Amenorrhea

Amenorrhea is the absence of menstruation. It is classified as either primary amenorrhea or secondary amenorrhea depending on whether menarche has occurred. Causes include physiological factors (e.g., pregnancy, lactation, menopause), dysfunction of the hypothalamic-pituitary-gonadal axis, anatomical reproductive tract abnormalities, gonadal dysfunction, and systemic diseases. Clinical evaluation involves a focused history and physical examination, including a pelvic examination, Tanner staging, and evaluation for signs of common causes of amenorrhea. All individuals with amenorrhea should be evaluated for pregnancy and, based on clinical evaluation, receive targeted testing for suspected causes. Causes of primary amenorrhea are often identified with clinical evaluation and, if indicated, pelvic ultrasound and certain laboratory studies (e.g., FSH, karyotype). Causes of secondary amenorrhea are identified using hormone testing and often a pelvic ultrasound, followed by additional testing if indicated. Management focuses on the underlying cause and may include lifestyle changes, hormone replacement therapy (HRT), surgical correction for anatomical abnormalities, and infertility treatment.

Amenorrhea is the absence of menstruation; it is classified as either primary amenorrhea or secondary amenorrhea.

• Primary amenorrhea: no menarche by 15 years of age or 5 years after thelarche, whichever comes first ^[1]
• Secondary amenorrhea is the absence of menstruation for more than: ^[1]
  • 3 months in individuals with previously regular cycles
  • 6 months in individuals with previously irregular cycles

Delayed puberty in female individuals is defined as an absence of breast development by 13 years of age, and its workup includes an evaluation for causes of primary amenorrhea. ^[1][2]

• Physiological
  • Pregnancy
  • Lactation
  • Menopause
  • Constitutional delay of growth and puberty
• Anatomical abnormalities
  • Transverse vaginal septum
  • Imperforate hymen
  • Agenesis of the lower vagina
  • Uterine adhesions (e.g., Asherman syndrome)
  • Cervical stenosis
  • Müllerian agenesis
  • Individuals with XY chromosomes and receptor or enzyme defects, e.g.:
    • 17α-hydroxylase deficiency
    • Androgen insensitivity syndrome
    • 5α-reductase deficiency
• Hypothalamic or anterior pituitary dysfunction (hypogonadotropic hypogonadism)
  • Functional hypothalamic amenorrhea
  • Brain injury, infection, infiltration, infarction
  • Isolated GnRH deficiency: Kallmann syndrome
  • Prader-Willi syndrome ^[5][6]
• Primary ovarian insufficiency (hypergonadotropic hypogonadism)
  • Congenital: gonadal dysgenesis (e.g., Turner syndrome)
  • Acquired: injury, tumor, or infection of the ovaries
• Other endocrine conditions
  • Polycystic ovary syndrome (PCOS)
  • Hyperprolactinemia: due to pituitary adenoma, medications
  • Thyroid disease: hypothyroidism, hyperthyroidism
  • Cushing syndrome
  • Adrenal disease (e.g., congenital adrenal hyperplasia; , adrenal insufficiency, adrenal tumors)
  • Obesity ^[7]
  • Uncontrolled diabetes mellitus
• Other chronic diseases: celiac disease, inflammatory bowel disease
• Medications: antipsychotics, antiepileptics, hormonal contraceptives, steroid hormones

Pregnancy, lactation, and menopause are the most common causes of amenorrhea. ^[1]

Ovarian insufficiency is the failure of adequate ovarian function (endocrine as well as reproductive) before the age of 40, which often leads to premature menopause

Primary ovarian insufficiency (POI) ^[8]

• Definition: ovarian insufficiency despite adequate gonadotropin stimulation (previously called premature ovarian failure)
• Etiology ^[9]
  • Idiopathic (90% of cases)
  • Genetic disorders associated with ovarian hypoplasia, especially in women < 30 years; (e.g., Turner syndrome; , Swyer syndrome, androgen insensitivity syndrome, adrenogenital syndrome, fragile X syndrome)
  • Autoimmune diseases; (e.g., autoimmune lymphocytic oophoritis, Hashimoto thyroiditis, Addison disease, type I diabetes mellitus, pernicious anemia)
  • Toxins: Smoking is a major risk factor.
  • Iatrogenic: irradiation and/or chemotherapy, prolonged GnRH agonist therapy, induction of multiple ovulation in infertility treatment
  • Infectious diseases (e.g., measles, mumps, tuberculosis of the genital tract)
• Pathophysiology: follicular dysfunction or depletion → ↓ estrogen levels → reduced feedback inhibition of estrogen on FSH and LH → ↑ FSH and LH (usually FSH > LH)
• Clinical features ^[10]
  • Climacteric symptoms such as vaginal dryness, night sweats, hot flashes, dyspareunia, and irritability
  • Abnormal/irregular bleeding pattern that can progress to secondary amenorrhea or permanent cessation of menstruation
  • Infertility or reduced fertility (Pregnancy is possible via in vitro fertilization.)
• Diagnostics
  • Confirmed by two ↑ FSH levels (> 30–40 mIU/mL) and two ↓ estradiol levels (< 50 pg/mL) at least 1 month apart after > 3 months of menstrual irregularities in a woman under age 40
  • Further tests help determine the underlying cause (e.g, karyotyping, thyroid function).
• Treatment
  • See “Hormone replacement therapy.”
  • Treatment of underlying causes

Secondary ovarian insufficiency

• Definition: ovarian insufficiency due to inadequate stimulation of the ovaries by the hypothalamus and/or pituitary
• See “Secondary hypogonadism.”

