Amenorrhea

Amenorrhea is the absence of menstruation and is always a presenting sign, not a diagnosis in itself — every case needs a structured work-up to identify the underlying cause before any treatment decision is made.^[1] Primary amenorrhea is the absence of menarche by age 15 in a patient with normal secondary sexual characteristics (breast development), or by age 13 in a patient with no secondary sexual characteristics at all; it is dominated by anatomic and chromosomal causes and always warrants specialist referral. Secondary amenorrhea is the absence of menses for at least 3 of the previous cycle intervals, or at least 6 months, in a patient who was previously menstruating — its differential spans hypothalamic, pituitary, ovarian, uterine/outflow-tract, and other endocrine causes, and pregnancy is the single most common cause and the essential first test in every reproductive-age patient, regardless of reported sexual activity or contraceptive use.^[1]

This chapter is authored from the 2024 American Society for Reproductive Medicine Practice Committee opinion on the current evaluation of amenorrhea, the 2017 Endocrine Society clinical practice guideline on functional hypothalamic amenorrhea (FHA), and the 2024 international evidence-based guideline on premature ovarian insufficiency (POI) developed by ESHRE, ASRM, and allied societies — cross-checked against the Society of Obstetricians and Gynaecologists of Canada's Guideline No. 422a on menopausal hormone therapy, whose route-selection and contraindication guidance applies directly to the estrogen therapy used in FHA and POI.^[2][3][4] It covers the full differential and diagnostic localization strategy, then focuses in depth on FHA and POI — the two causes with a genuine, often underappreciated pharmacist counselling point: untreated prolonged estrogen deficiency causes real, sometimes irreversible loss of bone density, even in young, otherwise healthy patients. Polycystic ovary syndrome and menopause are cross-referenced to their own dedicated chapters rather than duplicated here.

Primary vs. secondary amenorrhea

Differential diagnosis by compartment

Amenorrhea results from a disruption anywhere along the hypothalamic-pituitary-ovarian-uterine axis, plus outflow-tract obstruction and a handful of other endocrine mimics:

Hypothyroidism can itself raise prolactin, since increased TRH cross-stimulates the pituitary's lactotrophs — this is why TSH and prolactin are always interpreted together rather than in isolation (see Assessment & Diagnosis).

• Low body weight, a low body mass index, or a recent significant weight loss.
• Excessive or high-intensity exercise, particularly endurance sport, dance, and other lean/aesthetic sports — a component of the female athlete triad / relative energy deficiency in sport (RED-S).
• Disordered eating or an eating disorder.
• Significant psychological stress.
• Chronic illness or systemic disease causing malnutrition or a catabolic state.
• A family history of early menopause or primary ovarian insufficiency.
• Autoimmune disease — primary ovarian insufficiency has a recognized autoimmune subset and can cluster with autoimmune thyroid disease or Addison disease.
• Turner syndrome or another chromosomal cause of primary ovarian insufficiency.
• Pelvic or uterine surgery, dilation and curettage, or a uterine infection — risk factors for intrauterine adhesions (Asherman syndrome).
• Prior pelvic radiation or gonadotoxic chemotherapy — a recognized iatrogenic cause of primary ovarian insufficiency.
• Medications that raise prolactin (antipsychotics, metoclopramide, some antidepressants) or otherwise suppress the hypothalamic-pituitary-ovarian axis (chronic opioid use, GnRH agonists, depot medroxyprogesterone acetate, recent hormonal contraceptive discontinuation).
• A personal or family history of hirsutism, irregular cycles, or type 2 diabetes — raises the likelihood of PCOS (see the dedicated PCOS chapter).

Step 1 — always exclude pregnancy first

Measure a urine or serum beta-hCG in every patient of reproductive age presenting with secondary amenorrhea, regardless of reported sexual activity, contraceptive use, or how confident the history seems — this is the single most common cause and the mandatory first test before any other work-up proceeds.^[1]

Step 2 — history and physical examination

Ask specifically about: menstrual and reproductive history; recent weight change, exercise volume/intensity, and eating pattern; psychological stress; galactorrhea; headache or visual change; hot flashes, night sweats, or vaginal dryness (suggesting estrogen deficiency); hirsutism or other signs of hyperandrogenism; and a full medication review, including recently discontinued hormonal contraception, antipsychotics, and other prolactin-raising drugs. On examination, note body mass index, signs of hyperandrogenism, galactorrhea, and — in primary amenorrhea — the stage of breast development and whether a uterus is present.

