Hypogonadism and delayed puberty

• Hypogonadism means the gonads make too little sex steroid, or fail to respond to the signals that drive production; delayed puberty is its most common announcement in adolescence.
• The first question is where the fault lies: testicular or ovarian failure (primary, or hypergonadotrophic, hypogonadism, with high LH and FSH) or failure of brain signalling (secondary, or hypogonadotrophic, hypogonadism, with low or inappropriately normal LH and FSH).
• Most boys with delayed puberty have self-limited constitutional delay of growth and puberty; Klinefelter syndrome (primary) and Kallmann syndrome (secondary, with anosmia) are the two organic causes you must not miss.
• Puberty is induced with low-dose sex steroid, raised slowly over 2 to 4 years to full adult dose; lifelong replacement is needed when the defect is permanent, and testosterone never restores fertility on its own.
• In adult men, testosterone is prescribed only when symptoms and two low morning fasting values both exist; it has defined contraindications (fertility wishes, cancer, high haematocrit, sleep apnoea, recent cardiovascular events) and needs regular monitoring.

By the end of this page you should be able to:

1. Define hypogonadism and delayed puberty, and give the ages at which puberty is considered delayed in boys and in girls.
2. Explain the difference between primary (hypergonadotrophic) and secondary (hypogonadotrophic) hypogonadism using the LH/FSH pattern.
3. Recognise Klinefelter syndrome and Kallmann syndrome, state their core features and how each is confirmed.
4. Plan the investigation of delayed puberty and hypogonadism, including the tests that distinguish the main causes.
5. Induce puberty in a boy or a girl with the correct drug, starting dose and titration.
6. Manage adult male hypogonadism, including acceptable thresholds, contraindications and monitoring.
7. Adapt care for females with Turner syndrome or primary ovarian insufficiency.
8. State the long-term risks of untreated hypogonadism and how they are prevented.

Puberty is the process in which a child develops secondary sexual characteristics, reproductive capacity, adult body proportions and adult bone mass. In the male the first sign is enlargement of the testes to about 4 mL, which occurs at a median age of 11.5 years. In the female the first sign is breast development (thelarche). ^[1]

Delayed puberty means puberty has not started by an age about 2 standard deviations later than the population mean: no testicular enlargement to 4 mL by the age of 14 years in boys, and no breast development by the age of 13 years in girls. ^{[1] [6]}

Primary, or hypergonadotrophic, hypogonadism is primary testicular or ovarian failure. Sex-steroid levels are low and LH and FSH are high, because the pituitary is signalling a gonad that does not respond. Common causes include Klinefelter syndrome, anorchia, gonadal dysgenesis, chemotherapy, radiotherapy and autoimmune oophoritis.

Secondary, or hypogonadotrophic, hypogonadism is failure of the brain side of the axis. Sex-steroid levels are low and LH and FSH are low or inappropriately normal. Causes include congenital hypogonadotrophic hypogonadism (including Kallmann syndrome), pituitary tumours, cranial irradiation, trauma, hyperprolactinaemia and functional suppression from chronic illness or undernutrition.

Combined, or mixed, patterns occur, particularly in functional hypogonadism, where both gonadal output and central drive are reduced. ^[7]

Constitutional (self-limited) delay of growth and puberty is not true hypogonadism. The axis is intact but switches on late. It is the most common cause of delayed puberty in boys, and puberty usually occurs by 18 years. ^[1]

Delayed puberty is a common reason for referral to paediatric endocrinology. In boys presenting with absent pubertal signs by the age of 14 years, the relative frequencies of cause are approximately: constitutional delay of growth and puberty 60 to 70%, functional central hypogonadism 16 to 20%, primary (hypergonadotrophic) hypogonadism 2 to 7%, acquired central hypogonadism 4 to 6% and congenital hypogonadotrophic hypogonadism about 2%. Constitutional delay accounts for 60 to 80% of boys seeking medical attention for absent pubertal signs. ^{[1] [5]}

Klinefelter syndrome is the most common male sex chromosome aneuploidy. Its prevalence is about 1 in 450 to 600 male births; 47,XXY is the karyotype in about 90% of cases. Up to 75% of affected men are never diagnosed, and the mean age at diagnosis is about 25 years. ^[3]

Kallmann syndrome and other congenital hypogonadotrophic hypogonadism are rare. Congenital hypogonadotrophic hypogonadism has an estimated prevalence of 1 to 10 per 100,000 live births. ^[2] Men are affected far more often than women, although the precise ratio varies between series.

