Background

  • Infertility is the inability to conceive after 1 year of frequent unprotected sexual intercourse
  • It occurs in approximately 15% of reproductive-aged couples worldwide and is more common in developing countries
  • Causes of infertility may be multifactorial and include:
    • Combined male and female factors in about 40%
    • Male factor infertility in about 26%-30%
    • Ovulation disorders in about 21%-25%
    • Tubal factors in about 14%-20%
    • Cervical/uterine/peritoneal disorders in about 10%-13%
    • Idiopathic in about 25%-28%
  • Diagnosis usually based on history and physical; both partners are evaluated concurrently


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Pathogenesis in Women

  • Ovulation disorder infertility
    • Occurs when ovaries fail to produce a mature oocyte on a regular basis due to hypothalamic dysfunction, polycystic ovary syndrome (PCOS), ovarian failure, and/or hyperprolactinemia
  • Tubal factor infertility occurs when fallopian tubes fail to capture ovulated ova and/or transport sperm and embryo due to:
  • Uterine factor infertility occurs when uterus fails to allow embryo to implant and/or fails to support normal embryonic growth and development due to:
    • Congenital uterine anomalies
    • Endometrial polyps 
    • Intrauterine synechiae with adhesion of myometrium to opposing uterine wall
    • Uterine leiomyomas
  • Cervical factor infertility occurs when cervix fails to capture or transport sperm into uterus and fallopian tubes due to reduced cervical mucus quality/quantity or cervical conization

History and Physical Examination

  • Infertility history
    • Duration of infertility
    • Menstrual history
    • Sexual activity, including frequency and timing (in relation to cycle) of coitus
    • Previous contraceptive method (especially intrauterine device)
  • Past medical history
    • Previously abnormal pap smears
  • Physical
    • Measure height/weight
    • Evaluate skin – hirsutism (acne on face and/or chest may indicate hyperandrogenism); vitiligo may indicate autoimmune systemic disease
    • Assess for thyroid abnormalities
    • Assess for breast changes
    • Examine abdomen for organomegaly, ascites, surgical scars
  • Perform pelvic exam, assess for:
    • Vaginal, cervical, or adnexal abnormality
    • Size, shape, mobility, and position of uterus
    • Nodules or tenderness in posterior cul-de-sac (may indicate endometriosis/tuberculosis)

Diagnosis

  • Infertility evaluation is indicated
    • After 1 year of frequent unprotected sexual intercourse for women < 35 years old without known risk factors for infertility
    • After 6 months of frequent unprotected intercourse in couples with woman aged > 35 years and/or in couples with known clinical cause or predisposing factors for infertility  
    • Immediately in women > 40 years old, or if there is an obvious cause for infertility/subfertility

Management

  • Treatment of infertility is based on the underlying cause
    • For anovulation (WHO has classified anovulation into groups)
      • WHO Group I: hypogonadotropic hypogonadism (hypothalamic pituitary failure):
        • If BMI is < 19, advise weight gain and/or exercise moderation
        • First-line treatment includes ovulation induction with gonadotropins with luteinizing hormone activity or pulsatile administration of gonadotropin-releasing hormone
        • Second-line treatment is IVF
      • WHO Group II: normogonadotropic normoestrogenic anovulation (PCOS):
        • Weight loss may improve pregnancy outcomes if BMI is ≥ 30.
        • First-line treatment includes ovulation induction with clomiphene, metformin, or both
        • Second-line treatment may include laparoscopic ovarian drilling or ovulation induction with gonadotropins 
        • Third-line treatment is IVF
      • WHO Group III: hypergonadotropic hypoestrogenic anovulation (primary ovarian insufficiency), first-line therapy is IVF with donated oocytes
    • For hyperprolactinemic amenorrhea, treatment includes therapy with dopamine agonists (such as bromocriptine or cabergoline)
    • For fallopian tube disorders:
      • Tubal microsurgery or laparoscopic tubal surgery may restore tubal patency in patients with mild tubal disease
        • For patients with hydrosalpinx, consider laparoscopic salpingectomy prior to IVF
    • For amenorrhea and intrauterine adhesions, offer hysteroscopic adhesiolysis to restore normal menstruation and increase the likelihood of conception
    • For endometriosis-associated infertility, options include surgery or assisted reproductive technology (ART)
    • For idiopathic infertility:
      • Advise patients to try to conceive naturally for 2 years; to increase chance of conception:
        • Regular unprotected intercourse (2-3 times/week) near the time of ovulation
      • Intercourse on multiple days during the fertile window (5 days preceding and the day of ovulation) 
    • Consider IVF after 2 years of failed expectant management
    • Intrauterine insemination (IUI) should not be routinely offered to patients with idiopathic infertility
  • Ovarian hyperstimulation syndrome (OHSS)
    • Reported in about 1.4% of all IVF cycles
    • Considered the most serious complication resulting from controlled ovarian hyperstimulation in ART
    • Symptoms range from mild abdominal distension to organ failure or death

Prognosis

  • Probability of conception in fertile women < 40 years old and with regular, unprotected sexual intercourse:
    • 20%-25% per reproductive cycle
    • 60% within first 6 months
    • 84% within 1 year
    • 92% within 2 years
  • Factors associated with increased chance of conception in women with infertility
    • Short duration of infertility
    • Previous fertility
    • Age < 40 years
    • Ideal body mass index (> 19 and < 30)
  • About 50% overall pregnancy rate following treatment for infertility
    • 5% after timed intercourse
    • 10% after superovulation with IUI
    • 15%-25% after ART

Fertility preservation

  • In patients being treated for cancer
    • Consider oocyte/embryo cryopreservation in adolescents/patients of reproductive age at risk for infertility due to planned cancer treatments in cases when patients are well enough to undergo ovarian stimulation/oocyte collection
    • Consider ovarian tissue cryopreservation for patients requiring emergent chemotherapy or radiotherapy (allowing no time for oocyte stimulation and retrieval)

Kendra Church, MS, PA-C, is a physician assistant at Dana-Faber Cancer Institute/Brigham & Women’s Hospital and is also an Associate Deputy Editor for DynaMed, an evidence-based point-of-care database.

Sources

  1. National institute for Health Care Excellence. Fertility problems: assessment and treatment. Updated September, 2017. Accessed June 29, 2022. https://www.nice.org.uk/guidance/cg156
  2. O’Flynn Norma. Assessment and treatment for people with fertility problems: Nice guideline. Br J Gen Pract. 2014;64(618):50-51. doi: 10.3399/bjgp14X676609 
  3.  Kamel RM. Management of the infertile couple: an evidence-based protocol. Reprod Biol Endocrinol. 2010;8:21. doi:10.1186/1477-7827-8-21
  4. Lindsay TJ, Vitrikas KR. Evaluation and treatment of infertility. Am Fam Physician. 2015;91(5):308-314; Correction. Am Fam Physician. 2015;92(6):437. 
  5. Danis P. Natural procreative technology for treating infertility. Am Fam Physician. 2015;92(8):668.
  6. Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: a committee opinionFertil Steril. 2015;103(6):e44-e50. doi:10.1016/j.fertnstert.2015.03.019