Amenorrhoea: endocrine causes

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Normal menstruation requires a patent outflow tract, responsive endometrium, ovarian follicles and coordinated hypothalamic-pituitary signalling. A disruption at any level can stop bleeding. Primary amenorrhoea places greater emphasis on pubertal development, anatomy and genetic conditions; secondary amenorrhoea commonly reflects pregnancy, PCOS, functional hypothalamic suppression, hyperprolactinaemia, thyroid disease or POI.

Bleeding itself does not reveal the hormone mechanism. Chronic anovulation with oestrogen exposure can place the endometrium at risk, while low-oestrogen states threaten bone and genitourinary health. A person taking a progestogen-only contraceptive may have neither problem. Treatment should therefore follow physiology rather than prescribing a withdrawal bleed as a diagnostic substitute.

The central decision is whether pregnancy or an acute pituitary, adrenal or pelvic disorder makes the presentation urgent, then whether gonadotrophins indicate ovarian or central hypogonadism, and whether androgen excess or anatomy redirects the pathway. The consultation should also identify disordered eating, coercion, pregnancy intention and psychological burden sensitively.

Key points

Exclude pregnancy first in every person with pregnancy potential, regardless of stated infertility, contraception, sexual orientation or cycle irregularity.
Primary amenorrhoea concerns menstruation that has not begun by the age or pubertal stage in current guidance; secondary amenorrhoea is loss of established bleeding for a clinically significant interval.
The presence of breasts, uterus, cervix and androgen signs directs primary amenorrhoea assessment before a long laboratory list is ordered.
High FSH with low oestrogen indicates ovarian insufficiency, while low or inappropriately normal FSH and LH suggests hypothalamic-pituitary suppression or failure.
Functional hypothalamic amenorrhoea is caused by low energy availability, excessive exercise, stress or illness after alternative causes are excluded; a normal BMI does not exclude it.
Raised prolactin may reflect pregnancy, medicines, stress, renal disease, macroprolactin or a pituitary lesion; confirm appropriately before imaging unless mass symptoms demand urgency.
Hyperandrogenism with irregular cycles commonly suggests PCOS, but rapid virilisation, severe testosterone elevation and Cushing features require a different pathway.
Amenorrhoea on hormonal contraception may be an expected medicine effect, but new pregnancy symptoms, pain or systemic endocrine features still require assessment.
Management is cause specific and must protect bone during hypo-oestrogenism and endometrium during chronic anovulation, while discussing contraception and fertility explicitly.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Physiological or treatment-related suppression

Pregnancy, lactation, menopause and hormonal contraception can stop bleeding without the same pathological ovarian, pituitary or endometrial mechanism.

Ovarian dysfunction

Polycystic ovary syndrome commonly causes chronic anovulation, while premature ovarian insufficiency reduces oestrogen and raises gonadotrophins through loss of ovarian feedback.

Hypothalamic-pituitary suppression

Low energy availability, high training load, stress, pituitary disease or hyperprolactinaemia can reduce gonadotrophin drive and interrupt ovulation and endometrial cycling.

Other endocrine disease

Thyroid dysfunction, androgen excess and adrenal disorders can disturb coordinated reproductive signalling, particularly when accompanied by weight change, hirsutism or systemic features.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Reproductive signalling is disrupted
Normal menstruation requires coordinated hypothalamic, pituitary and ovarian signalling, responsive endometrium and a patent outflow tract; interruption at any level can stop bleeding.
2
Ovulation or oestrogen exposure changes
Failure to recruit and ovulate a follicle alters progesterone cycling, while ovarian or central failure may reduce oestrogen enough to prevent endometrial proliferation.
3
End-organ risks diverge
Chronic anovulation with continuing oestrogen can expose the endometrium, whereas prolonged low-oestrogen states impair bone and genitourinary health through a different mechanism.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Physiological amenorrhoea

Pregnancy, lactation and menopause are physiological contexts, while hormonal contraception can suppress bleeding; confirm the context before applying an endocrine disease label.

Functional hypothalamic pattern

Reduced intake, high training load, stress, weight loss, bradycardia, stress fracture or eating-disorder features with low oestrogen and non-raised gonadotrophins suggests relative energy deficiency.

PCOS pattern

Irregular or absent bleeding with hirsutism, acne or biochemical androgen excess supports PCOS after pregnancy, thyroid, prolactin and adrenal mimics are excluded.

