Female Infertility

Aka: Female Infertility, Infertility, Subfertility, Assisted Reproductive Technology, Assisted Reproductive Techniques

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II. Definitions

  1. Infertility
    1. No conception in 1 year without Contraception and with regular unprotected intercourse
      1. Primary Infertility: Nulligravida
      2. Secondary Infertility: Prior pregnancies

III. Epidemiology

  1. Affects 12% of couples in the United States (8 to 12% of couples worldwide)

IV. History

  1. History taken with both partners present
  2. Ages of both partners
  3. Medications and substances
    1. Teratogen Exposures (e.g. Isotretinoin, Warfarin, Lithium, Valproate)
    2. Substances (Tobacco, Alcohol, Marijuana, ilicit drug use)
  4. Obstetric History
    1. Prior Pregnancy and outcomes
  5. Sexually Transmitted Infections (STI)
    1. Pelvic Inflammatory Disease
    2. STI symptoms (e.g. Vaginal Discharge, Dysuria, Abdominal Pain, Fever)
  6. Menstrual History
    1. Menarche
    2. Menstrual period timing (i.e. ovulatory cycles)
  7. Male Factors
    1. See Male Infertility
    2. Erectile Dysfunction
    3. Libido
    4. Toxin exposures (e.g. Heavy Metals, Pesticides)
    5. Substances (Tobacco, Alcohol, Marijuana, ilicit drug use)
    6. Childhood illnesses (e.g. mumps, Cryptorchidism)
  8. Sexual History
    1. Number of contiguous months attempting conception
    2. Timing of intercourse in Menstrual Cycle
    3. Frequency of intercourse
      1. Optimally every day or every other day in Ovulation
    4. Lubricant use (spermatotoxic)
    5. Dyspareunia
    6. Technique

V. Exam: Women

  1. Breast Exam
    1. Breast formation
    2. Galactorrhea
  2. Genitourinary Exam
    1. Uterine masses
    2. Vaginal Discharge
  3. Endocrine
    1. Thyromegaly
    2. Hyperandrogenism
      1. Hirsutism
      2. Acne Vulgaris
      3. Clitoromegaly

VI. Exam: Men

  1. See Male Infertility

VII. Causes

  1. General
    1. Infertility is multifactorial in 40% of cases
    2. In at least 25% to 30% of cases, no Infertility cause is identified
  2. Female Infertility Causes
    1. See Female Infertility Causes
    2. Female factors overall account for 35 to 50% of cases
    3. Ovulatory Dysfunction accounts for 21-25% of cases
    4. Tubal factors account for 14-20% of cases
  3. Male Infertility Causes
    1. See Male Infertility
    2. Male factors account for 26-30% of cases (up to 40 to 50% of cases in some studies)

VIII. Evaluation: Indications

  1. Female age <35 years old
    1. Start Infertility evaluation after 12 months of no conception despite regular, unprotected sexual intercourse
  2. Female age 35 to 40 years old
    1. Start Infertility evaluation after 6 months of no conception despite regular, unprotected sexual intercourse
  3. Female age >40 years old
    1. Start evaluation immediately if suspected cause for Infertility (e.g. prior PID, tubal disease, prior Ectopic Pregnancy)
  4. Non-Heterosexual partners
    1. Start evaluation immediately

IX. Evaluation: Male Factor

  1. See Male Infertility
  2. History
    1. Prior conceived children
    2. History of testicular or scrotal surgery
    3. History of testicular infection (Mumps)
  3. Labs
    1. Semen Analysis
    2. Test for Sexually Transmitted Disease
      1. Mandatory for in vitro fertilization

X. Evaluation: Female Factors

  1. History related to Infertility Causes
  2. Confirm Ovulation
    1. See Ovulation
    2. Serum Progesterone (preferred)
      1. See Mid-Luteal Serum Progesterone for protocol
      2. Obtain Serum Progesterone on Day 21 of cycle (or 7 days before anticipated Menses onset)
      3. Serum Progesterone > 5 ng/ml (15.8 nmol/L) suggests Ovulation
    3. Other measures to confirm Ovulation
      1. Basal Body Temperature (not recommended, unreliable)
      2. Urine Luteinizing Hormone
  3. Aproach
    1. See below for evaluations of non-ovulating and ovulating women