Turner syndrome affects about 25 to 50 females per 100,000 live births. It is the classic cause of hypergonadotrophic hypogonadism in girls, with primary or secondary amenorrhoea. Spontaneous breast development occurs in about one-third, mainly when mosaicism is present. ^[4]

Primary ovarian insufficiency, loss of ovarian function before the age of 40 years, has a reported prevalence of about 3.5% and presents with delayed, incomplete or absent puberty, irregular cycles or early menopause. ^[8]

Constitutional delay is usually familial and polygenic. It is a normal variant rather than a disease, but it can have major psychosocial impact. ^[1]

Primary hypogonadism in adolescence usually arises from anorchia (congenital or acquired), long-standing cryptorchidism, orchitis, testicular torsion, chemotherapy or radiotherapy. Klinefelter syndrome is the principal genetic cause. Additional X-chromosome material leads to testicular hyalinisation and fibrosis, primary gonadal failure and infertility. ^[3]

Congenital hypogonadotrophic hypogonadism arises from failure of GnRH neuron specification, migration or signalling. Kallmann syndrome is the form with anosmia or hyposmia, because GnRH neurons migrate along the olfactory nerve; the normosmic form lacks smell disturbance. Over 60 genes have been implicated, and a molecular diagnosis is reached in about half of cases. Variants in FGFR1 and ANOS1 accounted for 53.5% of disease-causing variants in complete (absent puberty) cases, while variants in FGFR1, NR0B1 and GNRHR were found in 70.3% of partial (arrested puberty) cases in a recent meta-analysis. ^{[1] [2]}

Acquired central hypogonadism follows surgery or tumour of the sellar or suprasellar region, cranial trauma, high-dose cranial radiotherapy or infiltrative disease; it is almost always associated with multiple pituitary hormone deficiencies. ^[1]

Functional central hypogonadism is caused by chronic disease or malnutrition: coeliac disease, inflammatory bowel disease, cystic fibrosis, chronic kidney or liver disease, juvenile idiopathic arthritis, diabetes mellitus, Cushing syndrome, obesity and sustained psychological stress. It is reversible when the underlying condition is treated. ^[1] In adult men, functional hypogonadism is associated with obesity, type 2 diabetes, metabolic syndrome and chronic illness, and is a diagnosis of exclusion once organic disease has been ruled out. ^[7]

In women, the main causes of hypergonadotrophic hypogonadism are Turner syndrome and other gonadal dysgenesis, autoimmune ovarian failure, chemotherapy and radiotherapy, and the fragile X premutation. Hypogonadotrophic causes mirror the male list. ^[8]

The whole topic follows one chain: the hypothalamus releases GnRH, the pituitary releases LH and FSH, the gonads release sex steroid, and the steroid acts on target tissues.

In fetal life the testis differentiates independently of gonadotrophins until about the 17th week; thereafter LH drives androgen secretion (genital growth and testicular descent) and FSH drives Sertoli-cell proliferation and testicular enlargement. A first-trimester failure (for example a severe defect in androgen synthesis or action) produces ambiguous or female genitalia. A second- or third-trimester failure produces micropenis, micro-orchidism or cryptorchidism. These early clues separate congenital from acquired disease. ^[1]

After birth there is a transient activation of the axis, "minipuberty", lasting 3 to 6 months, during which gonadotrophins, testosterone and inhibin B rise. This is followed by childhood quiescence, when androgens are very low, so hypogonadism can go unnoticed unless AMH or inhibin B is measured. ^[1]

At puberty the axis reactivates progressively: FSH enlarges the testes from about 2 to 4 mL, then intratesticular testosterone matures the Sertoli cells, switches off AMH and drives spermatogenesis; serum testosterone rises only between Tanner stages 3 and 5. Bone mineralisation, muscle mass and erythropoiesis all depend on this rise. ^[1]

Primary hypogonadism is a problem at the end of the chain. The testes or ovaries fail, so steroid falls while LH and FSH climb because negative feedback is lost. The eunuchoid habitus, long arms and legs relative to the trunk, follows from delayed epiphyseal closure when oestrogen (aromatised from androgen) is lacking.