Ovarian insufficiency

Hot flushes, vaginal dryness and repeatedly raised FSH before age 40 suggests POI; iatrogenic, genetic and autoimmune causes require assessment.

HyperprolactinaemiaRed flag

Galactorrhoea, low libido, headache or visual change with suppressed gonadotrophins suggests prolactin excess, although galactorrhoea may be absent and medicine causes are common.

Primary anatomical clueRed flag

Normal breast development with absent uterus suggests Müllerian agenesis or androgen insensitivity, while cyclic pain with retained blood suggests outflow obstruction requiring gynaecological assessment.

Severe androgen excessRed flag

Rapid hair change, deep voice, clitoromegaly or marked testosterone abnormality suggests an ovarian or adrenal source rather than uncomplicated PCOS.

Pituitary or adrenal emergencyRed flag

Acute headache, ophthalmoplegia, visual loss, collapse, vomiting or severe postural hypotension can indicate apoplexy or cortisol deficiency and needs immediate treatment.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Urine or serum beta-hCGFirst step
Why
Exclude pregnancy before endocrine testing, imaging choices or hormone treatment.
Interpretation and limitations
Interpret with timing and repeat when pregnancy remains possible. Pain, bleeding or instability requires the pregnancy-of-unknown-location or ectopic pathway rather than reassurance from an early result.
02
FSH, LH and oestradiol
Why
Distinguish ovarian failure from central hypogonadism and support pubertal assessment.
Interpretation and limitations
High gonadotrophins with low oestrogen suggests ovarian insufficiency; low or normal gonadotrophins with low oestrogen suggests hypothalamic-pituitary disease. Hormonal treatments and cycle fluctuation alter values.
03
Serum prolactin
Why
Detect prolactin-mediated suppression of gonadotrophin secretion.
Interpretation and limitations
Repeat a non-emergency elevation under resting conditions, review pregnancy, antipsychotics, antiemetics, renal function and macroprolactin. Persistent or marked elevation and mass symptoms need endocrine MRI assessment.
04
Thyroid-stimulating hormone and free thyroxine
Why
Identify primary thyroid disease or a central thyroid pattern.
Interpretation and limitations
Both hypo- and hyperthyroidism can disturb cycles. A low free thyroxine with non-raised TSH suggests pituitary disease and requires adrenal assessment before thyroid replacement.
05
Total testosterone, SHBG and early-morning 17-hydroxyprogesterone
Why
Evaluate clinical androgen excess and screen for non-classic congenital adrenal hyperplasia.
Interpretation and limitations
Use reliable assays and specialist thresholds. Rapid virilisation or a severe result accelerates ovarian and adrenal imaging; a borderline 17-hydroxyprogesterone requires endocrine confirmation.
06
Pelvic ultrasound
Why
Confirm uterine anatomy, evaluate ovaries and investigate endometrium or obstruction.
Interpretation and limitations
In primary amenorrhoea establish whether a uterus is present; in suspected PCOS, do not diagnose from morphology alone or use adult criteria indiscriminately in adolescents.
07
Pituitary MRI and visual fields
Why
Identify sellar disease when central deficiency, hyperprolactinaemia or mass symptoms warrant imaging.
Interpretation and limitations
Assess cortisol safety first and use urgent pathways for sudden headache or visual loss. Incidental pituitary lesions need endocrine correlation rather than automatic attribution.
08
Bone-density and nutritional assessment
Why
Measure consequences of prolonged hypo-oestrogenism and relative energy deficiency.
Interpretation and limitations
Stress fracture, prolonged amenorrhoea, undernutrition or other risks support DXA. Include eating-disorder assessment, vitamin D and secondary bone factors; HRT cannot compensate for ongoing severe energy deficit alone.
09
Karyotype or genomic testing
Why
Investigate selected primary amenorrhoea, ovarian insufficiency or differences of sex development.
Interpretation and limitations
Arrange through specialist genetics with consent and counselling because results affect identity, fertility, tumour risk and relatives; avoid disclosing complex findings without support.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Pregnancy

Pregnancy is the immediate alternative in anyone with relevant reproductive potential; history alone does not reliably exclude it when bleeding has stopped.

Polycystic ovary syndrome

Irregular cycles with hirsutism, acne or biochemical androgen excess support PCOS after pregnancy, thyroid, prolactin and severe androgen disorders are excluded.