Step 3 — core laboratory panel: TSH, prolactin, and FSH/estradiol together

Once pregnancy is excluded, order thyroid-stimulating hormone, prolactin, and FSH with estradiol together as the core localizing panel — interpreting them together, not in isolation, is what actually localizes the cause:^[1]

• TSH abnormal — treat the thyroid dysfunction directly (see the dedicated Thyroid Disorders chapter for dosing) and reassess menstrual function once euthyroid; hypothyroidism can itself raise prolactin through increased TRH drive, so recheck prolactin after thyroid correction before pursuing a separate hyperprolactinemia work-up.
• Prolactin elevated — first exclude a non-tumour cause: recent stress, breast stimulation, a prolactin-raising medication, or a poorly timed non-fasting sample; repeat before proceeding. If prolactin remains persistently elevated, arrange pituitary MRI and manage per the dopamine-agonist pathway below.^[5]
• FSH elevated (above 25 IU/L) with a low estradiol, confirmed on a second sample 4-6 weeks later — primary ovarian insufficiency; order karyotype and FMR1 premutation testing in every patient with non-iatrogenic POI regardless of age, and refer.^[3]
• FSH low or inappropriately normal with a low estradiol, and no other cause identified on the panel above — functional hypothalamic amenorrhea by exclusion; assess energy availability, exercise pattern, and psychological stress specifically (see Risk Factors).^[2]
• FSH and estradiol both normal, especially with hyperandrogenism (hirsutism, acne) or a history of irregular cycles — most consistent with PCOS; apply the Rotterdam criteria in the dedicated PCOS chapter rather than repeating that work-up here.
• FSH and estradiol both normal, no hyperandrogenism, and no cause identified above — consider a uterine or outflow-tract cause; obtain a pelvic ultrasound and refer for gynecologic assessment (including consideration of a progestin-withdrawal challenge and, where indicated, hysteroscopy for suspected intrauterine adhesions).

Primary amenorrhea — a distinct pathway

In primary amenorrhea, physical examination — specifically, whether breast development and a uterus are both present — determines the work-up far more than the hormone panel above: a patient with normal breast development but no palpable/visualized uterus needs karyotype and androgen-insensitivity-syndrome testing; a patient with a uterus but no breast development needs an FSH/LH-driven work-up for hypergonadotropic versus hypogonadotropic causes. This structural and chromosomal work-up is specialist-driven — refer every case of primary amenorrhea rather than managing it in primary/community pharmacy practice.^[1]

• Identify and directly treat the underlying cause — amenorrhea is a sign to investigate, not a symptom to suppress.
• Confirm pregnancy status before any treatment decision.
• Protect the endometrium from unopposed estrogen exposure in anyone with a uterus, ongoing estrogen production, and chronic anovulation.
• Prevent, or reverse where possible, the bone density loss caused by prolonged untreated estrogen deficiency in functional hypothalamic amenorrhea and primary ovarian insufficiency.
• Normalize prolactin, and shrink a macroprolactinoma where present, to restore menses and fertility.
• Restore fertility when desired, or provide reliable contraception when it is not — including in primary ovarian insufficiency, where spontaneous ovulation can still occur.
• Support mental health and disordered-eating recovery as a core part of functional hypothalamic amenorrhea management, not an adjunct to it.
• Establish long-term cardiovascular and bone-health screening for primary ovarian insufficiency, given its extended duration of estrogen deficiency relative to natural menopause.