Secondary hypogonadism is a problem at the start of the chain. No GnRH means no LH/FSH, no steroid and no pubertal development, but also no negative feedback to raise gonadotrophins. In Kallmann syndrome the same embryonic defect affects olfactory-nerve development, so anosmia accompanies absent puberty. ^[2]

Klinefelter syndrome illustrates primary failure with a twist. Most boys enter puberty spontaneously, with normal penile growth and pubic hair, but reduced facial and body hair, gynaecomastia and small firm testes that rarely exceed 4 mL. Steroid output then declines to low or low-normal in adulthood in many men, and the chromosomal abnormality itself drives metabolic, skeletal and other risk beyond the hormonal deficit. ^[3]

If hypogonadism starts before puberty, growth, bone mass, muscle, sexual development and psychosocial health all suffer. If it starts in adulthood, the features are subtler: loss of libido, erectile dysfunction, reduced energy, anaemia, loss of muscle and bone, and visceral adiposity. ^[7]

In children and adolescents, ask where the child sits in puberty: voice change, body hair and growth spurt in boys; breast development, growth spurt and periods in girls. Parents often report that the boy "looks younger than his classmates" or that the girl's friends have all started but she has not. Family history of age at puberty in parents and siblings, consanguinity and fertility problems are all relevant.

Red-flag symptoms of congenital disease: cryptorchidism, micropenis, anosmia or hyposmia, cleft lip or palate, unilateral deafness, mirror movements of the hands and other midline defects. Systemic symptoms include headache, visual disturbance, galactorrhoea (suggesting prolactinoma), fatigue, weight change, bowel or malabsorption symptoms and chronic disease.

In adult men: sexual symptoms (loss of spontaneous and morning erections, reduced libido, infertility), general features (loss of muscle bulk and strength, increased fat, breast tenderness or swelling, fatigue, low mood, poor concentration), bone pain or fractures and anaemia. Drug history includes opioids, glucocorticoids, anabolic steroids, antipsychotics, chemotherapy, alcohol and recreational drugs.

Record height, weight and sitting height; a low upper:lower segment ratio (eunuchoid proportions) suggests pre-pubertal onset. Assess Tanner stage and testicular volume with an orchidometer; in Klinefelter syndrome the testes rarely exceed 4 mL and are firm. Test smell in every boy with delayed puberty (bedside essences or a validated test), because anosmia points to Kallmann syndrome. Palpate for gynaecomastia and check testicular location. Look for signs of chronic disease, malnutrition and Cushing syndrome. Perform fundoscopy and visual fields if a pituitary mass is suspected. In girls, record Tanner breast and pubic hair stage, height, and, when amenorrhoea persists, uterine size on ultrasound.

Klinefelter syndrome. Males with at least one extra X chromosome (47,XXY in about 90% of cases). Tall stature, eunuchoid proportions, small firm testes, gynaecomastia, decreased facial and body hair, and a variable neurocognitive profile (language and executive difficulties are common; attention deficit, anxiety, depression and autism spectrum traits are reported more often than in the general male population). Metabolic syndrome occurs in 34 to 44%, osteopenia in 25 to 48% and osteoporosis in 6 to 15%. Infertility is the usual reason for diagnosis. Confirmation is by karyotype. Testicular sperm extraction, especially microdissection, with intracytoplasmic sperm injection retrieves sperm in about 50% of non-mosaic 47,XXY men. ^[3]

Kallmann syndrome. Congenital hypogonadotrophic hypogonadism with impaired smell. Presentation is absent puberty plus anosmia or hyposmia. Additional anomalies include cryptorchidism, micropenis, cleft lip or palate, hearing loss and renal agenesis. MRI often shows hypoplastic or absent olfactory bulbs. Laboratory findings are low sex steroids with low FSH and LH, with otherwise normal pituitary function. The diagnosis rests on anosmia or an olfactory-bulb deficit on MRI in a patient with delayed puberty and hypogonadotrophic hypogonadism, with normal pituitary anatomy. Genetic testing is available but identifies a cause in roughly half of cases. ^{[1] [2]}

Girls with complete or partial loss of one X chromosome have hypergonadotrophic hypogonadism with primary or secondary amenorrhoea. Spontaneous menarche occurs in at most about one in five, mostly with mosaicism. Short stature, webbed neck, shield chest, bicuspid aortic valve and coarctation, renal anomalies and autoimmune thyroid disease are frequent. Cardiovascular and hearing surveillance is long term. ^[4]

Amenorrhoea or irregular cycles, hypo-oestrogenic symptoms or infertility in a woman under 40 years, with a raised FSH above 25 IU/L. Causes include Turner syndrome, fragile X premutation, autoimmune disease, chemotherapy, radiotherapy and unknown. Risks include osteoporosis, cardiovascular disease and infertility. ^[8]

The first fork is clinical: delayed puberty versus appropriately normal timing. The second fork is biochemical: primary versus secondary hypogonadism. The table lists common causes and the feature that separates each.