Focused history ^[1][3]

• Gynecologic and obstetric history
  • Age at thelarche and menarche
  • Menstrual history
  • Sexual history (e.g., sexual activity, history of STIs)
  • Recent pregnancy or breastfeeding
• Past medical history
  • Medication use (e.g., antipsychotics, oral contraceptives)
  • Preexisting medical conditions
  • History of chemotherapy
• Focused review of symptoms
  • Symptoms of estrogen deficiency
  • Symptoms of hypothyroidism or symptoms of hyperthyroidism
  • Symptoms of eating disorders, including excessive exercise
  • Symptoms of hyperandrogenism
  • Symptoms of hyperprolactinemia (e.g., galactorrhea)
• Psychosocial stressors

Physical examination ^[1][3]

• Blood pressure
• BMI
• Assessment for dysmorphic features (e.g., signs of Turner syndrome)
• Examination of the thyroid gland
• Evaluation for signs of hyperandrogenism (e.g., hirsutism, acne)
• Tanner stage
• Pelvic examination to assess for:
  • Structural abnormalities (e.g., imperforate hymen, transverse vaginal septum, blind or absent vagina)
  • Signs of low estrogen (e.g., prepubertal appearance, urogenital atrophy) ^[11][12]

Hypertension may be present in patients with congenital adrenal hyperplasia due to 17α-hydroxylase deficiency or in patients with Cushing syndrome. ^[1][13]

Approach ^[1][3]

Obtain a pregnancy test in all patients before initiating a diagnostic workup for amenorrhea.

Primary amenorrhea

• Cervix visualized on pelvic examination (i.e., a uterus is present): Obtain FSH; consider also obtaining other initial laboratory studies for amenorrhea.
  • FSH ↓ or normal
    • Breasts absent: Evaluate for constitutional delay of growth and puberty and isolated GnRH deficiency (e.g., Kallmann syndrome).
    • Breasts present: Perform workup for secondary amenorrhea.
  • FSH ↑: Perform karyotyping to evaluate for genetic causes of primary ovarian insufficiency (gonadal dysgenesis).
• Blind or absent vagina on pelvic examination: Perform pelvic ultrasound to assess internal reproductive organs.
  • Uterus absent: Perform karyotyping and measure testosterone level.
  • Uterus present: Consider ; congenital reproductive outflow tract obstruction (e.g., imperforate hymen, vaginal agenesis, and transverse vaginal septum).
• See “Common causes of primary amenorrhea” for further details on interpretation of findings.

Secondary amenorrhea

• Obtain:
  • Initial laboratory studies for amenorrhea
  • Targeted testing for amenorrhea as clinically indicated
  • Pelvic ultrasound, if readily available
• See “Common causes of secondary amenorrhea” for further details on interpretation of findings.
• If no cause is identified, consider hormone withdrawal testing for amenorrhea.

Initial laboratory studies for amenorrhea ^[1][3]

Tests commonly obtained include the following:

• FSH with or without LH
• Estradiol with or without anti-Müllerian hormone (AMH)
• TSH
• Prolactin

Targeted testing for amenorrhea ^[1][3]

Obtain targeted testing as indicated by clinical presentation, if not already obtained as part of initial testing.

• Laboratory studies
  • Signs of estrogen deficiency: FSH, LH, estradiol, AMH
  • Signs of hyperandrogenism: free and total testosterone, DHEA-S, 17-hydroxyprogesterone
  • Signs of hyperprolactinemia (e.g., galactorrhea): prolactin
  • Signs of hypothyroidism or signs of hyperthyroidism: TSH
  • Signs of adrenal insufficiency or hypercortisolism: cortisol
  • Signs of chronic systemic illness: CBC, BMP, ESR, CRP, urinalysis
  • Weight loss and/or gastrointestinal symptoms: diagnostics for celiac disease
• Imaging
  • Suspected PCOS and/or structural reproductive tract abnormalities: pelvic ultrasound or MRI
  • Suspected androgen-secreting tumor: adrenal imaging
  • Symptoms suggestive of CNS pathology (e.g., visual field defects) and/or persistent hyperprolactinemia: MRI brain

↑ TSH suggests hypothyroidism as a cause of amenorrhea.

