Endocrine causes of infertility

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

Endocrine infertility can result from failure to ovulate, deficient ovarian reserve, excess prolactin, thyroid disease, severe androgen excess, hypothalamic energy deficiency or testicular and pituitary failure. Age, semen quality, tubal patency, uterine disease and sexual function remain equally important. A diagnosis such as PCOS is not a complete fertility assessment.

Gonadotrophin patterns localise disease. Raised FSH with low sex steroid suggests primary gonadal failure; low or inappropriately normal gonadotrophins suggests hypothalamic-pituitary deficiency. In PCOS, androgen excess and irregular ovulation may occur with non-raised FSH. Male hypogonadotrophic hypogonadism is unusually amenable to hormonal induction of spermatogenesis, whereas testosterone replacement suppresses it.

The central decision is whether expectant conception remains reasonable, whether a reversible endocrine disorder should be treated first, or whether time-sensitive referral for ovulation induction, surgery, donor gametes or IVF is appropriate. Investigation and treatment should be inclusive of couples, single people, same-sex partners and trans or non-binary people according to organs, gametes, prior hormones and individual goals.

Key points

NICE NG257 replaced CG156 in March 2026; use the new guideline and current local commissioning rules rather than an inherited fertility checklist.
Assess both partners or gamete sources at the same time where relevant; finding an ovulation disorder does not remove the need for semen and tubal or uterine assessment.
Offer earlier specialist referral when age, amenorrhoea, previous gonadotoxic treatment, known tubal or male-factor disease, cancer or another clear risk makes waiting inappropriate.
Confirm ovulation with cycle history and correctly timed progesterone when needed; a fixed day-21 sample is wrong for every cycle that is not 28 days.
Measure FSH and LH in irregular or absent cycles, and add prolactin, thyroid and androgen assessment when symptoms or an ovulatory disorder justify them rather than screening indiscriminately.
Use anti-Müllerian hormone or antral follicle count to predict ovarian response to stimulation in the indicated setting, not as a stand-alone test of natural fertility or egg quality.
Semen analysis is the first male test. Severe oligozoospermia or azoospermia needs repeat confirmation, endocrine localisation and genetic or obstructive assessment through andrology.
Do not give exogenous testosterone or anabolic androgens to improve male fertility; they suppress gonadotrophins and intratesticular testosterone and can cause azoospermia.
Ovulation induction, gonadotrophins and assisted conception require monitored specialist protocols with cancellation rules to limit multiple pregnancy and ovarian hyperstimulation.
NHS treatment access differs across nations and commissioners; explain clinical recommendations separately from funding eligibility and direct people to an HFEA-licensed service.

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

Ovulatory endocrine disorders

Polycystic ovary syndrome, hypothalamic energy deficiency, hyperprolactinaemia, thyroid disease and ovarian insufficiency can prevent predictable ovulation.

Testicular or central hypogonadism

Primary testicular failure reduces sperm production despite raised gonadotrophins, while pituitary or hypothalamic deficiency provides inadequate hormonal stimulation.

Non-endocrine reproductive factors

Age, semen quality, tubal disease, uterine pathology and sexual dysfunction remain important even when an endocrine diagnosis is already present.

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

1
Gonadal signalling is disturbed
Inadequate or disordered gonadotrophin drive prevents coordinated follicular development, ovulation, testosterone production or spermatogenesis as the process continues.
2
Gamete availability falls
Reduced ovulation, diminished ovarian reserve or impaired sperm production lowers the likelihood that viable gametes meet during the fertile interval.
3
Time and treatment modify probability
Age-related decline, duration of unsuccessful conception and treatment that suppresses gonadal function can progressively narrow available reproductive options.

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

Anovulatory infertility

Infrequent or absent cycles suggest inconsistent ovulation from PCOS, hypothalamic suppression, hyperprolactinaemia, thyroid disease or ovarian insufficiency, although occasional bleeding does not guarantee ovulation.

Reduced ovarian reserve

Older reproductive age, prior ovarian surgery, chemotherapy, pelvic radiotherapy or family history of early menopause increases urgency, but reserve tests predict stimulation response better than spontaneous conception.

Hypothalamic energy deficiency

Restricted intake, excessive training, stress fractures and low-oestrogen amenorrhoea suggests functional central hypogonadism that needs medical and nutritional restoration before fertility stimulation.

