ovary Syndrome (PCOS)
• Uterine Fibroids
• Ovarian Cysts
• Ectopic Pregnancy
• Premature Ovarian Insufficiency
• PMS and PMDD
• Hypothyroidism
• Menopause and Hormone Replacement Therapy
• Vitamin D3
• Magnesium
• Zinc
• Iron
• Lab Tests
• Reproductive Medicine

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Featured Videos