Endocrinology: Reproductive Endocrinology (Complete)

• Basics: The Reproductive Axis
• Women: Polycystic Ovary Syndrome | Hirsutism and Virilisation | Menopause | Hormone Replacement Therapy | Premature Ovarian Insufficiency | Turner Syndrome
• Men: Male Hypogonadism | Klinefelter Syndrome | Kallmann Syndrome | Testosterone Replacement | Gynaecomastia
• Revision: Drug Reference Table | Spot the Diagnosis | Exam-style Scenarios | Key Points | Guidelines and Further Reading

⚥ Reproductive endocrinology covers the hormones that control puberty, fertility and sexual function - and what happens when the ovaries or testes, or the pituitary and hypothalamus above them, go wrong. It includes PCOS, male hypogonadism, the menopause and premature ovarian insufficiency.
Your four questions for every patient: Is the sex hormone level low or high? Are LH and FSH high (gland failure) or low (pituitary or hypothalamic failure)? Is there a tumour or a reversible cause (weight, drugs, prolactin)? What about fertility, bone and cardiovascular health?

The Reproductive Axis

The hypothalamic–pituitary–gonadal axis:

• The hypothalamus releases GnRH in pulses.
• GnRH makes the pituitary release LH and FSH.
• In men: LH drives testosterone production by Leydig cells; FSH drives sperm production with Sertoli cells.
• In women: FSH grows follicles, which make oestradiol; a mid-cycle LH surge triggers ovulation; the corpus luteum then makes progesterone.
• Sex hormones feed back to switch off GnRH, LH and FSH.

Reading the results - the key principle:

• Primary gonadal failure (the testis or ovary itself): low sex hormone with high LH and FSH - the pituitary is shouting at a gland that cannot respond. This is hypergonadotrophic hypogonadism.
• Secondary (pituitary or hypothalamic) failure: low sex hormone with low or "normal" LH and FSH. This is hypogonadotrophic hypogonadism.

Sex hormone-binding globulin (SHBG): Most testosterone is bound to SHBG. SHBG is raised by age, liver disease, hyperthyroidism and oestrogen, and lowered by obesity, insulin resistance and hypothyroidism. When SHBG is abnormal, total testosterone can mislead, so calculate free testosterone.

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Polycystic Ovary Syndrome

Mechanism: The commonest endocrine disorder in women of reproductive age (about 1 in 10). It combines:

• Excess ovarian androgens.
• Disordered follicle development, so ovulation is irregular or absent.
• Insulin resistance, which raises insulin. Insulin drives further ovarian androgen production and lowers SHBG.

It is strongly linked to obesity, but also occurs in lean women.

Clinical pattern:

• Irregular or absent periods (oligo- or amenorrhoea).
• Hirsutism, acne, scalp hair thinning.
• Subfertility.
• Weight gain, acanthosis nigricans.
• Low mood, anxiety, sleep apnoea.

Diagnosis (Rotterdam criteria - 2 of 3, as endorsed by the 2023 International PCOS Guideline):

• Irregular cycles or anovulation.
• Hyperandrogenism - clinical (hirsutism, acne) or biochemical (raised testosterone or free androgen index).
• Polycystic ovarian morphology on ultrasound, or a raised AMH in adults. Do not use ultrasound within 8 years of menarche, because multifollicular ovaries are normal in adolescents.

Exclude other causes:

• TFTs. Prolactin.
• 17-hydroxyprogesterone (non-classic congenital adrenal hyperplasia).
• Pregnancy test. Cushing's syndrome if suggested.
• Androgen-secreting tumour if testosterone is very high (e.g. above about 5 nmol/L) or virilisation is rapid.

Long-term risks and screening:

• Type 2 diabetes and gestational diabetes - check HbA1c or an OGTT at diagnosis and periodically.
• Dyslipidaemia and cardiovascular risk - check lipids and BP.
• Endometrial hyperplasia and cancer - from unopposed oestrogen when periods are infrequent.
• Depression and anxiety, eating disorders, obstructive sleep apnoea.