HyperprolactinaemiaRed flag

Amenorrhoea, galactorrhoea, low libido or visual symptoms may reflect prolactin-mediated gonadotrophin suppression; medicine causes and macroprolactin complicate interpretation.

Primary testicular failure

Small firm testes, gynaecomastia, reduced body hair and high gonadotrophins with impaired semen suggests Klinefelter syndrome, prior gonadotoxic injury or another testicular disorder.

Male central failure

Low testosterone with low or normal LH and FSH, delayed puberty, anosmia, opioid or anabolic exposure or pituitary symptoms points to deficient gonadotrophin drive.

Structural or sexual contributor

Pelvic pain, infection or surgery suggests tubal disease; erectile, ejaculatory or intercourse difficulty may coexist with endocrine disease and should be discussed without assumptions.

Treatment complicationRed flag

Post-stimulation pain, distension, breathlessness, oliguria, syncope or rapid weight gain suggests OHSS, torsion, bleeding or ectopic pregnancy and needs urgent specialist assessment.

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
Semen analysisFirst step
Why
Assess sperm concentration, motility and morphology early in every pathway using sperm relevant to conception.
Interpretation and limitations
Use a WHO-standard laboratory and repeat an abnormal result at the NICE-defined interval, sooner when severe deficiency is found. Fever, abstinence interval and sample completeness affect interpretation.
02
Mid-luteal serum progesterone
Why
Confirm that ovulation occurred in a spontaneous cycle when cycle history is insufficient.
Interpretation and limitations
Time the sample relative to the expected next period, not automatically on day 21. Irregular long cycles may need later or repeated testing; a single value does not assess ovarian reserve.
03
FSH, LH and oestradiol
Why
Localise anovulation to ovarian failure, hypothalamic-pituitary deficiency or a non-failure pattern.
Interpretation and limitations
Raised FSH with low oestrogen supports ovarian insufficiency; non-raised gonadotrophins with low oestrogen suggests central disease. Hormonal contraception and cycle timing alter interpretation.
04
Prolactin and thyroid function
Why
Identify treatable endocrine disruption when ovulatory symptoms, galactorrhoea, thyroid features or pituitary concern is present.
Interpretation and limitations
NICE does not support indiscriminate testing in everyone without relevant symptoms. Repeat prolactin appropriately and assess adrenal safety if central thyroid disease is possible.
05
Testosterone, SHBG, LH and FSH in men
Why
Distinguish primary testicular from central androgen deficiency when semen or symptoms indicate.
Interpretation and limitations
Confirm low testosterone on separate early-morning samples. High gonadotrophins indicate testicular failure; low values direct prolactin, pituitary, medicine and anabolic-exposure assessment.
06
Anti-Müllerian hormone or antral follicle count
Why
Estimate likely ovarian response to stimulation when assisted conception planning requires reserve assessment.
Interpretation and limitations
Use the current NICE assay thresholds and local laboratory calibration. These tests do not predict natural conception reliably and should not be sold as a fertility clock.
07
Pelvic ultrasound and tubal-patency assessment
Why
Evaluate uterine, ovarian and tubal contributors that endocrine tests cannot identify.
Interpretation and limitations
Select ultrasound, hysterosalpingography or alternative imaging from history, infection risk and specialist pathway. Polycystic morphology alone does not diagnose PCOS.
08
Genetic testing for severe male factor
Why
Identify karyotype, Y-chromosome or CFTR-related disease when sperm findings and anatomy indicate.
Interpretation and limitations
Arrange through andrology or genetics with counselling because results affect treatment, offspring and relatives. Do not order broad commercial panels without an evidence-based indication.
09
Pituitary MRI and visual assessment
Why
Find a sellar lesion when central hypogonadism, persistent prolactin elevation or mass-effect symptoms are present.
Interpretation and limitations
Assess cortisol before thyroid treatment and use the apoplexy emergency pathway for sudden headache or visual loss; stable imaging is coordinated by endocrinology.
10
Preconception infection and health assessment
Why
Prepare safely for pregnancy and licensed assisted-conception treatment.
Interpretation and limitations
Follow NICE and HFEA requirements for infection screening, folate, vaccination, genetics, medicines, smoking, alcohol and chronic disease without delaying urgent age- or gonadotoxicity-related referral.

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

Tubal or uterine disease

Regular ovulation does not exclude blocked tubes, endometriosis or uterine pathology; imaging and reproductive assessment distinguish mechanical from endocrine causes.

