Skip to content

Amenorrhea

Description:
- Primary amenorrhea: no menses by age 13 without secondary sexual characteristics OR no menses by age 15 with normal secondary characteristics.
- Secondary amenorrhea: absence of menses for ≥3 months (previously regular cycles) or ≥6 months (irregular cycles).

System(s) affected: endocrine/metabolic, reproductive

Pregnancy consideration: pregnancy is most common cause of secondary amenorrhea.

Epidemiology

  • Primary amenorrhea <1% female population
  • Secondary amenorrhea 3-4% female population
  • No race/ethnicity difference reported.

Etiology and Pathophysiology

  • Menses absence can be temporary, intermittent, or permanent due to dysfunction at hypothalamus, pituitary, uterus, ovaries, or vagina.

Primary Amenorrhea

  • Gonadal dysgenesis (e.g., Turner syndrome [45,X]), autoimmune, idiopathic gonadal failure
  • Anatomic abnormalities (Müllerian agenesis, imperforate hymen, transverse vaginal septum)
  • Hypothalamic-pituitary axis abnormalities: functional hypothalamic amenorrhea, central lesions, pituitary dysfunction
  • Thyroid dysfunction
  • PCOS
  • Androgen insensitivity syndrome
  • Congenital adrenal hyperplasia

Secondary Amenorrhea

  • Pregnancy
  • Hypothalamic dysfunction (reduced GnRH)
  • Functional hypothalamic amenorrhea (stress, anorexia nervosa, excessive exercise)
  • Hypothalamic tumors
  • Severe systemic illnesses (e.g., type 1 diabetes, celiac disease)
  • Pituitary diseases (hyperprolactinemia, Sheehan syndrome, Cushing syndrome)
  • Thyroid disease
  • PCOS
  • Ovarian disorders (primary ovarian insufficiency, tumors)
  • Anatomic abnormalities (intrauterine adhesions / Asherman syndrome)

Genetics

  • Turner syndrome, androgen insensitivity (testicular feminization) may cause amenorrhea.

Risk Factors

  • Obesity
  • Excessive exercise ("female athlete triad")
  • Eating disorders, malnutrition
  • Emotional or illness-induced stress
  • Family history of amenorrhea or early menopause
  • Antipsychotic medications

General Prevention

  • Maintain healthy BMI and lifestyle.

Commonly Associated Conditions

  • Autoimmune thyroiditis, type 1 diabetes (primary ovarian insufficiency).
  • Insulin resistance, obesity (PCOS).
  • Hypoestrogenism increases risk for osteopenia/osteoporosis.

Diagnosis

History

  • Menstrual history: rate, duration, distribution of hair loss, hair care practices.
  • Symptoms of pregnancy, menopause, virilization, pelvic pain, galactorrhea, headaches, vision changes.
  • Growth and puberty history: breast development, pubertal growth spurt, adrenarche.
  • Medical history: chronic illness, trauma, medications, chemotherapy, radiation.
  • Obstetrical, psychiatric, social history (diet, exercise, drug abuse, sexual history, stress).
  • Family history of delayed puberty or amenorrhea.

Physical Exam

  • General appearance, vitals, BMI, signs of anorexia nervosa (hypotension, bradycardia).
  • HEENT: dental erosions (bulimia), visual defects (prolactinoma), webbed neck (Turner).
  • Skin: androgen excess signs (acne, hirsutism), acanthosis nigricans (PCOS), fine downy hair (anorexia), striae, vitiligo.
  • Breast: development, galactorrhea, shield chest (Turner).
  • Pelvic exam: pubic hair presence, clitoromegaly, vaginal abnormalities, cervical mucus, ovarian enlargement.

Diagnostic Tests & Interpretation

Initial Labs (Primary Amenorrhea)

  • Serum hCG, prolactin, TSH, FSH.
  • Low FSH + no breast development: hypothalamic-pituitary etiology or constitutional delay.
  • High FSH + no breast development: gonadal failure → karyotype.
  • Normal breast development + low FSH: evaluate anatomic abnormalities → karyotype, testosterone, DHEA-S.

Initial Labs (Secondary Amenorrhea)

  • Serum hCG, prolactin, TSH, FSH.
  • PRL >50 ng/mL: consider pituitary adenoma, empty sella; MRI indicated.
  • PRL elevated <50 ng/mL: repeat fasting morning level.
  • High FSH: consider ovarian insufficiency or menopause.
  • Progestin challenge to assess endogenous estrogen:
  • Withdrawal bleed: suggests anovulation (often PCOS).
  • No withdrawal bleed: estrogen + progestin challenge indicated.
    • No bleed: outflow obstruction or hypoestrogenism.
    • Bleed: check FSH/LH.
  • Hyperandrogenism: total testosterone, DHEA-S, 17-OH progesterone; evaluate androgen-secreting tumor if testosterone >200 ng/dL.