XI. Evaluation: Female Factor - Not Ovulating (or Ovulatory Dysfunction)

  1. See Ovulatory Dysfunction
  2. Evaluate for Anovulation causes
    1. Follicle Stimulating Hormone
    2. Serum Prolactin
    3. Thyroid Stimulating Hormone
    4. Midluteal Phase Serum Progesterone (day 21)
      1. Serum Progesterone <3 ng/ml (<9.54 nmol/L) suggests annovulation
  3. Evaluate for Premature Ovarian Failure (age >35 years)
    1. See Premature Ovarian Failure
    2. Serum Follicle Stimulating Hormone (FSH) on Day 3 of cycle
      1. Increased FSH >10 IU/L on day 3 suggests decreased ovarian reserve
      2. Increased FSH >15-29 IU/L on day 3 suggests decreased likelihood of conception
      3. Increased FSH >30-40 IU/L (at any time) and low Serum Estradiol suggests Premature Ovarian Failure
        1. Consider Fragile X Syndrome carrier mutation testing in age <40 years
    3. Serum Estradiol (on Day 3 of cycle if menstruating)
      1. Decreased Serum Estradiol
        1. FSH increased: Premature Ovarian Failure
        2. FSH decreased: Hypothalamic-Pituitary failure
      2. Increased Serum Estradiol > 60-80 pg/ml and normal FSH predicts lower conception rate
        1. Associated with ovarian insufficiency (or decreased ovarian reserve)
    4. Antimullerian Hormone
      1. Antimullerian Hormone < 1.0 ng/ml suggests decreased ovarian reserve
      2. Unreliable marker of fertility in age 30 to 44 years without prior Infertility
        1. (2020) Fertil Steril 114(6): 1151-7 [PubMed]
    5. Other tests (low efficacy)
      1. Clomiphene Citrate (Clomid) challenge
      2. Antral follicle count (by Transvaginal Ultrasound)
        1. Count <5 to 7 suggests decreased ovarian reserve (poor efficacy)
  4. Consider Hyperandrogenism
    1. Serum 17a-Hydroxyprogesterone
    2. Serum Testosterone

XII. Evaluation: Female Factor - Ovulating

  1. Risk Factors for fallopian tube related Infertility cause
    1. Sexually Transmitted Infections and Pelvic Inflammatory Disease
    2. Prior abdominal or pelvic surgery
    3. Endometriosis
    4. Prior Ectopic Pregnancy
  2. Assess tubal patency
    1. No tubal obstruction risk factors
      1. Hysterosalpinography
    2. Tubal obstruction risk factors (Ectopic Pregnancy, pelvic infections, Endometriosis)
      1. Hysteroscopy
      2. Laparoscopy (with dye)
    3. Other first-line measures
      1. Transvaginal Ultrasound
  3. Other measures that are not recommended (do not affect management)
    1. Avoid post-coital Cervical Mucus testing
    2. Endometrial Biopsy for histologic dating
      1. Endometrial Biopsy is only indicated for suspected pathology (e.g. Endometrial Cancer Risk Factors)