Important mimics of delayed puberty include hypothyroidism, Cushing syndrome, coeliac disease, renal failure and eating disorder, which suppress the axis functionally and are usually reversible. Isolated growth-hormone deficiency, renal tubular disease and skeletal dysplasias can also look like late puberty. A flat or falling growth curve argues for pathology rather than constitutional delay.

First-line in any adolescent with delayed puberty or any adult with suspected hypogonadism:

1. Morning, fasting, before about 11:00, total testosterone or oestradiol measured with an accurate assay. Hypogonadism is confirmed when symptoms are present and a morning level is unequivocally low; roughly 30% of men with a low value have a normal value on repeat, so repeat the measurement before diagnosing. ^[7]
2. LH and FSH: this single step separates primary from secondary disease. ^[7]
3. Prolactin, TSH and free thyroxine, and a morning cortisol where appropriate, to exclude other pituitary disease. Ferritin if anaemia is present.
4. In males with low gonadotrophins: GnRH stimulation testing, inhibin B and AMH (low inhibin B supports GnRH deficiency over constitutional delay), and, when the result changes management, genetic testing. ^{[1] [2]}
5. Bone age (radiograph of the left wrist) and review of the growth chart.
6. Karyotype in males with primary hypogonadism (to exclude Klinefelter syndrome) and in females with primary ovarian failure (Turner syndrome and variants).
7. MRI of the pituitary and hypothalamus in secondary hypogonadism when a mass is suspected, or in any acquired or multiple pituitary hormone case.
8. Smell testing, renal ultrasound and brain MRI (olfactory bulbs) when Kallmann syndrome is suspected. ^[2]
9. Semen analysis once the patient is an adult, or whenever fertility is a question.
10. Bone density by DXA in long-standing deficiency; baseline assessment in Klinefelter and Turner syndrome. ^{[3] [4]}

Normal ranges are assay-specific. A morning fasting sample is essential because testosterone varies substantially across the day. In men whose total testosterone sits near the lower limit, or whose sex hormone-binding globulin is altered (obesity, ageing, liver disease, thyroid disease, HIV), free testosterone should be measured by equilibrium dialysis, or calculated. ^[7]

There is no single numeric threshold for hypogonadism. The widely used principle, reflected in the Dobs review of practice, is to diagnose only when symptoms and signs are present together with unequivocally and consistently low serum total testosterone (or free testosterone when indicated), and to avoid screening men without symptoms. ^[7]

Guideline cut-offs differ: one review quotes 264 ng/dL (9.2 nmol/L) as the lower limit of normal total testosterone for healthy non-obese men, 300 ng/dL as a reasonable diagnostic threshold in one guideline and 350 ng/dL in others. ^[7] National and andrological guidelines can therefore disagree on the exact number; what they agree on is the principle: screen only symptomatic men, confirm with two morning values, then look for the cause. One guideline advises that a therapeutic trial of testosterone in men above these cut-offs who are symptomatic is reasonable. ^[7]

Functional hypogonadism is a diagnosis of exclusion after organic disease is ruled out; in one adult cohort, weight loss alone raised testosterone levels. ^[7]

Severity is judged clinically: absent versus incomplete puberty; complications such as undescended testes, microphallus, osteoporosis and anaemia; and the impact on growth, bone age and quality of life.

Management depends on whether the defect is temporary or permanent, and on whether fertility is desired. For constitutional delay and functional hypogonadism, treat the underlying cause or observe and reassure; short courses of sex steroid may help psychosocially. For permanent hypogonadism, induce puberty (if growth remains) or replace in adults, for life, aiming to mimic normal physiology. Multidisciplinary care (paediatric or adult endocrinologist, urologist or gynaecologist, fertility specialist, psychologist) is recommended. ^{[6] [8]}

• Treat the underlying disease in functional hypogonadism: nutrition, control of coeliac or inflammatory bowel disease, weight loss, review of opioids and other offending drugs. Weight loss can raise endogenous testosterone. ^[7]
• Lifestyle: exercise, smoking cessation, alcohol reduction, treatment of sleep apnoea.
• Psychological and psychosexual support; counselling about body image, fertility and the timing of puberty.
• In constitutional delay, reassurance and watchful waiting are acceptable; many boys prefer a short course of testosterone for psychosocial reasons.

