Infertility

Infertility is generally defined as the inability to achieve pregnancy despite regular unprotected sex after at least one year in women under 35 years of age and after 6 months in women 35 years of age and over. Sperm disorders (e.g., impaired motility, reduced count) are the most common cause of male infertility, while anovulation and impaired fallopian tube motility are the prevalent causes of female infertility. Diagnosis involves the assessment of both the male and the female partner to determine the underlying causes. Commonly performed tests include semen analysis, hormone tests for assessment of ovulatory function, and evaluation of tubal patency. Treatment depends on the underlying cause, with conservative measures including sex hormone substitution and clomiphene citrate or gonadotropins to stimulate ovulation. Surgery is indicated in the presence of structural abnormalities (e.g., tubal adhesions, varicocele). In vitro fertilization is a potential option to facilitate conception in the light of male or female infertility.

• Infertility: inability to achieve pregnancy after 12 months of unprotected sex in women < 35 years and 6 months in women ≥ 35 years of age ^[1][2]
  • Primary infertility: infertility in persons who have never achieved pregnancy
  • Secondary infertility: infertility in persons who have previously achieved at least one pregnancy
• Recurrent pregnancy loss: the inability of a woman to carry to live birth even if conception is possible (e.g., due to uterine myomas, antiphospholipid syndrome)

• Infertility affects approx. 10–15% of couples of reproductive age. ^[3]
• Approx. 5% of women in the US aged 15–44 years old are infertile. ^[4]
• Approx. 5–10% of men in the US aged 15–44 years old are infertile. ^[5][6]

Epidemiological data refers to the US, unless otherwise specified.

Female infertility

• Systemic conditions
  • Thyroid disorders
  • Diabetes mellitus
  • Hypertension
  • Obesity
  • Cushing syndrome
  • Chronic diseases (e.g., hepatic or renal)
• Ovary-related causes
  • Menstrual cycle abnormalities (e.g., functional hypothalamic amenorrhea)
  • Hyperprolactinemia
  • Premature ovarian failure
  • Pituitary adenoma
  • Diminished ovarian reserve
    • A decline in functioning oocytes (either reduced number or impaired development)
    • A normal consequence of age, but can also be caused by an underlying disorder (e.g., endometriosis)
  • Hypogonadotropic hypogonadism
  • PCOS
• Tubal/pelvic causes
  • PID
  • Endometriosis
  • Fallopian tube adhesions and/or obstruction
    • Following tubal or pelvic surgery
    • Following infections: appendicitis, chronic chlamydia infection, acute salpingitis, inflammatory bowel disease
• Uterine causes
  • Anatomical anomalies (see “Anomalies of the female genital tract”)
    • Septate uterus
    • Bicornuate uterus
    • Mayer‑Rokitansky-Kuster‑Hauser syndrome
  • Uterine leiomyoma
  • Endometrial polyps
  • Asherman syndrome
    • Mostly iatrogenic (scarring, fibrosis, and/or adhesions of the endometrium caused by curettage)
    • Reduces the sensitivity of the endometrium to progestogens
• Cervical causes
  • Trauma (e.g., following cryotherapy, conization)
  • Immune factors (e.g., antisperm antibodies in the cervical mucus)
  • DES exposure in utero
  • Cervical anomalies (e.g., insufficient cervical mucus production)
• Psychiatric causes
  • Vaginismus
  • Sexual arousal disorder

Male infertility

• Chronic conditions
  • Liver cirrhosis
  • Renal insufficiency
• Sperm disorders
  • Reduced sperm count
  • Impaired motility
  • Reduced ejaculate volume
• Testicular causes
  • Scrotal injuries
  • Testicular torsion
  • Infections (e.g., mumps, gonorrhea)
  • Scrotal hyperthermia (varicocele)
  • Cryptorchidism
• Medication
  • Anabolic steroids
  • Spironolactone
  • Corticosteroids
  • Cimetidine
• Endocrine causes
  • Thyroid disorders
  • Hyperprolactinemia
  • Pituitary and hypothalamic tumors (e.g., pituitary macroadenomas, craniopharyngiomas)
  • 21–hydroxylase deficiency
• Inherited causes
  • Klinefelter syndrome
  • Kallmann syndrome
    • Often associated with structural/developmental abnormalities: cryptorchidism, cleft palate, scoliosis, renal agenesis
    • Characterized by delayed onset of puberty and hyposmia/anosmia
    • More common in men
  • Idiopathic hypogonadotropic hypogonadism
  • Y chromosome microdeletion
• Sexual dysfunction
  • Impaired libido
  • Anejaculation

Female infertility may manifest with symptoms of anovulation (e.g., amenorrhea, irregular menses).

