Female hypogonadism and premature ovarian insufficiency

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

Ovarian hypogonadism follows follicle depletion or dysfunction from genetic conditions, autoimmune disease, surgery, chemotherapy, radiotherapy or an unexplained process. Gonadotrophins rise because ovarian negative feedback is lost. Central hypogonadism follows deficient hypothalamic GnRH or pituitary LH and FSH, as in relative energy deficiency, pituitary lesions, hyperprolactinaemia, chronic disease or opioid exposure. These mechanisms lead to different investigations and fertility treatments.

Loss of oestradiol can cause hot flushes, sleep disruption, vaginal dryness, sexual pain, low libido and mood symptoms, but absence of symptoms does not protect bone. Prolonged deficiency before the expected menopause is associated with low bone density and adverse cardiometabolic effects. Replacement in POI is physiological restoration for a young deficient person, not the same risk-benefit question as initiating HRT decades after natural menopause.

The central decision is whether the biochemical pattern reflects primary ovarian or central disease, whether an urgent pituitary or autoimmune problem exists, and which replacement, contraception and fertility plan fits the person. Use inclusive language: eligibility for uterine protection and pregnancy depends on anatomy and physiology, while identity and preferred terms guide respectful care.

Key points

Female hypogonadism means inadequate ovarian sex-steroid action from ovarian failure, deficient hypothalamic-pituitary stimulation or treatment-related suppression; amenorrhoea is a presentation, not the complete diagnosis.
Premature ovarian insufficiency is ovarian dysfunction before age 40 with disordered cycles and biochemical evidence; ovarian activity may be intermittent, so the term does not mean irreversible absence of every ovulation.
NICE advises against diagnosing POI from one blood test and uses two elevated FSH results obtained four to six weeks apart after clinical assessment; hormonal treatment can make the tests uninterpretable.
Do not use anti-Müllerian hormone routinely to diagnose POI; it measures aspects of follicular reserve but does not replace the required clinical and gonadotrophin assessment.
High FSH with low oestrogen supports primary ovarian insufficiency, whereas low or inappropriately normal FSH suggests functional hypothalamic, pituitary or systemic suppression.
Offer sex-steroid replacement to people with POI unless contraindicated and normally continue until at least the average natural-menopause age, even when vasomotor symptoms are mild.
A uterus requires progestogen protection with systemic oestrogen; transdermal oestradiol is often favoured when venous thrombosis or metabolic considerations make oral exposure less suitable.
HRT is not contraception. Intermittent ovulation and spontaneous pregnancy can occur in POI, so discuss both fertility wishes and pregnancy prevention.
Bone, cardiovascular, sexual, psychological and fertility care should begin at diagnosis, with genetic and autoimmune investigation selected by age, phenotype and specialist guidance.

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

Primary ovarian dysfunction

Genetic conditions, autoimmune disease, surgery, chemotherapy, radiotherapy or unexplained follicular depletion reduce ovarian oestradiol production and release pituitary feedback.

Hypothalamic-pituitary deficiency

Low energy availability, pituitary lesions, hyperprolactinaemia, chronic disease or opioids can reduce gonadotrophin drive despite structurally capable ovaries.

Iatrogenic gonadal injury

Pelvic surgery and gonadotoxic cancer treatment can abruptly reduce ovarian reserve, making fertility preservation and long-term replacement planning time-sensitive.

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

1
Oestradiol production declines
Ovarian follicular failure or inadequate gonadotrophin stimulation reduces circulating oestradiol and disrupts ovulation and menstrual cycling.
2
Feedback pattern localises disease
Primary ovarian failure raises gonadotrophins through loss of feedback, whereas central hypogonadism leaves them low or inappropriately normal.
3
Oestrogen-sensitive tissues lose support
Prolonged deficiency affects thermoregulation, genital tissues, bone remodelling and cardiometabolic physiology even when vasomotor symptoms are mild or absent.

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

Oestrogen-deficiency symptoms

Hot flushes, night sweats, sleep disruption, vaginal dryness, dyspareunia, reduced libido and cognitive or mood change may accompany falling ovarian sex steroids.

Primary ovarian pattern

Amenorrhoea or oligomenorrhoea with repeatedly raised FSH and low oestrogen supports POI after pregnancy and hormonal-treatment effects are excluded.