Management:

• Lifestyle: Even 5% weight loss can restore ovulation.
• Irregular periods and hirsutism: The combined oral contraceptive pill is first-line.
• Endometrial protection: If periods are fewer than every 3–4 months and the patient is not on the COCP, induce a withdrawal bleed with a progestogen (or use an LNG-IUS). Investigate a thickened endometrium.
• Hirsutism:
  • Cosmetic measures, such as laser treatment.
  • Eflornithine cream for facial hair.
  • Anti-androgens (e.g. spironolactone) under specialist advice, always with reliable contraception - they are teratogenic to a male fetus.
• Metabolic: Metformin helps insulin resistance and weight, and is used alongside the COCP or alone. GLP-1 receptor agonists may be used for obesity.
• Fertility: Letrozole is now first-line for ovulation induction. Alternatives are clomifene, gonadotrophins, laparoscopic ovarian drilling and IVF.

💡 Clinical Pearl: PCOS is a diagnosis of exclusion. Rapid-onset virilisation (deep voice, clitoromegaly, male-pattern balding) or a very high testosterone is not PCOS until an androgen-secreting tumour has been excluded.

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Hirsutism and Virilisation

• Hirsutism: Excess terminal hair in a male pattern (face, chest, lower abdomen, back) in a woman. Scored with the modified Ferriman–Gallwey score.
• Virilisation: Hirsutism plus signs of significant androgen excess - deep voice, clitoromegaly, increased muscle bulk, temporal balding, breast atrophy. It suggests a tumour.

Causes:

• PCOS - most cases.
• Idiopathic - normal androgens and cycles.
• Non-classic congenital adrenal hyperplasia (21-hydroxylase deficiency) - raised 17-hydroxyprogesterone.
• Androgen-secreting ovarian or adrenal tumours - rapid onset, testosterone very high. A very high DHEAS suggests an adrenal source.
• Cushing's syndrome, acromegaly, hyperprolactinaemia.
• Drugs - anabolic steroids, testosterone, danazol.
• Ovarian hyperthecosis - postmenopausal, slowly progressive.

Investigations:

• Testosterone and SHBG (free androgen index). DHEAS.
• 17-hydroxyprogesterone.
• Prolactin, TFTs, LH and FSH.
• Pelvic ultrasound.
• If a tumour is suspected: CT or MRI of the adrenals, and specialist referral.

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Menopause

Definition: The permanent end of periods because the ovaries stop producing follicles, confirmed after 12 months without a period. The average age in the UK is 51. Perimenopause is the years of irregular cycles and symptoms beforehand.

Clinical pattern:

• Vasomotor: Hot flushes, night sweats. Poor sleep.
• Mood: Low mood, anxiety, "brain fog". Joint and muscle aches. Reduced libido.
• Genitourinary syndrome of menopause: Vaginal dryness, dyspareunia, urinary frequency, recurrent UTIs.
• Long term: Bone loss (osteoporosis) and increased cardiovascular risk.

Diagnosis (NICE NG23):

• Over 45 with typical symptoms: Diagnose clinically - no blood tests needed.
• FSH: Consider it in women aged 40–45 with symptoms, or under 40 if POI is suspected. Do not use it in women on combined hormonal contraception or high-dose progestogen.

Contraception: Still needed until 2 years after the last period if under 50, or 1 year if over 50 (or until 55). HRT is not a contraceptive.

Management:

• Individualised discussion of symptoms, benefits and risks.
• HRT is the most effective treatment for vasomotor symptoms.
• Vaginal oestrogen for genitourinary symptoms. Safe long-term, and can be used with or without systemic HRT.
• CBT for vasomotor symptoms, low mood and sleep (NICE 2024).
• Non-hormonal options when HRT is unsuitable:
  • SSRIs or SNRIs - avoid paroxetine and fluoxetine with tamoxifen.
  • Gabapentin. Clonidine.
  • Fezolinetant (NK3 receptor antagonist) - licensed; check local formulary and liver monitoring.

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Hormone Replacement Therapy

The basic rules:

• Oestrogen relieves symptoms.
• If the woman has a uterus, she must also take a progestogen. Oestrogen alone causes endometrial hyperplasia and cancer.
• Progestogen options: Cyclical (monthly bleed) in perimenopause; continuous combined (no bleed) once more than 12 months after the last period; or a 52 mg LNG-IUS (Mirena), which also gives contraception.
• Micronised progesterone has a more favourable breast and VTE profile than older synthetic progestogens.
• After hysterectomy: Oestrogen alone.

Routes:

• Oral oestradiol.
• Transdermal (patch, gel or spray) - no increase in VTE risk, so preferred with: BMI over 30. VTE risk factors. Migraine. Liver disease. Malabsorption.

