Infertility

Infertility is defined as the inability to achieve pregnancy after 12 months of unprotected sexual intercourse or therapeutic donor insemination in women < 35 years of age and after 6 months in those ≥ 35 years of age. Ovulatory dysfunction and tubal disorders are the most common causes of female infertility, while primary hypogonadism is the most common cause of male infertility. Diagnosis involves the assessment of both partners to determine the underlying causes and typically includes semen analysis, hormone tests for assessment of ovulatory function, and evaluation of tubal patency. Treatment depends on the underlying cause. Assisted reproductive technology (e.g., in vitro fertilization) is the main treatment to facilitate conception.

Infertility is defined as the inability to achieve pregnancy after 12 months of unprotected sexual intercourse or therapeutic donor insemination 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

Infertility affects approximately 1 in 6 people in their lifetime. ^[3]

Epidemiological data refers to the US, unless otherwise specified.

Female infertility

Ovulatory dysfunction

• Functional hypothalamic amenorrhea
• Idiopathic hypogonadotropic hypogonadism
• Hyperprolactinemia
• Pituitary adenoma
• Genetic causes (e.g., Turner syndrome, Kallmann syndrome)
• Systemic causes
  • Thyroid disorders
  • Cushing disease
  • Chronic renal or liver disease
  • Obesity
• Polycystic ovary syndrome (PCOS)
• Premature ovarian failure
• Diminished ovarian reserve
  • A decline in functioning oocytes (either reduced number or impaired development)
  • Can either be a normal consequence of age or caused by an underlying disorder (e.g., endometriosis)

Tubal/pelvic causes

• Pelvic inflammatory disease
• Blocked or damaged fallopian tubes (e.g., pelvic adhesions, obstruction)
• Endometriosis

Uterine causes

• Uterine leiomyoma
• Endometrial polyps
• Bicornuate uterus
• Septate uterus
• Asherman syndrome
• Mayer‑Rokitansky-Kuster‑Hauser syndrome

Cervical causes

• Trauma (e.g., following cryotherapy, conization)
• Immune factors (e.g., antisperm antibodies in the cervical mucus)
• Diethylstilbestrol exposure in utero
• Cervical anomalies (e.g., insufficient cervical mucus production)

Male infertility

Primary hypogonadism

• Testicular causes
  • Varicocele
  • Infection (e.g., mumps, gonorrhea)
  • Testicular torsion
  • Cryptorchidism
• Systemic causes
  • Chronic renal insufficiency
  • Liver cirrhosis
  • Medications (e.g., cimetidine, spironolactone)
• Genetic causes
  • Klinefelter syndrome
  • Y chromosome microdeletion
  • Idiopathic dysspermatogenesis

Secondary hypogonadism

• Pituitary or hypothalamic disease (e.g., tumors, infiltrative diseases, trauma, surgery)
• Idiopathic hypogonadotropic hypogonadism
• Hyperprolactinemia (e.g., drugs or lactotroph adenomas)
• Systemic conditions
  • Thyroid disorders
  • Cushing disease
  • Chronic renal insufficiency
  • Liver cirrhosis
  • Obesity
• Medications (e.g., opioids, prolonged glucocorticoid therapy, anabolic steroids)
• Genetic causes: Kallmann syndrome

Sperm transport disorders

• Obstructive azoospermia
  • Absence of spermatozoa in semen despite normal spermatogenesis due to structural or functional abnormalities (e.g., obstruction, absence, dysfunction) along the sperm transport system (epididymis, vas deferens, ejaculatory duct)
  • Possible causes include infection (e.g., gonorrhea), iatrogeny (e.g., due to vasectomy), congenital (e.g., absent vas deferens in patients with cystic fibrosis), or genetic conditions (e.g., decreased sperm motility in primary ciliary dyskinesia).
• Sexual dysfunction
  • Anejaculation
  • Premature ejaculation

General ^[2][4][5]

Comprehensive medical, reproductive, and family history of both partners, including:

• Duration of infertility and results of previous diagnostic tests and/or treatments
• Coital frequency and history of sexual dysfunction
• Previous methods of contraception
• Sexual history, including sexually transmitted infections
• Previous surgery or illness
• Childhood development and illness
• Medications
• Family history of infertility
• Exposure to gonadal toxins (e.g., tobacco, alcohol, recreational drugs)
• Trauma (e.g., blunt or penetrating trauma to the testes)

Female infertility ^[2][4]

Female infertility evaluation focuses on ovulatory function, ovarian reserve, and structural abnormalities.