XIII. Management

  1. General measures
    1. Tobacco Cessation
    2. Limit Alcohol to <2 drinks per day
    3. Avoid Marijuana
      1. May lower semen count and suppress Ovulation
    4. Target health weight
      1. Goal Body Mass Index (BMI) >20 kg/m2 and <30 kg/m2
      2. Obesity affects both male (semen quality, Erectile Dysfunction) and female (Ovulation, fertilization) factors
        1. Weight loss 5 to 10% improves spontaneous Ovulation and response to Ovulation induction
      3. Low BMI in women (e.g. RED-S) is associated with Anovulation
    5. Profertility Diet
      1. May improve pregnancy rates in women undergoing Assisted Reproductive Technology (ART)
      2. Folic Acid, Vitamin D and Vitamin B12
      3. Diet high in fruits and vegetables
      4. Seafood
      5. Gaskins (2019) Am J Obstet Gynecol 220(6): 567.e1-567.e18 [PubMed]
  2. Treat specific conditions if present
    1. Thyroid Disease (Hypothyroidism, Hyperthyroidism)
    2. Hyperprolactinemia
    3. Hypothalamic-Pituitary Failure
      1. Underweight women or over Exercisers with Amenorrhea, low Serum FSH and low Estradiol
      2. Encourage normalization of weight and moderation of Exercise
    4. Polycystic Ovary Syndrome (PCOS)
      1. Encourage weight loss, Exercise and lifestyle modification
      2. Clomiphene (Clomid)
      3. Letrozole (Femera)
      4. Metformin (Glucophage) 1500 mg daily
        1. Initial studies were promising and did increase Ovulation rates
        2. However does not increase the live birth rate
        3. Lord (2003) BMJ 327: 951 [PubMed]
        4. Sun (2013) Arch Gynecol Obstet 288(2): 423-30 [PubMed]
      5. Laparoscopic Ovarian Drilling
    5. Tubal disease
      1. Tubal repair surgery (tubal cannulation, tubal anastomosis)
      2. In vitro fertilization
    6. Intrauterine Abnormalities (e.g. Uterine Fibroids)
      1. Referral to gynecologic surgery
    7. Endometriosis
      1. Laparoscopic ablation
    8. Male Infertility
      1. Referral to male fertility specialist or urologist
      2. See general measures above (Tobacco Abuse, Obesity, limit Alcohol, avoid Marijuana)
      3. Treat cause (e.g. Varicocele Repair)
      4. Artificial Insemmination, Intrauterine insemination
  3. Ovulatory Dysfunction management
    1. Risk of Ovarian Hyperstimulation Syndrome and Multiple Gestation
    2. Clomiphene Citrate (Clomid) 50 mg (max 100 mg) daily for 5 days (starting on 2 to 5 of cycle)
    3. Letrozole (Femera) 2.5 (max 7.5 mg) daily for 5 days (starting on day 3 of cycle)
    4. Gonadotropins (for central Hypogonadism)
  4. Unexplained or refractory Infertility
    1. Precaution in unexplained Infertility
      1. Intrauterine insemination and Ovulation induction do not increase pregnancy rates
    2. Referral to Assisted Reproductive Technology (ART) as indicated
    3. Ovulatory Dysfunction management (as above)
    4. Intrauterine insemination
    5. In-Vitro Fertilization

XIV. Prognosis

  1. Overall fertility rate with treatment: 50%
  2. Even without treatment, 50% will conceive in the second year of attempting pregnancy
  3. Predictors of lower success rate
    1. Tubal causes of Infertility (20% fertility rate)
    2. Severe Endometriosis (17% fertility rate)
    3. Longer duration of Infertility
    4. No prior fertility history
    5. Women over age 30-35 years
  4. Reference
    1. Collins (2004) Hum Reprod Update 10:309-16 [PubMed]

XV. Complications: Assisted Reproductive Technology (ART)

  1. Ovarian Hyperstimulation Syndrome (OHSS)
  2. Heterotopic Pregnancy
  3. Mulitple Gestation
  4. Ovarian Torsion
    1. Increased risk with Assisted Reproductive Technology (ART), especially with Ovulation induction (e.g. Clomid)
    2. Multiple cysts that form on the stimulated ovary can act as a lead point for torsion

XVI. References

  1. (2012) Fertil Steril 98(2): 302-7 [PubMed]
  2. (2004) Fertil Steril 82(suppl 1):S169-72 [PubMed]
  3. Jose-Miller (2007) Am Fam Physician 75(6):849-58 [PubMed]
  4. Lindsay (2014) Am Fam Physician 91(5): 308-14 [PubMed]
  5. Phillips (2023) Am Fam Physician 107(6): 623-30 [PubMed]

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