• Nutritional counselling and increased caloric intake, ideally with dietitian involvement, for functional hypothalamic amenorrhea — the foundation of treatment, not an adjunct to pharmacologic estrogen.^[2]
• Moderation of exercise volume/intensity in FHA, with a nuance worth counselling on directly: moderate weight-bearing exercise protects bone health, while the excessive, underfuelled training pattern driving FHA is the pathologic exposure — the goal is a better-fuelled, sustainable training load, not a blanket instruction to stop exercising.
• Screen explicitly for disordered eating and relative energy deficiency in sport (RED-S) in an athlete or dancer with amenorrhea, and refer for multidisciplinary eating-disorder treatment when identified — do not treat this as a formality.
• Cognitive behavioural therapy or another structured stress-reduction intervention — shown to help restore ovulatory function in FHA specifically, not only to support mental health in general.^[2]
• Adequate dietary calcium and vitamin D intake in anyone with a prolonged estrogen-deficient state (FHA or POI), with supplementation where dietary intake is inadequate.
• Smoking-cessation support — adds to the bone and cardiovascular risk already present from estrogen deficiency in POI.
• Genetic counselling for a patient diagnosed with POI, once karyotype and FMR1 results are available.
• Psychological support for POI specifically — an unexpected, often early diagnosis with a significant emotional impact around fertility loss, independent of the hormonal management.

Adolescents

Evaluate primary amenorrhea by age 15 with normal secondary sexual characteristics, or by age 13 without any, rather than deferring further — early referral avoids delaying diagnosis of a structural or chromosomal cause and, for FHA specifically, avoids missing the critical window for peak bone mass accrual.^[1][2] Confidentiality and consent considerations for sexual history and pregnancy testing follow standard adolescent-care practice, not anything specific to amenorrhea.

Athletes and disordered eating

Manage as a genuine multidisciplinary case (physician, dietitian, mental health professional, and — for a competitive athlete — the athlete's sport-medicine team where appropriate) rather than a straightforward prescribing decision; pharmacologic estrogen is an adjunct to, never a substitute for, restoring adequate energy availability.^[2]

Pregnancy

Stop the amenorrhea work-up and route to prenatal care once pregnancy is confirmed. In a patient on a dopamine agonist for a prolactinoma, whether to continue therapy through pregnancy is specialist-directed and depends on tumour size and any mass-effect symptoms — most microprolactinomas are simply monitored clinically off therapy, while a macroadenoma may need continued or resumed treatment.^[5] A patient with POI who does not desire pregnancy still needs reliable contraception, since spontaneous ovulation can occur.

Breastfeeding

Dopamine agonists suppress lactation and are generally avoided if breastfeeding is desired; discuss timing with the patient's obstetric team. Standard postpartum considerations for hormone therapy or contraceptive timing (not specific to amenorrhea) apply once breastfeeding status is established.

Hepatic impairment

Use estrogen therapy (oral or transdermal) with caution, or avoid, in active liver disease — see the Menopause chapter's hormone-therapy contraindication table, which applies directly to estrogen use in FHA and POI. Dopamine agonists are hepatically metabolized; use caution with significant hepatic impairment.

Personal history of breast cancer, VTE, or another hormone-therapy contraindication

Apply the same contraindication framework used for menopausal hormone therapy — see the dedicated Menopause chapter — since the estrogen and progestogen agents and their risks are the same; individualize with specialist input rather than withholding all hormone therapy by default, particularly given the real bone-health cost of leaving FHA/POI-related estrogen deficiency untreated.

Reassess menstrual function after treating the identified cause: recheck TSH after starting/adjusting levothyroxine and confirm menses resume once euthyroid; track prolactin at regular intervals on a dopamine agonist and repeat pituitary imaging per the specialist's protocol, particularly for a macroadenoma. In FHA, ask specifically about energy intake, exercise pattern, and psychological stress at every visit — return of spontaneous menses is the key marker that the underlying energy deficit has resolved, not merely symptom control on estrogen therapy.^[2] In POI, obtain a baseline DXA scan at diagnosis; if bone density is normal and adherence to hormone therapy is good, a repeat scan within 5 years adds limited value, whereas a patient with low bone density or osteoporosis needs reassessment every 1-3 years based on individual risk factors.^[3] Review hormone-therapy contraindications at least annually in both FHA and POI, using the same screening cadence as the Menopause chapter. Reconfirm pregnancy status before escalating or changing any hormonal therapy, and revisit contraceptive needs specifically in POI, where spontaneous ovulation can still occur.