Diagnosis first. Treat only when hypogonadism is well documented: symptoms plus two low morning fasting total testosterone values, after reversible causes have been sought. Distinguish primary from secondary with LH and FSH before treatment. ^{[6] [7]}

When not to use testosterone. Men planning fertility in the near term; breast or prostate cancer; an unevaluated palpable prostate nodule, induration or elevated age-adjusted PSA; a baseline haematocrit above 50%; untreated severe obstructive sleep apnoea; a history of stroke or myocardial infarction in the previous 6 months; and, as a relative contraindication, a major cardiovascular event within the past 3 to 6 months. In older men, testosterone is not started to improve energy, vitality, physical function or cognition alone, and use solely for "anti-ageing" is not supported. ^[7]

Formulation and dosing. Transdermal gels or patches are the usual starting option because dose titration is easy and levels can be kept smooth. ^[7] Long-acting testosterone undecanoate (750 to 1,000 mg intramuscularly every 10 to 14 weeks) suits younger men with an irreversible cause; short-acting esters (testosterone enanthate or cypionate, typically 200 to 250 mg every 3 to 4 weeks in escalation schemes, or 150 to 200 mg every 2 weeks) are older but effective. Route and dose are individualised by age, sex hormone-binding globulin, preference and cost. ^{[5] [7] [1]}

Target and monitoring. Aim for a serum testosterone in the mid-normal range, typically 450 to 600 ng/dL. Measure according to formulation (trough levels before injections, levels after gel application per instructions). ^[7] Follow-up intervals depend on formulation and local guidance; re-evaluate symptoms within 6 months, monitor serum testosterone and haematocrit during treatment, and assess prostate cancer risk according to local screening policy. A haematocrit of 54% or greater during treatment warrants dose reduction and further assessment. ^[7]

Functional hypogonadism. A therapeutic trial of testosterone gel, with symptoms re-evaluated within 6 months. Overweight and obese men should have weight loss and lifestyle change first, because these can restore testosterone on their own; if there is no response, stop. ^[7]

Fertility. Testosterone suppresses spermatogenesis. Men with secondary hypogonadism who want fertility need gonadotrophin therapy (hCG plus FSH, or pulsatile GnRH). Typical gonadotrophin regimens start with recombinant FSH 75 to 150 IU two to three times per week for 2 to 3 months, then add LH (75 IU daily) or hCG (500 to 2,000 IU once or twice weekly), keeping serum testosterone in the mid-normal range. Responses vary, and cycles of treatment are usually prolonged. Testosterone alone never restores fertility. ^[1]

Sperm retrieval. In Klinefelter syndrome, microsurgical testicular sperm extraction plus intracytoplasmic sperm injection can yield sperm in about half of men; referral to a specialist centre is warranted, ideally before testosterone is started if fertility matters. ^[3]

Permanent hypogonadism requires puberty induction; constitutional delay usually needs only a short course. The aim is to mimic physiological development (secondary sexual characteristics, growth, bone mass and psychosocial wellbeing) without excessive bone-age advancement. ^{[5] [6]}