Functional hypothalamic amenorrhoea

Weight loss, restricted intake, heavy exercise, bradycardia or stress fracture with non-raised gonadotrophins suggests relative energy deficiency rather than ovarian failure.

Premature ovarian insufficiency

Hot flushes, vaginal dryness and repeatedly raised gonadotrophins with low oestrogen support ovarian insufficiency rather than central suppression.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01First stepsSecondary amenorrhoea assessmentFirst stepPreviously established menstruation has stopped beyond the current clinical threshold.

1Test for pregnancy and assess pain, bleeding, haemodynamic symptoms, contraception, lactation, medicines, weight or intake change, exercise, stress and chronic illness.
2Examine blood pressure, thyroid, galactorrhoea, androgen and Cushing features and signs of energy deficiency, using trauma-informed discussion of eating and pregnancy possibility.
3Measure FSH, LH, oestradiol, prolactin and thyroid function, adding androgen or adrenal tests when the phenotype supports them.
4DefinitiveDirect care to POI, functional hypothalamic, PCOS, prolactin, thyroid or structural pathways and plan bone or endometrial protection while definitive treatment proceeds.

02PrimaryNo menarche or incomplete pubertyMenstruation has not begun by the current age or pubertal-development threshold.

1Assess growth, pubertal sequence, breasts, androgen signs, cyclic pain, chronic disease, exercise, nutrition and family history, with sensitive external examination and consent.
2Use pelvic ultrasound to establish uterus and ovaries, then FSH, LH and oestradiol to separate gonadal from central patterns; add targeted androgen and genetic tests.
3Refer promptly for absent uterus, outflow obstruction, absent secondary sexual development, virilisation or suspected Turner or pituitary disease.
4Provide supported disclosure, pubertal induction or surgery only through the multidisciplinary pathway, incorporating fertility, bone, sexual function and psychological care.

03EnergyFunctional hypothalamic amenorrhoeaLow-oestrogen central pattern with low energy availability, excessive training, stress or eating-disorder features after exclusion of disease.

1Assess medical stability, ECG and electrolytes where eating-disorder risk is significant and urgently admit severe bradycardia, hypotension, electrolyte disturbance or suicidality under local criteria.
2Build a multidisciplinary nutrition, exercise and psychological plan that restores energy availability and reduces training safely without using shame or a single BMI threshold.
3Review cycle recovery, bone symptoms and biochemical context; provide physiological oestrogen and progestogen if recovery is unlikely or absent within the specialist-recommended interval.
4For desired pregnancy, refer for monitored gonadotrophin or pulsatile GnRH induction only after medical and nutritional optimisation.

04ProlactinHyperprolactinaemic amenorrhoeaPersistent raised prolactin with cycle suppression after pregnancy and transient causes are considered.

1Repeat the measurement appropriately, review antipsychotics, antiemetics and other causes, and check renal, thyroid and macroprolactin context without abruptly stopping psychiatric treatment.
2Assess headache, fields, pituitary axes and adrenal safety and arrange MRI under endocrinology when persistent elevation or symptoms indicate it.
3Treat the cause; NICE NG257 recommends cabergoline for ovulatory disorders due to hyperprolactinaemia, with formulation, pregnancy and valve considerations managed by the specialist service.
4Monitor prolactin, tumour response, cycles and fertility, coordinating pregnancy plans and avoiding unplanned withdrawal of essential mental-health medicines.

Key medicines and prescribing safety5 treatments · regimens, roles and cautions

Restores gonadotrophin function and ovulation in hyperprolactinaemic amenorrhoea and reduces many prolactinomas.

Cabergoline

Start and titrate using the endocrine or fertility protocol to prolactin response and clinical goal.

Nausea, postural hypotension, impulse-control effects and product-specific cardiac valve monitoring require counselling. Pregnancy and tumour plans are specialist led; do not stop antipsychotics abruptly.

Treats hypothyroidism causing cycle disturbance and supports safe preconception thyroid status.

Levothyroxine

Use the licensed once-daily regimen titrated to thyroid tests and pregnancy-specific targets when indicated.

Confirm primary versus central disease; in suspected pituitary failure assess and replace cortisol before thyroid hormone. Separate from interacting iron or calcium preparations.

Protects bone and treats oestrogen-deficiency symptoms in persistent central hypogonadism or POI.

Transdermal oestradiol with progestogen

Provide physiological replacement with a licensed or specialist schedule and uterine protection when a uterus is present.

