Amenorrhea

Clinical Snapshot

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.

Recognize the Condition

Primary vs. secondary amenorrhea

Definitions

Primary amenorrhea

No menarche by age 15 in a patient with normal secondary sexual characteristics, or by age 13 in a patient with no secondary sexual characteristics at all.^[1] Dominated by anatomic (müllerian anomalies, imperforate hymen, transverse vaginal septum), chromosomal (Turner syndrome, androgen insensitivity syndrome), and congenital hypothalamic-pituitary causes. Investigate every case — do not simply "wait and see."

Secondary amenorrhea

Absence of menses for at least 3 of the previous cycle intervals, or at least 6 months, in a patient who was previously menstruating.^[1] Shares the same hormonal differential as primary amenorrhea once anatomic causes are excluded, plus pregnancy, which must always be excluded first.

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:

Compartment	Common causes
Hypothalamic	Functional hypothalamic amenorrhea — low energy availability from excessive exercise, low body weight, or psychological stress, alone or combined — is the most common cause in an otherwise healthy young patient; less commonly a structural or infiltrative hypothalamic lesion.
Pituitary	Hyperprolactinemia (a prolactin-secreting adenoma, or a non-tumour cause — see Risk Factors); other pituitary tumours or infiltrative disease disrupting gonadotropin secretion; postpartum pituitary infarction (Sheehan syndrome).
Ovarian	Primary ovarian insufficiency (loss of ovarian follicular function before age 40); polycystic ovary syndrome — see the dedicated PCOS chapter for full Rotterdam-criteria diagnosis and management.
Uterine / outflow tract	Intrauterine adhesions (Asherman syndrome, typically after uterine instrumentation or infection); müllerian anomalies and imperforate hymen/transverse vaginal septum (primary amenorrhea); cervical stenosis.
Other endocrine	Thyroid dysfunction (hypo- or hyperthyroidism); non-classic congenital adrenal hyperplasia; Cushing syndrome; an androgen-secreting tumour.
Physiologic	Pregnancy, lactation, and natural menopause — see the dedicated Menopause chapter for the postmenopausal transition.

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).

Risk Factors

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).

Red Flags & Refer

Amenorrhea itself is rarely an emergency, but several accompanying presentations need urgent investigation or referral rather than a routine work-up:

Galactorrhea with a mass-effect symptom — headache, visual field loss, or diplopia — suggests a macroprolactinoma; obtain prolactin and arrange urgent pituitary imaging and specialist referral rather than starting empiric treatment.^[5]
Signs of virilization — clitoromegaly, rapidly progressive hirsutism, or significant voice deepening — suggest an androgen-secreting ovarian or adrenal tumour and need urgent imaging and referral, not empiric PCOS treatment (see the PCOS chapter's own red-flag section for the same principle).
Primary amenorrhea with no breast development by age 13, or no menses by age 15 despite normal breast development — refer for a structural and chromosomal work-up rather than waiting further.^[1]
Primary amenorrhea with cyclic pelvic pain — suggests outflow-tract obstruction (an imperforate hymen or transverse vaginal septum) with functioning endometrium behind the obstruction; refer promptly, as this can progress to hematocolpos.
Amenorrhea with significant, rapid weight loss or other signs of an eating disorder — refer for multidisciplinary eating-disorder assessment and treatment in parallel with, not instead of, the amenorrhea work-up.
Features suggesting Cushing syndrome — proximal muscle weakness, wide violaceous striae, easy bruising, a rapidly progressive centripetal weight-gain pattern.
Confirmed primary ovarian insufficiency (amenorrhea with a persistently elevated FSH before age 40) — refer for karyotype and FMR1 premutation testing and specialist management; the long-term cardiovascular and bone consequences of untreated prolonged estrogen deficiency make this more than a routine referral.^[3]

Assessment & Diagnosis

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]

Treatment Targets

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.

