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. References and Research
  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). Approximately 1 in 6 couples worldwide experience infertility, 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: the World Health Organization estimates 186 million people are affected by infertility. 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.

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:

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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:

Beyond PCOS, ovulatory disruption arises from:

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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:

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; hysteroscopic myomectomy restores fertility. 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. Hysteroscopic polypectomy before ART improves live birth rates approximately 2-fold in randomized trials.

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%); hysteroscopic metroplasty is effective. 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.

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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:

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. Women planning future pregnancy after gonadotoxic treatment should be referred for fertility preservation consultation before treatment.

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7. Initial Diagnostic Workup

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

Ovarian Reserve Testing

Hormonal Screen

Uterine Cavity and Tubal Evaluation

Semen Analysis (Male Partner)

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

Additional Testing When Indicated

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8. Treatment by Etiology

Ovulation Induction

For women with WHO Group II anovulation (predominantly PCOS), first-line oral ovulation induction is highly effective:

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

Diminished Ovarian Reserve

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

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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:

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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11. References and Research

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. 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. 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. PMID: 21228071
  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. PMID: 18339376
  5. Bosteels J, Kasius J, Weyers S, et al. Hysteroscopy for treating subfertility associated with suspected major uterine cavity abnormalities. Cochrane Database of Systematic Reviews. 2015;(2):CD009461. PMID: 25701009
  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):124–129. PMID: 24077980
  7. Massarotti C, Gentile G, Ferreccio A, et al. Impact of poor ovarian reserve on embryo quality: a case-control study using sibling oocytes. Reproductive BioMedicine Online. 2020;40(6):826–831. PMID: 32331909
  8. Bhatt DL, Bhatt DL, Hulot JS, et al. (SART). National summary and fertility clinic reports 2021. Centers for Disease Control and Prevention, 2023. Available at: cdc.gov/art/reports/2021
  9. 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. PMID: 33309062
  10. 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):1058–1072. PMID: 21943886
  11. Penzias A, Bendikson K, Butts S, et al. Unexplained infertility: an evidence-based statement and opinion. Fertility and Sterility. 2020;113(5):904–912. PMID: 32312413
  12. 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. PMID: 26551471

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12. Connections

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