Benefits and risks (NICE NG23, 2024 update):

• Benefits:
  • Symptom relief.
  • Prevents osteoporosis and fracture.
  • Genitourinary symptoms improve.
• Breast cancer:
  • Combined HRT slightly increases risk, related to duration; the risk falls after stopping.
  • Oestrogen-only HRT has little or no increase.
• VTE: Increased with oral HRT; not with transdermal.
• Cardiovascular disease: No increase when started under 60. Oral HRT slightly increases stroke risk.
• Dementia: No clear effect either way.
• Duration: There is no arbitrary limit. Review benefits and risks at least yearly.

Contraindications:

• Current, past or suspected breast cancer.
• Oestrogen-dependent cancer.
• Undiagnosed vaginal bleeding.
• Untreated endometrial hyperplasia.
• Active VTE or arterial disease (oral).
• Active liver disease.
• Pregnancy.

Testosterone: Can be added (off-label in women) for low libido not helped by HRT alone.

💡 Clinical Pearl: Unscheduled bleeding beyond the first 3–6 months of HRT, or any bleeding on continuous combined HRT after it has settled, needs investigation for endometrial cancer.

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Premature Ovarian Insufficiency

Definition: Loss of ovarian function before age 40. It affects about 1 in 100 women.

Causes:

• Idiopathic - most cases.
• Iatrogenic - chemotherapy, pelvic radiotherapy, oophorectomy.
• Autoimmune - with Addison's disease, hypothyroidism, type 1 diabetes.
• Genetic - Turner syndrome and fragile X premutation (FMR1).
• Infection, such as mumps.

Diagnosis (NICE NG23):

• Menopausal symptoms or absent or infrequent periods in a woman under 40.
• Raised FSH on two blood samples taken 4–6 weeks apart.
• Do not use AMH alone to diagnose it.

Further tests (specialist):

• Karyotype.
• FMR1 (fragile X) testing.
• Adrenal (21-hydroxylase) and thyroid antibodies, TFTs.
• Baseline DXA.

Management:

• Hormone replacement until at least the average age of menopause (about 51). HRT or a combined hormonal contraceptive both work.
• This protects bone and heart and relieves symptoms. The breast cancer risk is not higher than in women of the same age with working ovaries.
• Fertility: Spontaneous pregnancy occurs in about 5–10%, so contraception may still be needed if pregnancy is not wanted. Egg donation IVF is the main route to pregnancy.
• Psychological support; screen for associated autoimmune disease.

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Turner Syndrome

• Cause: Loss of all or part of one X chromosome - 45,X or mosaic. About 1 in 2,500 female births.
• Clinical pattern:
  • Short stature - almost universal.
  • POI - delayed or absent puberty, primary or secondary amenorrhoea.
  • Webbed neck, low hairline, wide-spaced nipples, cubitus valgus.
  • Lymphoedema of the hands and feet in newborns.
  • Normal intelligence, with some specific learning difficulties.
• Associated conditions:
  • Cardiovascular: Bicuspid aortic valve, coarctation of the aorta, aortic dilatation and dissection (highest risk in pregnancy), hypertension.
  • Kidneys: Horseshoe kidney.
  • Autoimmune: Hypothyroidism, coeliac disease.
  • Metabolic: Type 2 diabetes, dyslipidaemia.
  • Hearing loss.
  • Osteoporosis.
  • Liver enzyme abnormalities.
• Management:
  • Growth hormone in childhood.
  • Oestrogen to induce puberty and then continue replacement.
  • Lifelong cardiac imaging (echo and cardiac MRI).
  • Regular screening for thyroid, coeliac, diabetes and hearing problems.
  • Pregnancy (usually by egg donation) needs cardiology assessment first.

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Male Hypogonadism

Mechanism: Low testosterone, low sperm production, or both.

• Primary (testicular) - high LH and FSH:
  • Klinefelter syndrome.
  • Mumps orchitis.
  • Testicular trauma or torsion, undescended testes.
  • Chemotherapy and radiotherapy.
  • Haemochromatosis (can also be secondary).
• Secondary (pituitary or hypothalamic) - low or normal LH and FSH:
  • Obesity and type 2 diabetes - the commonest cause in adult men.
  • Opioids.
  • Anabolic steroid use, or stopping it.
  • Glucocorticoids.
  • Prolactinoma and other pituitary tumours.
  • Kallmann syndrome.
  • Haemochromatosis.
  • Severe illness, excessive exercise, eating disorders.