• Age to start. Permanent cause: 12 to 13 years. Constitutional delay: about 13 to 14 years. Delay if coexisting growth-hormone deficiency, so that growth hormone can act first to maximise height. ^{[5] [6]}
• Preparation and route. Intramuscular testosterone enanthate or mixed esters is the traditional and preferred option because experience and dosing flexibility are greatest. Low-dose 1% testosterone gel (starting at about 0.5 g daily) is an evidence-based alternative, better for boys with liver or haematological concerns. Transdermal patches have limited paediatric data, and oral testosterone undecanoate has been used mainly in trials. ^[5]
• Dose and titration. A typical scheme: testosterone enanthate or cypionate 50 mg intramuscularly every 4 weeks for 6 months; increase by about 50 mg every 6 to 12 months over 2 to 3 years until the adult dose of 200 to 250 mg every 4 weeks is reached. For constitutional delay, a single 3 to 6 month course of 50 mg monthly is usually enough, then stop and reassess; if the testes do not enlarge, further investigation or another course follows. ^{[1] [5] [4]}
• Alternative physiologic therapy. In hypogonadotrophic hypogonadism, hCG (with or without FSH) mimics natural testicular stimulation, supports testicular enlargement and spermatogenesis better than testosterone alone, and is used when fertility or testicular volume matters; GnRH by infusion pump is an option. Testosterone remains simplest and cheapest, and still produces virilisation and bone health. ^{[1] [6]}
• Monitor. Clinical progression (Tanner stage, stretched penile length, voice, hair), height velocity, bone age radiograph; total testosterone in the mid-normal range for pubertal stage measured between injections for injectable preparations, and 2 hours after application for gel; haematocrit and liver function monitored during treatment; bone mineral density at baseline, 1 year and then every 1 to 2 years in permanent hypogonadism. ^[5]
• Stopping criterion. In constitutional delay, testosterone may be stopped once testicular volume has reached 6 to 8 mL, signalling axis activation. In permanent hypogonadism, continue with gradual escalation to adult dose. ^{[1] [5]}
• Special cases. Klinefelter syndrome: most boys enter puberty spontaneously with normal penile growth and pubic hair but reduced facial and body hair; offer testosterone from puberty if hypogonadism emerges, individualised, and consider early androgen exposure in selected cases because it may improve neurodevelopmental outcomes. Anorchia: replacement, often from the usual pubertal age, with individualised escalation; early postnatal testosterone may be used for microphallus. Cryptorchidism is managed surgically, and hormonal treatment for undescended testes is not routinely recommended. ^[3]

Delayed or absent puberty in girls needs investigation for an underlying cause, commonly Turner syndrome or congenital hypogonadotrophic hypogonadism; prolactin and thyroid status must be normal. ^[6]

Turner syndrome (2024 guideline): ^[4]

• Measure LH, FSH and AMH at 8 to 9 years, annually to 11 to 12 years, to allow timely assessment of spontaneous puberty and fertility preservation. ^[4]
• Start low-dose oestradiol between 11 and 12 years if FSH is raised on at least two occasions; increase slowly over 2 to 4 years to the adult replacement dose. ^[4]
• Preferred routes: transdermal oestradiol first; oral 17-beta-oestradiol second; avoid ethinyl oestradiol where alternatives exist.
• Add cyclical progesterone once breakthrough bleeding occurs (usually after about 18 to 24 months of unopposed oestrogen, but sometimes later depending on pubertal stage and uterine growth); micronised progesterone 200 mg for 10 to 12 days per month. ^[4]
• Aim for an adult serum oestradiol of about 100 to 150 pg/mL (350 to 500 pmol/L); continue treatment until the usual age of menopause (about 50 to 55 years), then reassess. ^[4]
• Stepping: a transdermal patch starting at 7 micrograms weekly (or oral micronised oestradiol 0.25 mg daily), increased every 6 to 12 months; higher E2 doses may need higher progesterone doses (300 mg daily for 12 days per month, or 200 mg daily). Ethinyl oestradiol should not be used for pubertal induction. ^[4]
• Spontaneous puberty occurs in about one-third of girls, mostly with mosaicism; mosaicism should not delay starting a trial if FSH is raised.

Congenital hypogonadotrophic hypogonadism (including Kallmann syndrome) in girls: induce puberty with low-dose oestrogen at about 11 to 12 years, increasing over 2 to 4 years; long-term replacement is lifelong. (Fertility is offered later with exogenous gonadotrophins.) ^{[2] [6]}

Girls who present at 13 years with no puberty, or who have a known condition posing a risk of hypogonadism from the age of 8, need expert evaluation; combined oral contraceptives are not recommended to induce puberty. ^[6]