Male-factor infertility

Semen analysis may reveal concentration, motility or morphology problems even when the other partner has an apparent ovulatory disorder.

Age-related ovarian decline

Falling reproductive potential with age can coexist with normal cycles and requires time-sensitive interpretation rather than attributing delay solely to hormones.

Sexual dysfunction

Erectile, ejaculatory, pain or timing difficulties may reduce conception opportunity despite otherwise adequate endocrine and gamete function.

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

01AssessParallel initial fertility evaluationFirst stepPregnancy has not occurred within the current NICE timeframe or earlier risk factors justify review.

1Clarify duration, frequency and method of conception attempts, age, previous pregnancies, cycles, pelvic and sexual symptoms, medicines, hormones, gonadotoxic exposure, lifestyle and each person's goals.
2Arrange semen analysis and assess ovulation in parallel, adding pelvic or tubal evaluation according to history rather than completing one partner's tests before starting the other's.
3Use targeted endocrine tests for irregular cycles, galactorrhoea, thyroid symptoms, androgen excess or male hypogonadism and avoid AMH as a general natural-fertility screen.
4Refer earlier for amenorrhoea, severe semen abnormality, older reproductive age, prior cancer therapy or known disease, and explain current local NHS access separately from medical need.

02AnovulationTreatable female endocrine causeOvulation is absent or infrequent and pregnancy is desired after pregnancy and structural factors are assessed.

1Identify PCOS, functional hypothalamic deficiency, hyperprolactinaemia, thyroid disease or POI from cycle, gonadotrophin, androgen and symptom patterns and treat reversible health risks first.
2For PCOS, use the current NICE and local monitored oral ovulation-induction pathway; explain off-label status where relevant and set ultrasound or progesterone response checks.
3For hypogonadotrophic hypogonadism, offer specialist gonadotrophins with LH activity or GnRH under NG257, after restoring adequate energy and excluding pituitary danger.
4For hyperprolactinaemic ovulatory disorder, NICE NG257 recommends cabergoline; monitor prolactin, tumour and pregnancy plan through endocrinology and fertility teams.

03Male axisEndocrine male-factor infertilityAzoospermia or oligozoospermia with hypogonadal symptoms, abnormal testosterone or gonadotrophins.

1Repeat semen analysis as NICE specifies and examine testes, vasa, secondary sexual features and breast tissue, asking about puberty, infection, surgery, anabolic steroids, heat and gonadotoxins.
2Confirm early-morning testosterone and measure LH and FSH; investigate prolactin, pituitary disease, genetics or obstruction according to primary versus central pattern.
3Do not offer androgen treatment for semen abnormalities. Stop non-prescribed testosterone with specialist support and allow a monitored recovery interval where clinically reasonable.
4Offer gonadotrophin or anti-oestrogen treatment only for the current NG257 indications under andrology, and coordinate sperm retrieval, cryopreservation, ICSI or donor options as appropriate.

04SafetyMonitored stimulation and assisted conceptionOral or injectable ovulation induction, IUI or IVF is planned through a specialist service.

1Confirm indication, pregnancy exclusion, infection and medicine safety and agree the exact monitoring, dose-change and cycle-cancellation plan before treatment starts.
2Use ultrasound and hormone response to limit multifollicular development; the 2026 British Fertility Society IUI guidance stresses individual dosing and explicit cancellation criteria.
3Provide urgent written contacts for abdominal pain, distension, breathlessness, reduced urine, faintness or rapid weight gain and assess possible OHSS, torsion, bleeding and ectopic pregnancy promptly.
4Record outcomes, multiple-pregnancy risk, consent and add-on discussions in an HFEA-licensed service and avoid unproven adjuncts marketed without evidence.

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

Treats ovulatory infertility caused by persistent hyperprolactinaemia and often reduces a prolactinoma.

Cabergoline

Use the specialist-titrated oral regimen to normalise prolactin and restore ovulation under the 2026 NICE pathway.

Review nausea, postural hypotension, impulse-control symptoms, cardiac valve risk and pregnancy plan. Pituitary mass symptoms require urgent assessment; coordinate interacting psychiatric medicines.

Induces follicular development and ovulation in selected normogonadotrophic anovulation, commonly PCOS.

Letrozole or clomifene ovulation induction

Use only the fertility service's cycle-specific oral regimen with the required response monitoring.

Letrozole use for ovulation induction may be off-label; explain this. Multiple pregnancy, cysts and visual or other adverse effects require monitoring and cycle-stopping rules.