Choose Initial Treatment

Direct treatment rule

Treat the identified cause directly — do not treat "amenorrhea" as a single diagnosis

Pregnancy confirmed route to prenatal care; stop the amenorrhea work-up.

Hypothyroidism or hyperthyroidism identified

1st line treat the thyroid dysfunction directly with levothyroxine (hypothyroidism) or standard antithyroid therapy (hyperthyroidism) — see the dedicated Thyroid Disorders chapter for full dosing and titration; menses typically resume once euthyroid.

Hyperprolactinemia identified

1st line if a causative medication is identified, discuss an alternative with the prescriber rather than stopping it unilaterally. For a prolactinoma or another persistent, non-medication cause, start a dopamine agonist — cabergoline is preferred first-line given its superior efficacy, tolerability, and twice-weekly dosing.^[5]

Alternative, or preferred when conception is planned imminently bromocriptine — a longer track record of pregnancy safety data makes it the preferred agent specifically when the patient is actively trying to conceive, despite its less convenient daily dosing and higher rate of GI/orthostatic side effects.^[5]

PCOS identified (Rotterdam criteria met)

Manage per the dedicated Polycystic Ovary Syndrome chapter — combined hormonal contraceptives, metformin, spironolactone, and letrozole are not repeated here.

Functional hypothalamic amenorrhea (FHA)

1st line nonpharmacologic: increase energy availability (caloric intake), reduce exercise volume/intensity, and address psychological stress with a multidisciplinary team (physician, dietitian, and mental health professional) — this restores menses in most patients and is the foundation of treatment regardless of whether pharmacologic estrogen is also used.^[2]

Add if amenorrhea/estrogen deficiency persists despite an adequate (roughly 6-12 month) lifestyle trial, particularly in an adolescent or young adult still accruing peak bone mass transdermal estradiol plus cyclic oral progestin (for endometrial protection if the uterus is intact) — this route is specifically preferred over a combined oral contraceptive in FHA.^[2]

Do not default to a combined oral contraceptive as "estrogen replacement" for bone protection in FHA — oral estrogen's first-pass hepatic metabolism blunts hepatic IGF-1 production and has not been shown to reliably protect bone density in this specific population, and a COC also masks the return of spontaneous menses, making it harder to judge whether the underlying energy deficit has actually resolved.^[2]

Primary ovarian insufficiency (POI)

1st line hormone therapy — oral estradiol at least 2 mg/day, or a transdermal estradiol patch delivering at least 100 mcg/day, plus a cyclic or continuous progestin if the uterus is intact — continued until at least the average age of natural menopause (about 51) for primary prevention of the bone and cardiovascular consequences of prolonged estrogen deficiency; see the dedicated Menopause chapter for progestogen selection, route considerations, and the hormone-therapy contraindication table, which apply directly here.^[3]^[4]

Alternative when reliable contraception is also wanted a combined hormonal contraceptive — unlike natural menopause, spontaneous ovulation and pregnancy can still occur in POI, so a patient who does not desire pregnancy needs reliable contraception; a COC supplies both symptom control and contraception, though the skeletal-protection evidence base is smaller than for standard estradiol-plus-progestin hormone therapy.

Fertility desired refer for reproductive endocrinology assessment (donor oocyte IVF is the most effective option; spontaneous conception remains possible but uncommon) rather than attempting ovulation induction, which is not effective in POI.

Uterine or outflow-tract cause identified

Refer for gynecologic/surgical management (hysteroscopic adhesiolysis for Asherman syndrome, surgical correction of an obstructive anomaly) — these causes are not a pharmacologic treatment target.

Chronic anovulation with an intact uterus and ongoing endogenous estrogen, no other treatable cause identified

Protect the endometrium with either a combined hormonal contraceptive or cyclic oral progestin (norethindrone or medroxyprogesterone acetate) — do not leave chronic anovulatory unopposed-estrogen exposure unaddressed.

Non-Pharmacologic Treatment

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.