1. Reconfirm pregnancy has been excluded (or re-excluded, if enough time has passed) before escalating any pathway.
2. If menses do not resume after adequate TSH normalization, reassess for a second, concurrent cause rather than assuming thyroid dysfunction was the sole driver.
3. If a dopamine agonist has not normalized prolactin or restored menses at an adequate dose and duration, increase the dose per specialist guidance, or switch between cabergoline and bromocriptine; obtain (or repeat) pituitary MRI if not already done.
4. If FHA has not resolved after a genuine 6-12 month trial of adequate nutritional, exercise, and stress intervention, reassess actual adherence to the energy-availability target with the dietitian, escalate mental health support, and add transdermal estradiol plus cyclic progestin for bone protection rather than continuing to wait indefinitely.
5. If POI hormone therapy does not adequately control symptoms at the guideline-minimum dose, increase the estradiol dose — this is physiologic replacement without a fixed low ceiling, not a treatment that has "failed" at the starting dose.
6. If no cause is identified despite a complete initial work-up (an unexplained hypothalamic-pattern low FSH/estradiol with normal pituitary imaging, for example), refer to a reproductive endocrinologist for further investigation rather than repeating the same panel.
7. If a uterine or outflow-tract cause is suspected or confirmed on imaging, refer for gynecologic/surgical evaluation rather than trialing hormonal therapy first.

• Skipping beta-hCG because a patient reports no current sexual activity, uses contraception, or seems an unlikely candidate for pregnancy.
• Diagnosing PCOS or FHA before TSH and prolactin have actually been checked and interpreted together.
• Defaulting to a combined oral contraceptive as first-line "estrogen replacement" for bone protection in functional hypothalamic amenorrhea, instead of transdermal estradiol plus cyclic progestin.
• Treating FHA purely pharmacologically without addressing the underlying energy deficit — pharmacologic estrogen is an adjunct to, not a substitute for, restoring adequate nutrition and moderating exercise load.
• Missing the window for genetic counselling in POI by not ordering karyotype and FMR1 premutation testing at diagnosis, in every patient regardless of age.
• Under-dosing hormone therapy in POI relative to what a naturally postmenopausal patient would receive — POI patients are younger and need adequate physiologic replacement for bone and cardiovascular protection, not a token low dose.
• Assuming a patient with POI cannot become pregnant and skipping contraception counselling.
• Treating galactorrhea as reassuringly benign without asking about headache or visual change that would suggest a prolactinoma with mass effect.
• Not screening explicitly for disordered eating or relative energy deficiency in sport in an athlete or dancer presenting with amenorrhea.
• Re-deriving the full PCOS or menopause work-up here instead of cross-referencing those dedicated chapters.

How to use this table: Doses are adult doses and require patient-specific confirmation, including renal/hepatic adjustment. Thyroid dysfunction, PCOS, and full menopausal hormone-therapy dosing/contraindications are covered in the dedicated Thyroid Disorders, Polycystic Ovary Syndrome, and Menopause chapters and are not repeated here. Select any drug name to open its complete Pharmasist Drug Database page.

Estrogen and progestogen hormone therapy

For functional hypothalamic amenorrhea (FHA) with persistent estrogen deficiency despite an adequate lifestyle trial, and for primary ovarian insufficiency (POI). A progestin is required alongside estradiol whenever the uterus is intact, to protect the endometrium from unopposed estrogen.

Evidence note: the minimum-dose and until-average-age-of-menopause duration recommendations for POI hormone therapy follow the current international evidence-based POI guideline;^[3] the preference for transdermal estradiol plus cyclic progestin over a combined oral contraceptive in FHA follows the current Endocrine Society FHA guideline.^[2] Route selection, contraindication screening, and dose titration otherwise follow the same framework used for menopausal hormone therapy — see the dedicated Menopause chapter.^[4]

Dopamine agonists

For hyperprolactinemia from a prolactinoma or another persistent, non-medication cause, once a medication cause has been excluded or addressed with the prescriber.

Evidence note: dopamine-agonist selection and the pregnancy-planning preference for bromocriptine follow the current Endocrine Society hyperprolactinemia guideline.^[5]

Bone-protection adjuncts

For anyone in a prolonged estrogen-deficient state (FHA or POI) — used alongside, never instead of, hormone therapy addressing the underlying estrogen deficiency.