Imaging

  • Not routinely first-line.
  • Pelvic US: ovarian cysts, uterus presence, endometrial thickness.
  • MRI if US not tolerated.

Follow-up & Special Tests

  • Women <30 yrs with ovarian failure: karyotype, FMR1 premutations, adrenal antibodies.
  • Absent uterus or foreshortened vagina: karyotype.
  • Laparoscopy for streak ovaries or polycystic ovaries.
  • Hysterosalpingogram: rule out Asherman syndrome, outflow obstruction.
  • Bone age if constitutional delay suspected.
  • DEXA scan if functional hypothalamic amenorrhea suspected.

Treatment

General Measures

  • Identify and correct underlying pathology.

Medication

  • Progesterone challenge: medroxyprogesterone 10 mg/day × 10 days; withdrawal bleed indicates intact HPG axis.
  • Estrogen replacement: cycling combined oral contraceptives or conjugated estrogen + progesterone challenge → withdrawal bleed if uterus intact.
  • Hormonal therapies do not correct underlying cause; additional medications may be needed (e.g., dopamine agonists for hyperprolactinemia).
  • Hormone replacement not recommended long-term in older women; may be used in young women for secondary sex characteristics and osteoporosis prevention (3)[A].
  • OCPs improve bone mineral density except in functional hypothalamic amenorrhea (4)[A].
  • Metformin used in PCOS for metabolic correction and ovulation improvement (5)[A].

Contraindications to Estrogen

  • Pregnancy, thromboembolism, MI, stroke, estrogen-dependent malignancy, severe hepatic disease.

Precautions

  • Women desiring pregnancy should avoid hormone replacement; treat infertility per cause.

Issues for Referral

  • OB/GYN, endocrine, surgery, psychiatry as indicated.

Surgery/Other Procedures

  • Hymenectomy for imperforate hymen.
  • Adhesion lysis for Asherman syndrome.
  • Gonadectomy if karyotype XY (tumor risk).
  • Vaginal reconstruction for congenital short vagina.
  • Pituitary tumor surgery for prolactinomas.

Ongoing Care

Follow-up

  • Reduce activity 25-50% if excessive exercise suspected.
  • Monitor per etiology and treatment.
  • Discontinue hormone therapy after 6 months to assess spontaneous menses.

Diet

  • Correct under/overweight via diet and behavior.
  • Weight loss improves ovulation in PCOS.

Patient Education

  • Discuss condition, fertility impact, treatment duration, complications (osteoporosis, vaginal dryness).
  • Provide contraceptive advice (fertility returns before menses).
  • Support for fertility loss as needed.

Prognosis

  • Depends on underlying cause.
  • Functional hypothalamic amenorrhea: 83% reversal if contributing factors addressed.

Complications

  • Estrogen deficiency symptoms (hot flashes, vaginal dryness).
  • Osteoporosis risk in prolonged hypoestrogenism.
  • Endometrial cancer risk with chronic anovulation and estrogen excess (obesity, PCOS).
  • Premature ovarian failure increases cardiovascular risk.

References

  1. Gordon CM. Functional hypothalamic amenorrhea. N Engl J Med. 2010;363(4):365-371.
  2. Klein DA, Poth MA. Amenorrhea: diagnosis and management. Am Fam Physician. 2013;87(11):781-788.
  3. Marjoribanks J, Farquhar C, Roberts H, et al. Long-term hormone therapy in peri/postmenopausal women. Cochrane Database Syst Rev. 2012;(7):CD004143.
  4. Liu SL, Lebrun CM. Effects of contraceptives and HRT on bone mineral density. Br J Sports Med. 2006;40(1):11-24.
  5. Tang T, Lord JM, Norman RJ, et al. Insulin-sensitizing drugs for PCOS. Cochrane Database Syst Rev. 2012;(5):CD003053.

Additional Reading

  • Practice Committee ASRM. Evaluation of amenorrhea. Fertil Steril. 2008;90(Suppl 5):S219-S225.
  • Santoro N. Update in hyper- and hypogonadotropic amenorrhea. J Clin Endocrinol Metab. 2011;96(11):3281-3288.

See Also

  • Hyperthyroidism
  • Adult Hypothyroidism
  • Osteoporosis and Osteopenia

Algorithms

  • Amenorrhea, Primary (Absence of Menarche by Age 16 Years)
  • Amenorrhea, Secondary
  • Delayed Puberty

ICD10 Codes

  • N91.1 Secondary amenorrhea
  • N91.2 Amenorrhea, unspecified
  • N91.0 Primary amenorrhea

Clinical Pearls

  • Determine if amenorrhea is primary or secondary; exclude pregnancy.
  • TSH and prolactin are standard initial labs.
  • Progestin challenge bleeding indicates intact hypothalamic-pituitary-ovarian axis.