Pharmacologic Treatment Options

Drug / intervention	Role	Dose / use	Important adverse effects	Teaching points
Estradiol Preferred	1st line hormone therapy for FHA (if pharmacologic estrogen is needed) and POI	Transdermal (preferred route): a patch delivering at least 100 mcg/day Oral (POI alternative; not preferred in FHA): at least 2 mg PO once daily	Breakthrough bleeding, breast tenderness, headache, bloating; local patch-site irritation with the transdermal route	Transdermal is preferred over oral estrogen/a COC in both FHA and POI — it avoids the first-pass hepatic effect that blunts IGF-1 and, in FHA, does not mask the return of spontaneous menses.
Progesterone, micronized Preferred	Cyclic progestin for endometrial protection when estradiol is used and the uterus is intact	200 mg PO QHS x12-14 days/month (cyclic), or 100 mg PO QHS continuously	Drowsiness, bloating, breast tenderness	Take at bedtime given its sedating effect. Formulated with sunflower oil — caution with soy allergy (contains soy lecithin).
Medroxyprogesterone acetate Alternative	Alternative cyclic progestin for endometrial protection	5-10 mg PO once daily x12-14 days/month	Irregular bleeding, bloating, mood change	A reasonable alternative to micronized progesterone, particularly where cost or a soy allergy is a concern.
Levonorgestrel/ethinyl estradiol Alternative	Alternative for endometrial protection with chronic anovulation, or for POI when contraception is also needed	1 tablet PO daily x21 days then a 7-day hormone-free interval, or continuous/extended-cycle per product labeling	Breakthrough bleeding, breast tenderness, nausea, headache; rare VTE	In POI, provides reliable contraception that physiologic hormone therapy does not — but its skeletal-protection evidence base is smaller than standard estradiol-plus-progestin therapy.
Cabergoline Preferred	1st line dopamine agonist for hyperprolactinemia	0.25 mg PO twice weekly, titrated by prolactin response to a usual maximum of 1 mg twice weekly	Nausea, dizziness, orthostatic hypotension; rare cardiac valvulopathy at high cumulative doses	Preferred over bromocriptine for superior efficacy, tolerability, and twice-weekly dosing. Stop once pregnancy is confirmed unless a macroadenoma requires continued monitoring per specialist direction.
Bromocriptine Alternative	Alternative dopamine agonist, preferred immediately pre-conception	1.25-2.5 mg PO once daily at bedtime, titrated to a usual maintenance of 2.5-15 mg/day in divided doses	Nausea, orthostatic hypotension, headache; rare erythromelalgia, pleural/pulmonary fibrosis with prolonged high-dose use	A longer track record of pregnancy safety data than cabergoline makes it preferred specifically when conception is planned imminently.
Levothyroxine Preferred	1st line replacement for hypothyroidism-driven amenorrhea	See the dedicated Thyroid Disorders chapter for weight-based dosing and titration	Palpitations, insomnia, weight loss if over-replaced	Menses typically resume once euthyroid; recheck prolactin after correction, since hypothyroidism can itself raise it.
Calcium carbonate Preferred	Bone-protection adjunct in FHA or POI	500-600 mg elemental calcium PO with meals, in divided doses, to meet total daily intake recommendations	Constipation, bloating	Counsel on total daily elemental calcium intake from diet plus supplement combined, not the supplement dose in isolation.
Vitamin D3 (cholecalciferol) Preferred	Bone-protection adjunct in FHA or POI	800-2000 IU PO once daily, adjusted to a target 25(OH)D level	Hypercalcemia at high doses	Used alongside, never instead of, hormone therapy in POI or persistent FHA — vitamin D alone does not substitute for estrogen replacement.

Special Populations

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.

Monitoring & Follow-Up

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.