Central hypogonadism pattern

Low oestrogen with low or inappropriately normal gonadotrophins points to hypothalamic energy deficiency, pituitary disease, hyperprolactinaemia, systemic illness or medicine suppression.

Turner phenotype

Short stature, absent or incomplete puberty, webbed neck, lymphoedema, cardiac or renal anomaly may accompany sex-chromosome disease and requires specialist multisystem assessment.

Pituitary red flagRed flag

Headache, visual field loss, diplopia, galactorrhoea, polyuria or additional cortisol and thyroid deficits suggests sellar disease; abrupt severe symptoms may represent apoplexy.

Autoimmune clusterRed flag

Vitiligo, autoimmune thyroid disease, weight loss, postural hypotension, pigmentation or electrolyte disturbance raises concern for associated adrenal or thyroid autoimmunity.

Iatrogenic risk

Pelvic surgery, alkylating chemotherapy, pelvic radiotherapy and some immune therapies can impair ovarian function; fertility preservation should be considered before gonadotoxic treatment where feasible.

Skeletal consequence

Stress fracture, low-trauma fracture, height loss or chronic musculoskeletal pain may reveal prolonged oestrogen deficiency, especially with undernutrition or glucocorticoid exposure.

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
Pregnancy testFirst step
Why
Exclude pregnancy before interpreting amenorrhoea or prescribing replacement and progestogen.
Interpretation and limitations
Intermittent ovarian activity means pregnancy remains possible in POI. Pain, bleeding, collapse or shoulder-tip symptoms require urgent early-pregnancy assessment.
02
Two serum FSH measurements
Why
Confirm the gonadotrophin pattern supporting POI under current NICE guidance.
Interpretation and limitations
Obtain samples four to six weeks apart when not rendered uninterpretable by combined hormonal treatment. Do not diagnose from one result; specialist guidance addresses uncertainty or newer international criteria.
03
Oestradiol with LH
Why
Support distinction between ovarian failure and central hypogonadism.
Interpretation and limitations
Low oestradiol with high gonadotrophins supports ovarian failure; low oestradiol with low or normal gonadotrophins suggests central disease. Results fluctuate and should be integrated with clinical context.
04
Thyroid function and prolactin
Why
Identify common endocrine causes and associated autoimmune disease.
Interpretation and limitations
Repeat an unexpected prolactin under suitable conditions, review medicines and macroprolactin, and arrange pituitary assessment when persistent elevation or mass symptoms warrant it.
05
Karyotype and FMR1 premutation testing
Why
Identify sex-chromosome and fragile-X-associated causes in eligible unexplained POI.
Interpretation and limitations
Testing is specialist and counselling led because results can affect cardiac, pregnancy and family risk. A Y-chromosome component may alter tumour-risk management.
06
Adrenal and thyroid autoimmunity assessment
Why
Detect associated autoimmune endocrine disease when POI is unexplained or symptoms suggest it.
Interpretation and limitations
Use current endocrine guidance for adrenal antibodies and functional testing. Symptoms of adrenal crisis demand immediate cortisol treatment and assessment rather than waiting for antibody results.
07
Pelvic ultrasound
Why
Assess uterus, ovaries and structural causes when presentation or fertility planning requires imaging.
Interpretation and limitations
Small ovaries or low follicle count may support diminished reserve but do not alone diagnose POI; ultrasound also informs uterine development in primary amenorrhoea.
08
Bone-density scan
Why
Measure skeletal consequence after prolonged hypogonadism or in those with additional fracture risk.
Interpretation and limitations
Use age-appropriate interpretation and repeat interval based on baseline density, replacement adherence and risk. A normal scan does not remove the need for physiological replacement in POI.
09
Cardiometabolic and nutritional profile
Why
Identify blood-pressure, lipid, glucose, vitamin D and undernutrition factors relevant to long-term health.
Interpretation and limitations
Manage established risks without stigmatising weight. Functional hypothalamic disease requires careful energy and eating-disorder assessment even when routine blood tests look normal.

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

Pregnancy

Pregnancy is an immediate cause of amenorrhoea and can coexist with previously irregular cycles, so reproductive context must be confirmed first.

Polycystic ovary syndrome

Chronic anovulation with androgen excess and non-raised FSH favours PCOS rather than low-oestrogen ovarian failure when combined with the history and other findings.

