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BASICS

  • Definition: Failure to conceive after 12 months of regular unprotected intercourse.
  • Evaluation: Start at 6 months if woman >35 years; immediate if >40 years.
  • Types: Primary (never pregnant), Secondary (previous pregnancy).

EPIDEMIOLOGY

  • Fertility declines starting early 30s, accelerates late 30s.
  • 85% couples conceive within 12 months; 95% within 24 months.
  • ~12.7% of reproductive-age women seek infertility treatment annually in the US.
  • Prevalence: 8.8% of US women aged 15-49 affected.
  • Higher infertility rates in women >35 years.

ETIOLOGY AND PATHOPHYSIOLOGY

  • ~85% due to identifiable causes: tubal disease, ovulatory dysfunction, male factor.
  • Acquired causes: PID (most common), endometriosis, PCOS, premature ovarian failure.
  • 25% due to ovulatory disorders (PCOS, hyperprolactinemia, thyroid disease, etc.).
  • Diminished ovarian reserve (DOR): low oocyte quantity/quality.
  • Congenital/genetic abnormalities: Klinefelter syndrome, Turner syndrome, fragile X, Y chromosomal microdeletions, CFTR mutations.

RISK FACTORS

Female

  • Gynecologic: irregular menses, STIs, fibroids, dysmenorrhea.
  • Medical: advanced age, endocrinopathies, autoimmune disease, obesity, cancer.
  • Surgical: appendicitis, pelvic/intrauterine surgery, tubal ligation.
  • Social: smoking, alcohol/substance use, eating disorders, delayed childbearing.

Male

  • Medical: STIs, prostatitis, endocrinopathy, cancer.
  • Surgical: orchiopexy, hernia repair, vasectomy/reversal.
  • Social: smoking, alcohol/substance abuse, anabolic steroids, environmental heat exposure.

COMMONLY ASSOCIATED CONDITIONS

  • Pelvic pathology, endocrine dysfunction, anovulation (e.g., PCOS).

DIAGNOSIS

HISTORY

  • Reproductive history, menstrual cycles, sexual function.
  • Prior pregnancies, abortions, surgeries.
  • STI, malignancy, chronic illness.
  • Family reproductive issues.
  • Medications and environmental exposures.

PHYSICAL EXAM

  • BMI, fat distribution, waist circumference.
  • Female: Tanner staging, PCOS signs, vaginal and uterine exam.
  • Male: genital exam (penis, testes, vas deferens, varicocele).

DIFFERENTIAL DIAGNOSIS

  • Kallmann syndrome, hypogonadotropic hypogonadism, hormonal deficiencies, hemochromatosis, endometriosis, thyroid disease, prolactinoma, PCOS.

DIAGNOSTIC TESTS

Initial Tests

  • Ovulation assessment: basal body temperature, LH surge testing, progesterone levels.
  • Ovarian reserve: day 3 FSH, estradiol, AMH, antral follicle count.
  • Semen analysis: volume, concentration, motility, morphology; repeat 2-3 times.
  • Additional labs: prolactin, TSH, 17-hydroxyprogesterone, androgens.
  • Infectious disease screening: HIV, HSV, chlamydia, gonorrhea, RPR, hepatitis B, CMV.
  • Imaging: transvaginal US, hysterosalpingogram (HSG).

Follow-Up

  • Hysteroscopy and laparoscopy for anatomical abnormalities or endometriosis.

TREATMENT

GENERAL MEASURES

  • Lifestyle: ideal BMI, smoking cessation, limit caffeine/alcohol.
  • Timing intercourse around ovulation.
  • Folate supplementation (0.4-0.8 mg/day) for all women.
  • Male diet: carotenoids may improve sperm quality.

Assisted Reproductive Techniques

  • IVF: egg retrieval, fertilization outside body, embryo transfer.
  • IUI: sperm placed directly into uterus; success 7-10% per cycle.
  • ICSI: single sperm injected into egg for severe male factor.

MEDICATIONS

First Line

  • Women with anovulation:
  • Hypogonadotropic: daily FSH/LH injections.
  • Normogonadotropic (mostly PCOS): letrozole preferred over clomiphene.
  • Unexplained infertility: controlled ovarian hyperstimulation, IUI, IVF.
  • Male: lifestyle, discontinue offending meds, clomiphene to improve sperm count.

Second Line

  • Metformin for PCOS with glucose intolerance.
  • Oral contraceptives for certain anovulatory cases.
  • Dopamine agonists (cabergoline, bromocriptine) for hyperprolactinemia.
  • Gonadotropins for clomiphene-resistant or hypogonadotropic patients.

ISSUES FOR REFERRAL

  • To reproductive endocrinologists and urologists.
  • Consider surrogate pregnancy if female cannot conceive.

SURGERY/OTHER PROCEDURES

  • For anatomical causes: polypectomy, myomectomy, salpingectomy.
  • Male surgery: varicocele repair, vasectomy reversal, sperm retrieval.
  • Ovarian drilling/wedge resection for PCOS.

ONGOING CARE

  • Refer if no success after 3-6 cycles of oral ovulation induction.

DIET

  • Limit caffeine and alcohol intake.

PATIENT EDUCATION

  • American Society for Reproductive Medicine: https://www.asrm.org
  • Resolve: The National Infertility Association: https://www.resolve.org

PROGNOSIS

  • 80-90% of couples conceive within 12 months of trying.
  • Fertility declines with age.

COMPLICATIONS

  • Anxiety, multiple pregnancies, ovarian hyperstimulation syndrome (OHSS).
  • Slightly increased risk of congenital anomalies.
  • Higher maternal morbidity in infertile women and those receiving fertility treatments.

REFERENCES

  1. Carson SA, Kallen AN. Diagnosis and management of infertility: a review. JAMA. 2021;326(1):65-76.

ICD10

  • N97.9 Female infertility, unspecified
  • N46.9 Male infertility, unspecified
  • N97.1 Female infertility of tubal origin

CLINICAL PEARLS

  • Infertility is often multifactorial and requires a comprehensive approach.