Diagnostics ^[2]

• Medical history of both partners, especially gynecological history (e.g., children, family history)
• Assess ovulatory function
  • Menstrual history
  • Body temperature analysis to monitor menstrual cycle
  • Hormone tests
    • Midluteal serum progesterone levels: progesterone should increase shortly after ovulation → failure of progesterone levels to rise indicates anovulation
    • Ovulation prediction test (detect LH levels)
    • Androgen levels: elevated levels induce negative feedback to the hypothalamus → inhibition GnRH secretion → decreased estrogen levels and suppression of ovulation
    • Ovarian reserve
      • Early follicular FSH levels: elevated in ovarian insufficiency and indicate reduced ovarian reserve
      • Early follicular estradiol levels
      • Anti-Müllerian hormone levels
    • TSH levels: elevated levels in hypothyroidism
    • Prolactin levels: hyperprolactinemia
  • Ovarian sonography: antral follicle count
  • Endometrial biopsy
    • Usually performed 1–3 days before menstruation to determine thickness of endometrium
    • A flat endometrial lining indicates a defect in the luteal phase of the menstrual cycle.
• Imaging: assess the patency of fallopian tubes and uterus
  • Indications
    • If the initial workup does not reveal any abnormalities and no history suggestive of tubal obstruction
    • Screen for tubal occlusion and structural uterine abnormalities (e.g., septate uterus, submucous fibroids, intrauterine adhesions)
  • Hysterosalpingography: an imaging technique involving the injection of contrast dye into the cervical canal and serial radiographs to evaluate the uterine cavity and morphology/patency of the fallopian tubes
  • Sonohysterosalpingography: an ultrasound technique in which fluid is inserted into the uterus via the cervix to examine the uterine lining
  • Hysteroscopy and/or laparoscopy
    • Indicated if there is evidence of intrauterine abnormalities or tubal occlusion.
    • Can also be used therapeutically to remove small adhesions or mucous plugs obstructing the tubal lumen
• Examine cervix
  • Physical examination
  • Pap smear
  • Testing for antisperm antibodies in cervical mucus (see “Diagnostics” in male infertility below)

Treatment ^[2][7][8][9]

• Lifestyle modifications: cessation of alcohol, nicotine, and recreational drug use as they contribute to subfertility.
• Treatment of underlying causes (e.g., levothyroxine for hypothyroidism, bromocriptine for hyperprolactinemia, metformin for PCOS) ^[10]
• Ovulation induction
  • Clomiphene citrate
  • GnRH (pulsatile): stimulation of FSH and LH release → follicle maturation
  • Gonadotropins (e.g., recombinant hCG, recombinant LH): stimulate final oocyte maturation → ovulation
  • Tamoxifen (selective estrogen receptor modulator)
  • GnRH-antagonists ^[7][8][9]
• Assisted reproductive technology
  • In vitro fertilization
    • The most common form of assisted reproduction technology
    • Involves hormonal follicular stimulation followed by a transvaginal follicular puncture for oocyte retrieval with ultrasound monitoring
    • The recovered oocytes are mixed with processed spermatozoa and incubated.
    • Two (in young women) to a maximum of five embryos (in women over 40 years of age) are transferred into the uterus.
  • Intracytoplasmic sperm injection: a type of assisted reproductive technology, in which a single spermatozoon is introduced into an oocyte under a microscope using an injection pipette
• Intrauterine insemination (IUI): a procedure in which washed and concentrated sperm are introduced directly into the uterine cavity
• Oocyte donation
• Surgery: removal of tubal, cervical, or uterine adhesions, myomas, and/or scar tissue

Ovarian hyperstimulation syndrome (OHSS) ^[11][12]

• Definition: a potentially life-threatening complication of ovulation induction with exogenous human chorionic gonadotropin (hCG)
• Pathophysiology
  • Exogenous hCG is thought to be responsible for the massive luteinization of the ovarian granulosa cells.
  • Formation of multiple ovarian follicles and corpus luteum cysts with rapid ovarian enlargement
  • ↑ Release of vasoactive mediators (e.g., VEGF) that induce an increase in capillary permeability and consequent third spacing into the abdominal cavity
• Clinical features
  • Onset: between 3 days (early onset) and ≥ 9 days (late onset) after hCG administration
  • Abdominal pain and distention
  • Nausea and/or vomiting
  • Weight gain
  • Severe features
    • Pleural effusion
    • Acute kidney injury with oliguria/anuria
    • Venous or arterial thromboembolic events
• Diagnostics
  • Laboratory analysis
    • Leukocytosis, ↑ Hct
    • Serum electrolyte concentrations and renal function tests
    • Liver function tests
  • Transvaginal ultrasound: ascites and ovarian enlargement
• Management
  • Mild and moderate cases (usually early onset): manage on an outpatient basis
    • Limit physical activity
    • Pain management with acetaminophen
    • Daily monitoring of body weight (should not increase by > 1 kg/day) and urine output
    • Sufficient hydration (1–2 L/day)
    • Paracentesis to relieve symptoms of ascites
  • Severe cases (usually late onset)
    • Hospitalization
    • Multidisciplinary management approach: supportive care, monitoring, and prevention of complications (e.g., prophylactic anticoagulation)

Diagnostics

• Medical history of both partners
• Semen analysis
• Mixed antiglobulin reaction test for antisperm antibodies
  • Antisperm antibodies form in disruption of the blood-testis barrier (composed of Sertoli cell tight-junctions)
  • The antibodies can lead to immobilization and agglutination of sperm or have a spermatotoxic effect.
• TSH levels
• Prolactin levels
• Karyotype test (Klinefelter syndrome)

Treatment

Treatment of underlying cause (see Etiology above).

• Modification of lifestyle factors such as alcohol, nicotine, and recreational drug use
• Medical therapy: clomiphene citrate, tamoxifen
• Assisted reproductive technology
  • Intrauterine insemination
  • In vitro fertilization
  • Intracytoplasmic sperm injection
• Surgical treatment of testicular anomalies and/or defects