• Physical examination
  • Weight, BMI, vital signs
  • Thyroid abnormalities (e.g., nodules, diffuse enlargement)
  • Secondary sex characteristics, including Tanner stages of breasts and pubic area
  • Vaginal or cervical abnormalities (e.g., discharge)
  • Abdominal or pelvic tenderness
  • Uterine shape, size, mobility, position
  • Adnexal abnormalities (e.g., masses, tenderness)
  • Tenderness or masses in the pouch of Douglas
• Ovulatory function assessment
  • Menstrual history
  • Basal body temperature analysis
  • Midluteal serum progesterone measurement
  • Luteinizing hormone tests (ovulation prediction test)
  • Further evaluation
    • Endocrine evaluation: prolactin levels, TSH levels
    • Endometrial biopsy
      • Endometrial dating is no longer recommended to assess ovulatory or luteal function because it lacks diagnostic accuracy.
      • Only recommended if there is suspicion of endometrial disease (e.g., neoplasia)
    • Serial transvaginal ultrasonography
      • Monitors ovulatory cycle (e.g., progressive follicular growth, collapse of the preovulatory follicle)
      • Logistically challenging and costly
      • Only indicated if other diagnostic tests fail to accurately assess ovulatory function
• Ovarian reserve assessment
  • FSH and estradiol levels (measured between the 2^nd and 5^th days of the cycle)
  • Anti-Müllerian hormone levels
  • Antral follicle count
  • Clomiphene citrate challenge test
• Structural uterine, tubal, and pelvic assessment
  • Ultrasonography: used to screen for ovarian, uterine, and pelvic abnormalities (e.g., adnexal adhesions, endometriosis)
  • Hysterosalpingography: used to evaluate the morphology/patency of the fallopian tubes (e.g., tubal occlusion) and uterine cavity abnormalities (e.g., septate uterus, submucous fibroids, intrauterine adhesions)
  • Sonohysterosalpingography
  • Hysteroscopy: indicated for further evaluation and treatment of intrauterine abnormalities or tubal occlusion

Male infertility ^[2][5]

Male infertility evaluation focuses on medical history and semen parameters.

• Physical examination
  • Penile abnormalities, including the location of the urethral meatus
  • Palpation and measurement of the testes
  • Palpation of ductus deferens and epididymis
  • Presence of varicocele
  • Secondary sex characteristics, including Tanner stages of genital and pubic hair development
  • Digital rectal examination
• Semen analysis
• Further evaluation
  • Tests for antisperm antibodies
    • Antisperm antibodies form when the blood-testis barrier is disrupted.
    • These antibodies can lead to immobilization and agglutination of sperm or have a spermatotoxic effect.
  • Endocrine evaluation
    • FSH and testosterone levels
    • Prolactin levels
    • TSH levels
  • Postejaculatory urinalysis: to rule out retrograde ejaculation
  • Ultrasonography: to assess for structural abnormalities of the genital tract
  • Karyotype testing: to assess for genetic conditions associated with male infertility (e.g., Klinefelter syndrome)

General

• Lifestyle modifications: cessation of alcohol, nicotine, and recreational drug use as they contribute to subfertility
• Treatment of underlying causes
  • Ovulatory dysfunction
    • Weight management (e.g., for obesity)
    • Ovulation induction
      • Clomiphene citrate (e.g., for PCOS)
      • Gonadotropins (recombinant HCG, recombinant LH) e.g., for hypopituitarism, hypothalamic amenorrhea
      • Pulsatile GnRH (e.g., for functional hypothalamic amenorrhea)
      • Tamoxifen
      • GnRH-antagonists ^[6][7][8]
      • Other (e.g., bromocriptine for hyperprolactinemia, levothyroxine for hypothyroidism, metformin for PCOS)
    • Oocyte donation (e.g., for primary ovarian insufficiency)
  • Uterine anomalies: surgical treatment (e.g., for removal of uterine adhesions, uterine leiomyomas)
  • Tubal anomalies: in vitro fertilization, surgical treatment (e.g., removal of tubal adhesions)
  • Testicular anomalies and/or defects: surgical treatment (e.g., large varicoceles)
  • Sperm transport disorders: assisted reproductive technology

Assisted reproductive technology

An umbrella term for all types of fertility treatments involving the handling of embryos or eggs. Most treatments are based on surgical egg removal, combining the eggs with sperm, and transferring the resulting embryo into the uterus of the egg donor or another woman.

• 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 form of in vitro fertilization.
  • A single spermatozoon is introduced into an oocyte under a microscope using an injection pipette, after which the same procedure is followed as described for in vitro fertilization.

Patients who start assisted reproductive technology are at risk of developing complications related to ovarian stimulation.

Ovarian hyperstimulation syndrome (OHSS) ^[9][10]

• 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
  • Ascites
  • Oliguria or anuria
  • Dyspnea
  • Pleural effusion
  • Syncope
  • Venous thrombosis
• Diagnostics
  • Laboratory analysis
    • CBC (↑ Hct, leukocytosis)
    • Serum electrolyte concentrations
    • 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)
• Complications
  • Sepsis
  • Thromboembolism
  • Pericardial effusion
  • Arrhythmias
  • Acute respiratory distress syndrome
  • Acute kidney injury