• Treat with systemic hormone therapy that achieves replacement levels of oestrogen (oral or transdermal), with a progestogen added when the uterus is present. This is first-line. ^[8]
• Indications: menopausal-type symptoms, prevention of osteoporosis, cardiovascular and urogenital atrophy, and quality of life. ^[8]
• Continue to the average age of natural menopause (50 to 51 years), or to 55 to 56 years if there were prolonged gaps in treatment, then reassess. ^[8]
• 17-beta-oestradiol (tablets, patches, gel) is preferred to ethinyl oestradiol and conjugated equine oestrogens; combined hormonal contraceptives are an alternative when contraception matters, but provide inferior bone protection. ^[8]
• Micronised progesterone 100 to 200 mg for 12 to 14 days per month (or 100 mg daily), or dydrogesterone 10 mg, gives endometrial protection. Doses may need to rise if oestrogen doses exceed standard levels. ^[8]
• Transdermal oestradiol with micronised progesterone, dydrogesterone or a levonorgestrel intrauterine system is recommended, and oral oestrogens and androgenic progestins strongly discouraged, where migraine with aura, stroke, angina, thromboembolism, inherited procoagulant states, obesity, type 2 diabetes, dyslipidaemia or smoking coexist. HRT should be paused for about 6 months after a myocardial infarction if tolerated. ^[8]
• Reasonable target serum oestradiol ranges are 350 to 550 or 300 to 600 pmol/L; adjust only after adherence and correct use are confirmed. Baseline bone density should be measured in all women with hypogonadism of six months or more. ^[8]
• HRT is the recommended treatment for prevention or treatment of osteoporosis and for fracture prevention in women with female hypogonadism up to the normal age of menopause; there is no long-term alternative to HRT in premenopausal women. ^[8]
• HRT in this context is contraindicated only by past or current breast cancer and active endometrial cancer. ^[8]
• BRCA carriers should not be routinely denied HRT, and vaginal oestrogen is supported for urogenital symptoms after curative breast cancer treatment. Donor oocytes make pregnancy possible. ^[8]

Adolescents with Klinefelter syndrome. Most enter puberty spontaneously, with normal penile growth and pubic hair but reduced facial and body hair; offer testosterone if hypogonadism becomes evident (often late adolescence). Screen for autism spectrum traits and educational needs; metabolic syndrome in up to 44%. Bone mineral density falls early and responds to testosterone, calcium and vitamin D. ^[3]

Older men. Do not diagnose or treat on biochemistry alone in men over 65 without symptoms; decisions must be individualised, and anti-ageing use is not supported. Functional hypogonadism comes first, with reversible causes addressed before replacement. Reassess symptoms within 6 months of starting. ^[7]

Pregnancy and fertility. Hypogonadism with infertility is managed by reproductive endocrinology and urology or gynaecology. Women with primary ovarian insufficiency can carry pregnancies with donor oocytes. Men with Klinefelter can father children after sperm retrieval in roughly half of cases. ^{[3] [8]}

Women on long-term oestrogen. Screen for thromboembolic risk where indicated (family or personal history). Mammography and cervical screening follow age-based protocols.

Special note on Klinefelter. A higher incidence of thromboembolic events has been observed in patients with Klinefelter syndrome receiving testosterone therapy compared with untreated groups, so thrombotic risk should be assessed and discussed before starting. ^[7]

Untreated hypogonadism risks:

• Incomplete or arrested puberty and reduced adult height.
• Osteopenia in 25 to 48% and osteoporosis in 6 to 15% of men with Klinefelter syndrome; fractures more generally. ^[3]
• Anaemia (testosterone is erythropoietic).
• Loss of muscle mass and visceral adiposity; metabolic syndrome in 34 to 44% of men with Klinefelter syndrome. ^[3]
• Infertility and sexual dysfunction.
• Psychological and social morbidity: low self-esteem, anxiety, depression.
• In Klinefelter syndrome: breast cancer (small absolute risk), extragonadal germ-cell tumours, non-Hodgkin lymphoma, autoimmune disease (including thyroid disease), obstructive sleep apnoea and hearing loss.
• In Kallmann and other hypogonadal states: bone, metabolic and cardiovascular consequences of long-standing deficiency.
• Early 17-beta-oestradiol exposure matters: premature progesterone, before breast branching morphogenesis is complete, can limit breast and uterine development in girls with Turner syndrome or primary ovarian insufficiency. ^[8]

Treatment-related complications include polycythaemia (haematocrit 54% or greater during therapy), liver enzyme elevation with oral regimens, suppression of spermatogenesis, gynaecomastia, acne, and virilisation if pubertal dosing is excessive.

Constitutional delay resolves spontaneously by the age of 18 years and pubertal development completes normally after treatment. Functional hypogonadism reverses when its cause is treated.