Functional hypothalamic amenorrhoea

Restricted intake, intense exercise, weight loss or stress with non-raised gonadotrophins suggests reversible central suppression rather than follicular depletion.

Hyperprolactinaemia

Galactorrhoea, medicine exposure or pituitary features with raised prolactin indicate dopamine or stalk-related suppression of the gonadal axis.

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

01Confirm POISuspected primary ovarian insufficiencyFirst stepDisordered cycles or oestrogen-deficiency symptoms before age 40 with no physiological explanation.

1Exclude pregnancy, record hormonal treatment, surgery, cancer therapy, autoimmune and family history, and assess pubertal development, vasomotor, genitourinary and fertility concerns.
2Obtain FSH on two occasions four to six weeks apart under current NICE guidance, with oestradiol, LH, thyroid and prolactin as clinically useful.
3Refer for cause assessment including genetic and autoimmune testing where eligible, and address urgent adrenal or pituitary features immediately.
4At diagnosis, discuss hormone replacement, contraception, fertility, bone and cardiovascular health and psychological support rather than arranging an isolated annual blood test.

02ReplacePhysiological sex-steroid replacementConfirmed POI or persistent central hypogonadism without a contraindication to systemic hormones.

1Offer HRT or, where contraception is also desired and medically suitable, a combined hormonal contraceptive, explaining differences in physiology, bleeding and bone evidence.
2If a uterus is present, provide continuous or cyclical progestogen protection matched to the oestrogen regimen; choose route around thrombosis, migraine, absorption and preference.
3Treat persistent genitourinary symptoms with vaginal oestrogen where appropriate and address sexual pain, pelvic-floor and psychosexual needs alongside systemic treatment.
4Continue replacement normally until at least the average natural-menopause age, reviewing benefit, adherence, bleeding and contraindications without requiring routine hormone-level chasing.

03CentralFunctional or structural central hypogonadismLow oestrogen with low or inappropriately normal gonadotrophins.

1Assess energy availability, exercise, stress, eating disorder, chronic illness, opioids and all pituitary symptoms; measure prolactin, thyroid and adrenal axes with endocrine support.
2For functional hypothalamic suppression, restore nutrition and reduce excessive training through a multidisciplinary plan, avoiding a weight target that worsens disordered eating.
3Arrange pituitary MRI and visual assessment for severe biochemical deficiency, persistent hyperprolactinaemia, additional pituitary deficits or mass-effect symptoms.
4If recovery is unlikely or remains absent after an appropriate interval, provide physiological oestrogen and progestogen replacement and specialist fertility treatment when desired.

04FertilityPregnancy goals with POI or central deficiencyThe person wants pregnancy now or wishes to preserve future reproductive options.

1Explain uncertainty honestly: intermittent ovulation can occur in POI, but no treatment reliably restores the depleted follicle pool; avoid unsupported supplements or commercial claims.
2Refer promptly to reproductive medicine for ovarian-reserve context, donor-oocyte or embryo options, and fertility preservation before gonadotoxic treatment when possible.
3For central hypogonadism, specialist gonadotrophin or pulsatile GnRH ovulation induction can be effective and must be monitored to reduce multiple pregnancy and hyperstimulation.
4Optimise cardiovascular and obstetric safety, especially with Turner syndrome or prior cancer treatment, and coordinate medication, genetic and psychological counselling before conception.

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

Replaces deficient oestrogen for vasomotor, bone, cardiovascular and genitourinary protection in POI and central hypogonadism.

Transdermal oestradiol

Use the licensed patch or gel regimen titrated to physiological replacement and symptom control through specialist guidance.

A uterus requires progestogen. Review unexplained bleeding, hormone-sensitive cancer, liver disease and thrombosis context; transdermal delivery avoids first-pass exposure but still needs individual assessment.

Protects the endometrium from hyperplasia and cancer when systemic oestrogen is used with a uterus present.

Oral micronised progesterone or alternative progestogen

Give continuously or cyclically in the licensed or specialist regimen matched to systemic oestrogen exposure.

Adherence is essential; unscheduled bleeding follows the current BMS and local pathway. Sedation, mood effects and product-specific thrombosis considerations inform choice.

Provides both contraception and sex-steroid exposure for selected people with POI who prefer this approach.

