Residency · Residency · Obstetrics Gynecology

Amenorrhea: Systematic Evaluation

Definitions

Primary amenorrhea is the absence of menarche by age 15 in the presence of normal secondary sexual characteristics, or by age 13 with no secondary sexual development. Secondary amenorrhea is the absence of menses for 3 months or more in a woman with previously regular cycles, or 6 months or more in a woman with previously irregular cycles. Oligomenorrhea, defined as menstrual cycles more than 35 days apart, is often evaluated similarly to amenorrhea.

Normal Menstrual Physiology

Normal menstruation requires an intact and functional hypothalamus (producing GnRH), anterior pituitary (producing FSH and LH), ovaries (producing estrogen and progesterone), and uterus with a patent outflow tract. Pulsatile GnRH secretion drives FSH and LH release. FSH stimulates follicular development and estrogen production. The LH surge triggers ovulation. The corpus luteum produces progesterone, which stabilizes the endometrium. Withdrawal of progesterone in the absence of pregnancy triggers menstruation. Disruption at any level of the hypothalamic-pituitary-ovarian axis or the outflow tract causes amenorrhea.

Primary Amenorrhea

Workup Algorithm

The evaluation of primary amenorrhea begins by assessing the presence of secondary sexual characteristics, which indicates estrogen effect (breast development), and checking for the presence of the uterus by pelvic exam and ultrasound.

With Breast Development and Uterus Present

The most likely diagnoses include constitutional delay, hypothalamic amenorrhea, and PCOS. Outflow obstruction from an imperforate hymen or transverse vaginal septum should be excluded. Initial laboratory testing includes a pregnancy test, TSH, prolactin, FSH, and LH. Pelvic ultrasound assesses anatomy.

With Breast Development but Absent Uterus

Two conditions must be distinguished by karyotype. Mullerian agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome) presents in a patient with 46,XX karyotype, normal ovarian function, normal secondary sexual characteristics, and an absent or rudimentary uterus and upper vagina. It is the second most common cause of primary amenorrhea. Complete androgen insensitivity syndrome presents in a patient with 46,XY karyotype who is phenotypically female with breast development from peripheral aromatization. The uterus is absent, and there is a blind-ending vagina. Testes are present in the inguinal region or intra-abdominally, and gonadectomy is performed after puberty due to the risk of malignancy. Karyotype is essential to differentiate these conditions.

Without Breast Development (No Estrogen Effect)

Hypergonadotropic hypogonadism, characterized by elevated FSH, points to gonadal failure. Turner syndrome (45,X or mosaic) is the most common cause of primary amenorrhea overall, presenting with short stature, webbed neck, shield chest, cardiac anomalies (coarctation of the aorta), and streak gonads. 46,XY gonadal dysgenesis (Swyer syndrome) presents as a phenotypically female individual with streak gonads and a uterus present; gonadectomy is required due to the high risk of gonadoblastoma. Other causes of gonadal failure include autoimmune disease, radiation, and chemotherapy. Hypogonadotropic hypogonadism, with low or normal FSH and low LH, may result from constitutional delay of puberty, hypothalamic causes (functional from stress, low weight, or excessive exercise; or Kallmann syndrome with anosmia and GnRH deficiency), pituitary lesions (craniopharyngioma, prolactinoma), or systemic illness.

<image>Diagnostic algorithm for primary amenorrhea starting with assessment of breast development and uterine presence, branching into four categories: breasts present/uterus present (outflow obstruction, PCOS), breasts present/uterus absent (MRKH vs. CAIS with karyotype), breasts absent/uterus present with high FSH (Turner, Swyer) or low FSH (hypothalamic, pituitary), with key tests at each decision point</image>

Secondary Amenorrhea

Initial Evaluation

The evaluation of secondary amenorrhea always begins with a pregnancy test. The next steps are TSH (for hypothyroidism or hyperthyroidism), prolactin (for hyperprolactinemia), and FSH (to distinguish ovarian failure from hypothalamic/pituitary causes).

Etiologic Categories

Hypothalamic Amenorrhea (Functional)

Functional hypothalamic amenorrhea is the most common cause of secondary amenorrhea after pregnancy. Low GnRH pulsatility leads to low FSH, LH, and estrogen. Causes include excessive exercise, low body weight or eating disorders, psychological stress, and chronic illness. It is a diagnosis of exclusion, characterized by low or normal FSH, low LH, and low estradiol. Consequences include bone loss from hypoestrogenism, cardiovascular risk, and infertility. Treatment involves addressing the underlying cause through weight gain, stress reduction, or decreased exercise. Hormone replacement protects bone health, and fertility treatment with pulsatile GnRH or gonadotropins is available when pregnancy is desired.

Hyperprolactinemia

Prolactin inhibits GnRH pulsatility. Causes include prolactinoma (the most common pituitary adenoma), medications (antipsychotics, metoclopramide), hypothyroidism, chest wall irritation, and renal failure. The workup involves serum prolactin measurement, and if elevated, brain MRI to evaluate for a pituitary adenoma. Treatment uses dopamine agonists, with cabergoline preferred over bromocriptine. Surgery is reserved for resistant macroadenomas.

Thyroid Dysfunction

Hypothyroidism causes elevated TRH, which stimulates prolactin release and also disrupts GnRH pulsatility. Hyperthyroidism alters SHBG, estrogen metabolism, and gonadotropin dynamics. Treatment of the thyroid disorder often restores normal menses.

Ovarian Causes

Polycystic ovary syndrome causes chronic anovulation with hyperandrogenism. Premature ovarian insufficiency is defined as menopause before age 40, with elevated FSH (above 25 to 40 mIU/mL on two occasions 4 weeks apart) and low estradiol. Androgen-secreting ovarian tumors are rare but can suppress the HPO axis.