Treatment Failure / Next Step

Reconfirm pregnancy has been excluded (or re-excluded, if enough time has passed) before escalating any pathway.
If menses do not resume after adequate TSH normalization, reassess for a second, concurrent cause rather than assuming thyroid dysfunction was the sole driver.
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.
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.
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.
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.
If a uterine or outflow-tract cause is suspected or confirmed on imaging, refer for gynecologic/surgical evaluation rather than trialing hormonal therapy first.

Common Errors to Avoid

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.

Clinical Decision Algorithm

Primary amenorrhea — initial pathway

No menarche by age 15 with normal secondary sexual characteristics, or by age 13 without any

Examine: stage of breast development; confirm whether a uterus is present

Refer for a structural and chromosomal work-up (karyotype, pelvic imaging, androgen-insensitivity testing as indicated) — do not manage primary amenorrhea in primary/community pharmacy practice

Secondary amenorrhea — diagnostic algorithm

Absence of menses for 3+ cycles or 6+ months in a previously menstruating patient

Screen for red flags: galactorrhea with mass-effect symptoms, virilization, significant rapid weight loss/eating-disorder signs, Cushingoid features

Red flag present

Investigate/refer urgently per the red flag identified — do not proceed with the routine work-up below

No red flag

Measure beta-hCG

Positive

Route to prenatal care; stop the amenorrhea work-up

Negative

Order TSH, prolactin, and FSH with estradiol together

FSH elevated (>25 IU/L x2, 4-6 weeks apart), estradiol low

Primary ovarian insufficiency — order karyotype and FMR1 testing; refer

FSH low/inappropriately normal, estradiol low, no other cause found

Functional hypothalamic amenorrhea — assess energy availability, exercise pattern, and stress

FSH/estradiol normal

Hyperandrogenism present: apply Rotterdam criteria (PCOS chapter). No hyperandrogenism: pelvic ultrasound and gynecologic referral for a uterine/outflow-tract cause

Estrogen-deficiency management: FHA vs. POI

Functional hypothalamic amenorrhea or primary ovarian insufficiency confirmed

FHA

Nonpharmacologic 1st: increase energy availability, moderate exercise load, multidisciplinary stress/eating-disorder support

Menses resume within 6-12 months

Continue lifestyle support; no pharmacologic estrogen needed

Amenorrhea/estrogen deficiency persists

Add transdermal estradiol + cyclic progestin (not a combined oral contraceptive); obtain a baseline DXA

POI

Karyotype + FMR1 testing; baseline DXA

Hormone therapy — estradiol ≥2 mg PO or ≥100 mcg/day transdermal + progestin if the uterus is intact — continued until the average age of natural menopause

Contraception counselling if pregnancy is not desired (ovulation can still occur); fertility referral if pregnancy is desired

Drug Tables

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.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Estradiol, transdermal	Dosing: Patch delivering at least 100 mcg/day, applied per product labeling	Breakthrough bleeding/spotting, breast tenderness, headache, bloating; local patch-site irritation.	CYP3A4 inducers (rifampin, carbamazepine, phenytoin, St. John's wort) lower levels; CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir) raise levels.	Preferred route in FHA specifically — avoids the first-pass hepatic effect that blunts IGF-1 and, unlike a combined oral contraceptive, does not mask the return of spontaneous menses.
Estradiol, oral	Dosing: At least 2 mg PO once daily	Breakthrough bleeding/spotting, breast tenderness, headache, bloating.	Same as transdermal estradiol.	An acceptable alternative route in POI specifically (unlike FHA, where transdermal is preferred). Minimum effective dose for skeletal protection in POI is higher than the typical starting dose used for natural menopause.
Progesterone, micronized	Cyclic: 200 mg PO QHS x12-14 days/month Continuous: 100 mg PO QHS	Drowsiness, bloating, breast tenderness.	None significant.	Preferred progestogen given its observational safety profile; take at bedtime given its sedating effect. Formulated with sunflower oil — caution with soy allergy (contains soy lecithin).
Medroxyprogesterone acetate	Dosing: 5-10 mg PO once daily x12-14 days/month	Irregular bleeding, bloating, mood change.	None significant.	A reasonable alternative to micronized progesterone, particularly where cost or a soy allergy is a concern.
Levonorgestrel/ethinyl estradiol	Dosing: 1 tablet PO daily for 21 days, then 7 hormone-free days, or continuous/extended-cycle per product labeling	Breakthrough bleeding, breast tenderness, nausea, headache; rare venous thromboembolism.	Enzyme-inducing drugs (certain anticonvulsants, rifampin, St. John's wort) may reduce contraceptive efficacy.	Alternative to physiologic hormone therapy in POI specifically when reliable contraception is also needed — spontaneous ovulation can still occur in POI, unlike natural menopause.