Clinical pattern:

• Low libido, erectile dysfunction, fewer morning erections.
• Fatigue, low mood. Reduced muscle mass and body hair.
• Gynaecomastia. Small testes. Infertility. Osteoporosis.
• Before puberty: Delayed puberty and a eunuchoid build (long arms and legs).

Diagnosis:

• Morning (before 11 am), fasting total testosterone, repeated on two occasions.
• Interpretation:
  • Below about 8 nmol/L is usually low.
  • 8–12 nmol/L is borderline - check SHBG and calculate free testosterone.
  • Avoid testing during acute illness.
• If low: LH, FSH and prolactin to separate primary from secondary causes. Also FBC, HbA1c, lipids and ferritin (haemochromatosis).
• Secondary hypogonadism with no obvious cause (or prolactin raised, or very low testosterone): check the other pituitary hormones and get a pituitary MRI.
• Primary hypogonadism in a young man: Karyotype (Klinefelter).
• Fertility concerns: Semen analysis.

💡 Clinical Pearl: In an overweight man with borderline low testosterone and normal or low LH, weight loss often restores testosterone. Always ask about opioids and anabolic steroids, which are common hidden causes.

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Klinefelter Syndrome

• Cause: 47,XXY - an extra X chromosome. It is the commonest cause of primary hypogonadism (about 1 in 600 male births), and is often undiagnosed.
• Clinical pattern:
  • Tall stature with long legs. Small, firm testes.
  • Incomplete puberty and sparse body hair.
  • Gynaecomastia. Infertility (usually azoospermia).
  • Learning and language difficulties in some.
• Associated risks:
  • Male breast cancer - markedly increased risk.
  • Osteoporosis. Type 2 diabetes and metabolic syndrome.
  • VTE. Autoimmune disease. Mediastinal germ cell tumours.
• Tests: Low testosterone, high LH and FSH, karyotype 47,XXY (or mosaic).
• Management:
  • Testosterone replacement from puberty.
  • Fertility: micro-TESE (testicular sperm extraction) with ICSI can achieve biological fatherhood in some.
  • Educational support, bone health care.

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Kallmann Syndrome

• Mechanism: GnRH neurons fail to migrate to the hypothalamus during development. Smell neurons travel the same path, so GnRH deficiency comes with anosmia (absent sense of smell). Several genes are involved (e.g. ANOS1, X-linked).
• Clinical pattern:
  • Delayed or absent puberty.
  • Eunuchoid build. Small testes.
  • Anosmia - often unnoticed until asked.
  • Sometimes cleft palate, renal agenesis or colour blindness.
  It occurs in both sexes, but is commoner in males.
• Tests:
  • Low testosterone (or oestradiol) with low LH and FSH.
  • Other pituitary hormones are normal.
  • MRI may show absent olfactory bulbs.
• Differential diagnosis: Constitutional delay of growth and puberty - common, and resolves on its own.
• Management:
  • Testosterone (or oestrogen) for puberty and lifelong replacement.
  • For fertility, hCG and FSH injections (or pulsatile GnRH) can induce sperm production or ovulation.

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Testosterone Replacement

Indication: Confirmed hypogonadism (symptoms plus consistently low testosterone) after correctable causes have been dealt with - weight, opioids, prolactinoma. Not for "low T" with normal levels, or for age-related decline alone.

Preparations:

• Transdermal gel, daily. Gives steady levels. Skin-to-skin transfer can affect partners and children, so cover the area and wash hands.
• Testosterone undecanoate 1 g IM, every 10–14 weeks after a loading dose at 6 weeks. Long-acting.
• Testosterone esters (e.g. Sustanon 250 mg IM), every 2–4 weeks. Peaks and troughs cause mood swings.

Contraindications and cautions:

• Prostate or breast cancer.
• Wanting fertility - testosterone switches off LH and FSH and stops sperm production. Use hCG instead.
• Haematocrit above about 50%.
• Untreated severe sleep apnoea.
• Uncontrolled heart failure.

Monitoring (at 3, 6 and 12 months, then yearly):

• Testosterone level - trough for injections.
• Symptoms.
• Haematocrit - reduce the dose or pause if above about 54% (erythrocytosis risk).
• PSA and prostate assessment in men over 40.
• Lipids, BP, bone density if osteoporotic.