Combined hormonal contraception

Use a licensed contraceptive regimen selected with the UK medical eligibility criteria and patient preference.

Assess thrombosis, migraine with aura, smoking and blood pressure. It suppresses endogenous markers and is not suitable for every cardiovascular or cancer context.

Treats vaginal dryness, soreness, dyspareunia and recurrent urinary symptoms through local tissue oestrogenisation.

Vaginal oestrogen

Use the licensed local loading and maintenance schedule for the chosen preparation, adjusting to symptom response.

Persistent bleeding, discharge, pain or a mass requires assessment. Systemic absorption is low but complex hormone-dependent cancer histories need specialist shared decision-making.

Supports skeletal mineralisation alongside adequate energy, weight-bearing activity and physiological sex-steroid replacement.

Calcium and vitamin D supplementation

Supplement only to close a documented dietary or biochemical gap using the current bone-health formulary.

It does not replace oestrogen in POI. Avoid excessive dosing and review renal stones, hypercalcaemia, malabsorption and interactions.

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

Low bone density

Prolonged oestrogen deficiency increases bone turnover and limits peak bone maintenance, raising fragility-fracture risk before the usual menopause age.

Subfertility

Reduced follicular reserve or inadequate gonadotrophin stimulation disrupts ovulation and may require cause-specific fertility treatment or donor-gamete discussion.

Genitourinary and sexual symptoms

Vaginal dryness, dyspareunia, urinary symptoms and low libido can impair relationships and quality of life if not addressed directly.

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

Review symptoms, adherence, blood pressure, weight trajectory, smoking and sexual or genitourinary health after starting replacement and at least annually thereafter.
Ask about unscheduled bleeding and investigate under current BMS and local guidance rather than simply increasing progestogen indefinitely.
Assess bone density at a risk-based interval, with fracture, nutrition, vitamin D, exercise and glucocorticoid review; replacement adherence matters more than routine FSH monitoring.
Track cardiovascular risk factors including lipids, glucose and blood pressure without extrapolating older postmenopausal HRT data mechanically to young people with POI.
Revisit contraception and pregnancy wishes because spontaneous ovarian activity may recur and HRT does not prevent conception.
For Turner syndrome or previous cardiotoxic treatment, follow the specialist cardiac, renal, hearing, thyroid and pregnancy surveillance programme.
Screen for grief, depression, anxiety, body-image and relationship effects and offer fertility counselling and peer or psychological support.

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

Insufficiency is intermittent

POI does not guarantee permanent anovulation. This explains both occasional spontaneous pregnancy and why HRT cannot be relied upon as contraception.

Replacement differs from late HRT

For a young person missing ovarian hormones, treatment restores expected physiology. Risk discussions should not copy data from much older initiators without context.

FSH can be masked

Combined contraception and some replacement regimens suppress gonadotrophins. Interpret prior testing and specialist washout decisions carefully rather than stopping hormones casually.

AMH is not diagnostic

A low value may reflect reduced reserve but NICE does not recommend routine AMH to diagnose POI; clinical cycles and gonadotrophin confirmation remain central.

Bone protection needs oestrogen

Calcium and vitamin D alone cannot counter prolonged sex-steroid deficiency. Adequate physiological replacement and nutrition are foundational when not contraindicated.

Central fertility can respond well

When the ovary retains follicles but hypothalamic-pituitary drive is absent, monitored GnRH or gonadotrophin therapy can induce ovulation; oral PCOS agents are not interchangeable.

Diagnosis carries family information

Karyotype and FMR1 results may affect relatives, pregnancy risk and counselling. Testing belongs in a consented genetics pathway, not a reflex panel.

Treat the whole loss

POI can involve grief about fertility, identity, sexuality and unexpected ageing. Offering hormones without psychological and reproductive support is incomplete care.

11Common pitfallsFrequent interpretation and management errors.

01
Diagnosing POI from a single FSH result.
02
Using anti-Müllerian hormone as the sole diagnostic test.
03
Prescribing systemic oestrogen without progestogen when a uterus is present.
04
Assuming standard HRT provides reliable contraception.
05
Withholding replacement because vasomotor symptoms are mild despite young age and bone risk.
06
Missing central disease when gonadotrophins are not raised.
07
Ignoring adrenal symptoms in autoimmune POI.
08
Promising that supplements will restore ovarian reserve.