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.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Cabergoline	Starting dose: 0.25 mg PO twice weekly Titration: Increase by prolactin response to a usual maximum of 1 mg twice weekly	Nausea, dizziness, orthostatic hypotension; rare cardiac valvulopathy at high cumulative doses.	Additive hypotension with other antihypertensives; avoid with other ergot derivatives.	Preferred first-line dopamine agonist — superior efficacy, tolerability, and twice-weekly dosing compared with bromocriptine. Stop once pregnancy is confirmed unless a macroadenoma requires continued monitoring per specialist direction.
Bromocriptine	Starting dose: 1.25-2.5 mg PO once daily at bedtime Maintenance: 2.5-15 mg/day PO in divided doses	Nausea, orthostatic hypotension, headache; rare erythromelalgia, pleural/pulmonary fibrosis with prolonged high-dose use.	Additive hypotension with other antihypertensives; avoid with other ergot derivatives.	A longer track record of pregnancy safety data than cabergoline makes it the preferred agent specifically when conception is planned imminently.

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.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Calcium carbonate	Dosing: 500-600 mg elemental calcium PO with meals, in divided doses	Constipation, bloating.	Reduces absorption of tetracyclines, quinolones, iron salts, levothyroxine, and bisphosphonates — separate dosing by at least 2 hours.	Counsel on total daily elemental calcium intake from diet plus supplement combined, not the supplement dose in isolation.
Vitamin D3 (cholecalciferol)	Dosing: 800-2000 IU PO once daily, adjusted to a target 25(OH)D level	Hypercalcemia at high doses.	Additive hypercalcemia risk with active vitamin D analogs or calcium supplements.	Used to correct nutritional 25(OH)D deficiency/insufficiency alongside hormone therapy — not a substitute for it.

References

Current Evaluation of Amenorrhea: A Committee Opinion — Fertility and Sterility, Practice Committee of the American Society for Reproductive Medicine. Fertil Steril 2024;122(1):52-61
Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline — Journal of Clinical Endocrinology & Metabolism, Endocrine Society (Gordon CM, Ackerman KE, Berga SL, et al.). J Clin Endocrinol Metab 2017;102(5):1413-1439
Evidence-Based Guideline: Premature Ovarian Insufficiency — Human Reproduction Open, ESHRE/ASRM/CREWHIRL/IMS Guideline Group on POI (Panay N, Anderson RA, et al.). Hum Reprod Open 2024;2024(4):hoae065
Guideline No. 422a: Menopause: Vasomotor Symptoms, Prescription Therapeutic Agents, Complementary and Alternative Medicine, Nutrition, and Lifestyle — Journal of Obstetrics and Gynaecology Canada, Society of Obstetricians and Gynaecologists of Canada (Yuksel N, Evaniuk D, Huang L, et al.). J Obstet Gynaecol Can 2021;43(10):1188-1204
Diagnosis and Treatment of Hyperprolactinemia: An Endocrine Society Clinical Practice Guideline — Journal of Clinical Endocrinology & Metabolism, Endocrine Society (Melmed S, Casanueva FF, Hoffman AR, et al.). J Clin Endocrinol Metab 2011;96(2):273-288

Professional reference only. Apply clinical judgment and verify patient-specific decisions against current authoritative guidance and product information.