Elevated levels of androgens (testosterone, DHEA-S) can be seen with PCOS, congenital adrenal hyperplasia, Cushing syndrome, or an androgen-secreting tumor. ^[3]

Hormone withdrawal testing in amenorrhea ^[14]

The following studies can be used to evaluate patients with secondary amenorrhea if there is no identified cause after the initial workup. ^[1]

• Progestin challenge test: typically the initial test
  • Method: Administer a progestin for 5–10 days. ^[15]
  • Interpretation: Assess for withdrawal bleeding within 14 days of progestin cessation.
    • Withdrawal bleeding: indicates anovulation (e.g., PCOS, idiopathic anovulation)
    • No withdrawal bleeding: indicates hypoestrogenism (i.e., hypogonadism) or reproductive outflow tract obstruction
• Estrogen-progesterone challenge test: performed in patients with no withdrawal bleeding on initial testing
  • Method
    • Administer estrogen for 21–25 days.
    • Add progesterone during the last 5–10 days of estrogen administration.
  • Interpretation: Assess for withdrawal bleeding within 2–7 days of progesterone cessation.
    • Withdrawal bleeding: indicates hypoestrogenism (i.e., hypogonadism)
    • No withdrawal bleeding: indicates reproductive outflow tract obstruction or endometrial dysfunction (e.g., Asherman syndrome; , endometritis)

Primary amenorrhea ^[1][3]

Most causes of secondary amenorrhea can also cause primary amenorrhea.

Secondary amenorrhea ^[1][3]

Pregnancy, breastfeeding (lactation amenorrhea), and menopause are the most common causes of secondary amenorrhea.

Management is based on the underlying cause. ^[1][3]

• Goals
  • Progression of puberty in patients with primary amenorrhea
  • Prevention of complications (e.g., osteoporosis, symptoms of estrogen deficiency)
  • Optimization of reproductive health (e.g., functional anatomy, fertility)
• Options
  • Lifestyle changes (e.g., in PCOS, functional hypothalamic amenorrhea)
  • Pharmacological treatment, e.g.:
    • HRT and COCs for hypogonadism
    • Dopamine agonists (bromocriptine, cabergoline) for prolactinoma
  • Surgery for tumors or anatomical abnormalities
• Indications for specialist referral
  • Procedural interventions: gynecology or surgery
  • Hormonal abnormalities: endocrinology
  • Infertility treatment: reproductive endocrinology

Definition ^[15]

Functional hypothalamic amenorrhea is defined as anovulation due to dysfunctional GnRH secretion.

Etiology ^[15]

• Reduced calorie intake: e.g., in eating disorders such as anorexia nervosa
• Excessive exercise: e.g., in competitive athletes (also called exercise-induced amenorrhea)
• Stress

Pathophysiology ^[15]

Decreased leptin (low body fat) and/or increased cortisol (exercise/stress) → decreased pulsatile release of GnRH from the hypothalamus → decreased secretion of FSH and LH → decreased estrogen levels → anovulation and secondary amenorrhea → infertility

Clinical features ^[15]

• Low BMI or fluctuations in BMI
• Menstrual cycle abnormalities: cycles > 45 days or absent for ≥ 3 months ^[15]
• Symptoms of eating disorders
• Stress, anxiety, and/or perfectionism
• Stress fractures
• Infertility
• Relative energy deficiency in sport, including the following findings traditionally associated with the female athlete triad syndrome in adolescent and young adult female athletes: ^[25][26]
  • Relative calorie deficit compared to energy needs, with or without an eating disorder
  • Menstrual dysfunction
  • Decreased bone density

Diagnosis ^[15]

Functional hypothalamic amenorrhea is a diagnosis of exclusion.

• All patients
  • Exclude other causes: See “Clinical evaluation of amenorrhea” and “Diagnostics for amenorrhea.”
  • Consider hormone withdrawal testing. ^[15]
• Suspected underlying chronic disease: CBC, CMP, ESR and CRP
• ≥ 6 months of amenorrhea: DEXA scan to assess for reduced bone mineral density ^[15]

Management ^[15]

• Identify and treat the underlying cause.
  • Improve nutritional status and evaluate suspected eating disorders.
  • Screen for psychological stressors and recommend stress reduction (e.g., through lifestyle changes, ; cognitive behavioral therapy).
  • Exercise reduction if indicated
• Refer patients with refractory amenorrhea to appropriate specialists (e.g., endocrinology, reproductive endocrinology).
  • Short-term transdermal estradiol with cyclic oral progestin may be used. ^[15]
  • Individuals who want to conceive with a BMI > 18.5 kg/m²: ovulation-induction therapy, e.g., pulsatile GnRH, gonadotropins, clomiphene citrate ^[15]

Ongoing energy imbalances and resulting complications may be masked by the use of cyclical COCs in individuals with functional hypothalamic amenorrhea. ^[15]