It is not a treatment for restoring energy balance and standard HRT is not contraception. Investigate unscheduled bleeding and individualise for thrombosis, migraine and cancer history.

Produces planned endometrial shedding in PCOS or another oestrogenised anovulatory state when no contraceptive hormonal method is selected.

Cyclical progestogen

Use the locally recommended periodic course to protect the endometrium during chronic anovulation after pregnancy exclusion.

It does not treat hypo-oestrogenic bone loss, prove ovulation or reliably prevent pregnancy. Persistent abnormal bleeding requires investigation.

Induces ovulation in hypogonadotrophic hypogonadism when pregnancy is desired after medical optimisation.

Gonadotrophin or pulsatile GnRH fertility therapy

Use only a reproductive-medicine protocol with ultrasound and hormone monitoring and explicit cancellation criteria.

Multiple pregnancy and ovarian hyperstimulation are preventable treatment harms; self-directed or unmonitored use is unsafe and local access criteria vary.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Endometrial hyperplasia

Persistent anovulation with unopposed oestrogen can cause prolonged endometrial stimulation, increasing irregular bleeding and longer-term endometrial risk.

Reduced bone strength

Prolonged oestrogen deficiency reduces bone accrual or accelerates bone loss, increasing stress injury and later fragility-fracture risk.

Subfertility

Absent or unpredictable ovulation reduces opportunities for conception and may signal ovarian reserve or pituitary disease requiring time-sensitive assessment.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Track menstrual pattern, pregnancy possibility and the underlying endocrine marker rather than assuming one withdrawal bleed proves recovery.
In hypo-oestrogenic states, review fracture, bone density, nutrition, vitamin D, exercise and adherence to physiological replacement at risk-based intervals.
In chronic anovulation, confirm endometrial protection and investigate heavy, persistent or intermenstrual bleeding according to the gynaecology pathway.
For hyperprolactinaemia, monitor symptoms, prolactin, visual fields and tumour imaging through endocrinology, with cabergoline adverse-effect and pregnancy review.
For functional hypothalamic amenorrhoea, follow medical stability, energy availability, exercise, mood and eating-disorder recovery; menstrual return is important but not the only outcome.
Revisit contraception, fertility goals and sexual health at each transition because ovulation can resume unpredictably during cause treatment.
Adolescents with delayed puberty need growth, pubertal progression, bone and psychosocial monitoring within paediatric or transition endocrinology.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Pregnancy precedes hormones

No endocrine pattern safely excludes pregnancy before beta-hCG testing. Irregular ovulation and prior infertility labels frequently create false reassurance.

FSH localises the axis

Raised FSH indicates loss of ovarian feedback, while a non-raised value in low oestrogen points upstream. This simple split structures the rest of the investigation.

Bleeding is not ovulation

A progestogen withdrawal bleed demonstrates a responsive outflow tract and endometrium but does not establish spontaneous follicular ovulation or fertility.

Normal BMI can hide deficiency

Energy availability depends on intake relative to expenditure, not appearance alone. Athletes and people with restrictive eating can be medically compromised at many weights.

Prolactin needs context

Stress, medicines, macroprolactin and renal failure can elevate a result. Repeat thoughtfully, but do not delay imaging when visual or severe pituitary features are present.

An absent uterus changes questions

In primary amenorrhoea, distinguish Müllerian agenesis from androgen insensitivity and outflow disorders through anatomy, karyotype and hormones with supported specialist disclosure.

Hormones cannot replace nutrition

Oestrogen may protect some bone endpoints, but ongoing severe energy deficit harms cardiovascular, skeletal, immune and psychological health beyond amenorrhoea.

Identity and anatomy coexist

Use the person's language and never infer sexual behaviour or pregnancy possibility from gender or partner identity; explain why anatomy-specific questions affect safe testing.

11Common pitfallsFrequent interpretation and management errors.

01
Ordering a hormone panel before excluding pregnancy.
02
Diagnosing functional hypothalamic amenorrhoea without excluding pituitary and ovarian disease.
03
Using BMI alone to assess low energy availability.
04
Treating a single stressed prolactin result as a pituitary tumour.
05
Missing ectopic pregnancy because the person has PCOS or prior infertility.
06
Giving oestrogen without uterine progestogen protection.
07
Using a withdrawal bleed as proof that ovulation has returned.
08
Failing to protect bone during prolonged hypo-oestrogenism.