Induces ovulation in hypogonadotrophic hypogonadism or selected oral-agent-resistant anovulation.

Female gonadotrophin therapy

Start at the individual specialist dose and adjust only from ultrasound and hormone response.

Ovarian hyperstimulation and multiple pregnancy are major preventable risks. Never use without trained ultrasound monitoring, explicit maximum-response and cancellation criteria and emergency contacts.

Restores intratesticular testosterone and can induce spermatogenesis in hypogonadotrophic hypogonadism.

Male gonadotrophin therapy

Use the prolonged andrology regimen of LH-like stimulation with added FSH when indicated and monitor semen response.

Treatment takes months and differs from systemic testosterone. Monitor haematocrit, gynaecomastia, testes and semen and coordinate cryopreservation when sperm appears.

Treats overt hypothyroidism that impairs ovulation and supports safe pregnancy physiology.

Levothyroxine

Use the licensed daily replacement regimen titrated to current preconception and pregnancy thyroid targets.

Routine treatment of every borderline TSH in infertility is not evidence free. Confirm the diagnosis, check interactions and assess cortisol first when central hypothyroidism is possible.

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

Delayed effective referral

Focusing on one endocrine label can postpone semen, tubal or age assessment and reduce access to useful time-sensitive fertility options.

Treatment-related multiple pregnancy

Unmonitored ovulation induction can recruit several follicles, increasing maternal and fetal risks and requiring specialist ultrasound surveillance.

Psychological and relationship burden

Prolonged uncertainty, repeated testing and treatment failure can cause distress, stigma and relationship strain that merit active support.

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

Time progesterone to the individual cycle and document ovulation, intercourse or insemination timing and pregnancy testing rather than repeating fixed day-21 samples.
During ovulation induction, follow follicle number and size, endometrium and hormone response exactly to the specialist protocol and cancel unsafe multifollicular cycles.
After gonadotrophin or IVF treatment, monitor weight, abdominal symptoms, urine output, breathlessness and haemoconcentration or renal markers when OHSS is possible.
For prolactin disease, review prolactin, fields and MRI as indicated, cabergoline adverse effects and the plan once pregnancy occurs.
For male hypogonadotrophic treatment, repeat semen at the andrology interval and track testosterone, haematocrit, testicular volume and treatment burden over months.
Reassess emotional wellbeing, sexual function, relationship strain and financial or access burden and offer independent counselling before and during assisted conception.
Verify that referrals, funding decisions and HFEA consents progress; a clinical recommendation is not complete when administrative delay threatens age-dependent prognosis.

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

Investigate in parallel

An ovulatory diagnosis can coexist with male or tubal factor. Sequential partner-by-partner testing wastes time and creates misplaced blame.

Day 21 is shorthand

Progesterone belongs in the mid-luteal phase, roughly before the expected next bleed. Calendar day 21 is inappropriate for most long or irregular cycles.

AMH predicts response

Ovarian reserve markers help anticipate stimulation yield and hyper-response; they do not provide a reliable yes-or-no prediction of spontaneous pregnancy.

Testosterone suppresses sperm

Systemic replacement can improve libido while shutting down intratesticular testosterone. Never treat a fertility request with exogenous androgen.

Central causes are treatable

When gonadotrophin drive is deficient but gonads remain capable, specialist pulsatile GnRH or gonadotrophins can restore ovulation or spermatogenesis.

Funding is not physiology

NHS eligibility varies geographically and changes over time. Explain evidence-based options and local access distinctly, with appeal or alternative pathways where appropriate.

Add-ons need evidence

HFEA regulation and transparent counselling help separate licensed core treatment from expensive adjuncts with uncertain live-birth benefit.

Fertility care includes loss

Repeated testing and treatment can produce grief, shame and relationship strain. Counselling is a core part of safe care, not a consolation after treatment failure.

11Common pitfallsFrequent interpretation and management errors.

01
Completing one partner's investigation before starting the other's.
02
Using a fixed day-21 progesterone for every cycle length.
03
Selling AMH as a definitive natural-fertility test.
04
Giving testosterone to improve an abnormal semen analysis.
05
Starting gonadotrophins without ultrasound monitoring and cancellation rules.
06
Ignoring thyroid or prolactin symptoms while ordering indiscriminate hormone panels in everyone.
07
Missing ectopic pregnancy or OHSS after fertility treatment.
08
Quoting superseded CG156 instead of current NICE NG257.