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Gynaecomastia

Mechanism: Benign growth of male breast glandular tissue, caused by an imbalance with too much oestrogen action relative to androgen. It feels like a rubbery, often tender disc under the nipple, and is often bilateral.

• Physiological:
  • Newborns (maternal oestrogen).
  • Puberty - very common, and usually resolves within 2 years.
  • Older age.
• Drugs (a common, reversible cause):
  • Spironolactone.
  • Anti-androgens (bicalutamide), finasteride, GnRH analogues.
  • Oestrogens. Anabolic steroids.
  • Digoxin, cimetidine. Some antipsychotics (via prolactin).
  • Cannabis, alcohol.
• Disease:
  • Liver cirrhosis.
  • Hypogonadism (including Klinefelter). Hyperthyroidism. CKD. Refeeding.
  • Tumours - testicular (hCG- or oestrogen-secreting), adrenal, lung (hCG).
• Pseudogynaecomastia: Fat alone, in obesity, without glandular tissue.

Investigations (if not clearly physiological or drug-related):

• LFTs, U&E, TFTs.
• Testosterone, oestradiol, LH and FSH, prolactin.
• hCG and AFP - germ cell tumours.
• Testicular examination and ultrasound.

Management:

• Treat the cause or stop the drug.
• Reassure in puberty.
• Tamoxifen (specialist) for painful, recent gynaecomastia.
• Surgery for long-standing cases.

⚠️ Safety Pearl: A unilateral, hard, painless, eccentric lump, especially with nipple changes or skin tethering, needs urgent referral for male breast cancer. Examine the testes in every man with gynaecomastia.

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Drug Reference Table

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Spot the Diagnosis

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Exam-style Scenarios

1. A 26-year-old woman has irregular periods, hirsutism and a BMI of 33. She does not want pregnancy now.
Answer: Likely PCOS.

• Exclude other causes - TFTs, prolactin, 17-hydroxyprogesterone, testosterone.
• Screen HbA1c and lipids.
• Lifestyle and weight loss.
• COCP for cycles, hirsutism and endometrial protection.
• Consider metformin.

2. A 32-year-old man has low libido. Testosterone is 5 nmol/L, LH and FSH are low, and haematocrit is 0.53. He trains at the gym.
Answer: Secondary hypogonadism - think anabolic steroid use.

• Ask directly and non-judgementally.
• Check prolactin and consider pituitary tests if steroids are denied.
• Advise stopping; recovery of the axis can take months.
• Do not start testosterone if he wants children.

3. A 37-year-old woman has had no periods for 8 months and has hot flushes. FSH is high on two samples 6 weeks apart.
Answer: Premature ovarian insufficiency.

• Karyotype, FMR1, thyroid and adrenal antibodies, DXA.
• HRT or a combined hormonal contraceptive until at least age 51.
• Discuss fertility (egg donation) and psychological support.

4. A 49-year-old woman with a uterus has night sweats and low mood; periods are irregular.
Answer: Perimenopause - diagnose clinically, no blood tests needed over 45.

• Offer HRT with oestrogen plus cyclical progestogen (or an LNG-IUS).
• Transdermal oestrogen if VTE risk factors.
• She still needs contraception.

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Key Points

• Low sex hormone with high LH and FSH means gonadal failure. With low or normal LH and FSH, it means pituitary or hypothalamic failure.
• PCOS is a diagnosis of exclusion. Treat the cycles, androgens and metabolic risk, and protect the endometrium.
• Rapid virilisation or a very high testosterone is a tumour until proven otherwise.
• Measure testosterone in the morning, twice. Address obesity, opioids and anabolic steroids.
• Testosterone replacement stops sperm production - use hCG if fertility is wanted.
• Examine the testes in every man with gynaecomastia; a hard eccentric lump needs urgent referral.
• Diagnose menopause clinically over 45. A woman with a uterus on HRT needs a progestogen.
• POI needs HRT until at least 51.

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Guidelines and Further Reading

• NICE NG23: Menopause - identification and management
• International Evidence-based Guideline for the Assessment and Management of PCOS (2023)
• Society for Endocrinology: Testosterone replacement and male hypogonadism guidance
• British Society for Sexual Medicine: Guidelines on adult testosterone deficiency
• British Menopause Society: Consensus statements and tools for clinicians
• Turner Syndrome Support Society and international clinical practice guidelines (2024)
• BNF / BNFc - for current doses

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