Permanent primary hypogonadism is lifelong; with physiologic replacement, growth, bone mass, sexual development and quality of life are usually excellent, provided treatment is not delayed. Men with Klinefelter syndrome have a modestly reduced life expectancy of about 2 years, driven mainly by metabolic, respiratory and thromboembolic disease, with early diagnosis improving outcomes. ^[3]

Kallmann syndrome does not shorten life expectancy, but bone, cardiovascular and fertility sequelae require ongoing management; partial or transient recovery of gonadal function can occur. ^[2]

Turner syndrome and primary ovarian insufficiency carry risks of osteoporosis and cardiovascular disease that are mitigated by timely oestrogen replacement to the normal age of menopause. ^{[4] [8]}

• Lifestyle modification in adolescent and adult men with functional hypogonadism (weight, exercise, sleep apnoea, drug review). ^[7]
• Karyotype boys with primary hypogonadism for Klinefelter syndrome. ^[3]
• In Turner syndrome, measure LH, FSH and AMH from 8 to 9 years and start cardiovascular and renal surveillance early. ^[4]
• Screen siblings and family when a genetic cause (Kallmann syndrome, Klinefelter mosaicism) is known. ^[2]
• Bone-health measures (calcium, vitamin D, weight-bearing exercise) and routine bone density in long-standing deficiency. ^{[3] [4]}
• Do not screen healthy, asymptomatic men for hypogonadism. ^[7]
• In women with hypogonadism of 6 months or more, arrange baseline bone density. ^[8]

• A bone-age radiograph and a single morning testosterone change management even where budgets are tight; where laboratory testing is limited, clinical assessment of Tanner stage, testicular volume and the growth curve remains highly informative.
• When LH and FSH are unavailable, the combination of age, clinical picture and response to a cautious trial of sex steroid helps distinguish constitutional delay from pathology, but beware of treating a boy who actually has a tumour. Red flags (headaches, visual change, neurological signs, very short testes with gynaecomastia) warrant referral.
• Testosterone enanthate and basic oestradiol preparations are inexpensive and widely available in injectable form; pubertal induction with monthly injections is feasible. Transdermal preparations are often unavailable or unaffordable.
• Refer early any child with red flags, any girl with suspected Turner syndrome (for cardiovascular imaging), and any suspected tumour.

Turner syndrome; primary ovarian insufficiency; gynaecomastia; infertility; osteoporosis; pituitary tumours; precocious puberty; childhood growth disorders.

• Hypogonadism is insufficient sex-steroid production or action; delayed puberty is the usual adolescent presentation, considered delayed when testicular volume has not reached 4 mL by the age of 14 years in boys and breast development has not started by 13 years in girls.
• Split cases into primary (high LH/FSH) versus secondary (low or inappropriately normal LH/FSH) using a morning fasting sex-steroid level and gonadotrophins on the same sample.
• Most boys with delayed puberty have constitutional delay; persistent red flags point to pathology.
• Klinefelter syndrome (47,XXY, about 1 in 450 to 600 male births) is the most common defined cause of primary male hypogonadism, yet up to three-quarters of affected men are undiagnosed until infertility is investigated.
• Kallmann syndrome combines absent puberty with anosmia from an embryonic defect in GnRH neuron migration; testosterone virilises and restores bone health but does not restore spermatogenesis, which needs hCG plus FSH or pulsatile GnRH.
• Treat permanent hypogonadism with low-dose sex steroid, titrated over 2 to 4 years to adult dose; lifelong replacement when the defect is permanent.
• In adult men, diagnose on symptoms plus two low morning values, screen for reversible causes, respect contraindications (fertility wish, prostate and breast cancer, high haematocrit, untreated sleep apnoea, recent cardiovascular events), aim for mid-normal testosterone and monitor testosterone and haematocrit.
• Girls with Turner syndrome start low-dose oestradiol at 11 to 12 years, increasing over 2 to 4 years, with progesterone added when breakthrough bleeding occurs; ethinyl oestradiol should be avoided for pubertal induction. ^[6]
• Women with primary ovarian insufficiency need systemic hormone therapy with replacement-level oestrogen (plus progestogen if the uterus is present) to the normal age of menopause; HRT at this stage is contraindicated only by past or current breast cancer and active endometrial cancer. ^[8]
• Untreated disease risks poor growth, low bone mass, anaemia, infertility and long-term cardiovascular and metabolic disease.