Uterine Causes

Asherman syndrome (intrauterine adhesions) is most commonly caused by endometrial damage from D&C, especially postpartum. Scarring obliterates the endometrial cavity. The hormonal profile is normal (normal FSH, estradiol, and ovulation). A progestogen challenge test produces no withdrawal bleed despite adequate estrogen. Diagnosis is made by hysteroscopy (the gold standard) or saline infusion sonography showing adhesions. Treatment involves hysteroscopic adhesiolysis with post-operative estrogen therapy and/or an IUD or balloon stent to prevent re-adhesion. Cervical stenosis from prior conization, LEEP, or radiation may also cause amenorrhea, and hematometra may develop.

Pituitary Causes

Pituitary adenomas include prolactinomas, non-functioning adenomas, and Cushing disease. Sheehan syndrome is postpartum pituitary necrosis resulting from hemorrhage and hypotension. Inability to lactate due to absent prolactin is often the first sign, followed by panhypopituitarism with multiple hormone deficiencies. Other pituitary causes include lymphocytic hypophysitis and empty sella syndrome.

<image>Comprehensive workup flowchart for secondary amenorrhea: pregnancy test first, then TSH, prolactin, and FSH; branching based on results into hypothyroidism (treat thyroid), hyperprolactinemia (MRI for prolactinoma), elevated FSH (premature ovarian insufficiency workup), normal/low FSH with clinical hyperandrogenism (PCOS workup), and normal hormones with no withdrawal bleed (Asherman syndrome, hysteroscopy)</image>

Progestogen Challenge Test

The progestogen challenge test has historically been used to assess estrogen status and outflow tract patency. Medroxyprogesterone acetate 10 mg daily is given for 10 days. A positive result, in which a withdrawal bleed occurs, indicates adequate endogenous estrogen and a patent outflow tract, suggesting anovulation such as PCOS. A negative result, with no bleed, suggests either low estrogen from hypothalamic or ovarian failure, outflow tract obstruction from Asherman syndrome, or very low endometrial response. The test has limitations and is increasingly replaced by direct hormone measurement, as a positive test does not reliably exclude significant hypothalamic dysfunction.

Estrogen-Progestogen Challenge Test

If the progestogen challenge is negative, conjugated estrogen 1.25 mg daily is administered for 21 days with medroxyprogesterone 10 mg for the last 10 days. A positive result with a withdrawal bleed confirms that the outflow tract is intact and the amenorrhea results from low estrogen due to a hypothalamic or ovarian cause. A negative result with no bleed indicates outflow tract obstruction such as Asherman syndrome or an unreceptive endometrium.

Special Considerations

Eating Disorders

Anorexia nervosa is the most severe cause of functional hypothalamic amenorrhea. Amenorrhea occurs when body fat drops below a critical threshold of approximately 17 to 22%. Associated complications include severe bone loss, electrolyte abnormalities, and cardiac complications. Multidisciplinary treatment is essential, with weight restoration as the primary goal. A DEXA scan is recommended for bone density assessment.

Exercise-Associated Amenorrhea (Female Athlete Triad / RED-S)

The female athlete triad consists of low energy availability, menstrual dysfunction, and low bone mineral density. Relative Energy Deficiency in Sport (RED-S) is an expanded concept that includes broader health consequences. Treatment involves increasing caloric intake relative to energy expenditure and reducing training intensity if needed.

Post-Pill Amenorrhea

Amenorrhea lasting more than 3 to 6 months after discontinuing hormonal contraception is evaluated as secondary amenorrhea. It is usually unrelated to pill use. Hormonal contraception may have masked underlying hypothalamic dysfunction or PCOS.

Clinical Pearls

Always start with a pregnancy test. Pregnancy is the most common cause of secondary amenorrhea.

Primary amenorrhea with an absent uterus requires a karyotype to distinguish Mullerian agenesis (46,XX) from androgen insensitivity syndrome (46,XY).

Turner syndrome (45,X) is the most common cause of primary amenorrhea overall and should be considered in any short-statured girl with delayed puberty.

Sheehan syndrome should be suspected in any woman with a history of postpartum hemorrhage who fails to lactate and develops amenorrhea.

Asherman syndrome is best diagnosed by hysteroscopy, not by ultrasound alone. Saline infusion sonography or hysterosalpingography can be helpful adjuncts.

Functional hypothalamic amenorrhea is a diagnosis of exclusion. Organic hypothalamic and pituitary pathology must be ruled out first.

Bone density is significantly affected by hypoestrogenic amenorrhea. Bone health should be addressed proactively in all patients with prolonged amenorrhea.

<image>Summary table comparing the major causes of amenorrhea with their characteristic hormonal profiles: functional hypothalamic amenorrhea (low FSH, low LH, low estradiol), PCOS (normal/high LH, normal FSH, normal estradiol, high androgens), POI (high FSH, low estradiol), hyperprolactinemia (elevated prolactin, low FSH/LH), and Asherman syndrome (normal FSH, LH, estradiol, no withdrawal bleed)</image>

References

• ACOG Committee Opinion No. 651: Menstruation in Girls and Adolescents (2015, reaffirmed 2023)
• ACOG Practice Bulletin No. 128: Diagnosis of Abnormal Uterine Bleeding in Reproductive-Aged Women (2012)
• Gordon CM et al. Functional hypothalamic amenorrhea: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2017;102:1413-1439
• Klein DA et al. Amenorrhea: a systematic approach to diagnosis and management. Am Fam Physician. 2019;100:39-48
• Practice Committee of ASRM. Current evaluation of amenorrhea. Fertil Steril. 2008;90:S219-S225
• Mountjoy M et al. IOC consensus statement on relative energy deficiency in sport (RED-S). Br J Sports Med. 2018;52:687-697

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