Hypogonadism

Hypogonadism is reduced function of the gonads, with deficient sex steroid production, gametogenesis or both. It may arise at the gonadal level (primary, with raised gonadotropins), at the hypothalamus or pituitary (secondary or central, with low or inappropriately normal gonadotropins), or through target tissue resistance. This article addresses hypogonadism across both sexes with attention to female forms.

Primary (hypergonadotropic) hypogonadism

• Male: Klinefelter syndrome (47,XXY, the commonest genetic cause, about 1 in 600 males), cryptorchidism, orchitis (mumps), testicular torsion or trauma, chemotherapy (alkylating agents), radiotherapy, autoimmune testicular failure, myotonic dystrophy, and Leydig cell hypoplasia.
• Female:
• Turner syndrome (45,X, 1 in 2500 live female births).
• Premature ovarian insufficiency (loss of ovarian function before age 40, prevalence about 1%): idiopathic (most), FMR1 premutation, autoimmune oophoritis (with Addison disease, thyroiditis), chemotherapy and radiotherapy, galactosaemia, bilateral oophorectomy, infection, and 46,XX gonadal dysgenesis.
• Swyer syndrome (46,XY gonadal dysgenesis).

Secondary (hypogonadotropic) hypogonadism

• Congenital: Kallmann syndrome (anosmia, ANOS1 and other mutations) and normosmic idiopathic hypogonadotropic hypogonadism.
• Acquired hypothalamic: functional hypothalamic amenorrhoea (low energy availability, excessive exercise, eating disorders, stress), chronic illness, critical illness, opioids, and tumours (craniopharyngioma).
• Pituitary: prolactinoma and other adenomas, hypopituitarism (surgery, radiation, Sheehan syndrome, apoplexy), empty sella, haemochromatosis, hypophysitis, traumatic brain injury, and infiltrative disease.
• Metabolic: obesity, type 2 diabetes, anabolic steroid use, glucocorticoids, and ageing.

Complications

• Infertility, reduced bone density (osteoporosis), cardiovascular risk, metabolic syndrome, anaemia (in men), sexual dysfunction, mood disturbance and reduced quality of life. Lifelong consequences of delayed puberty include reduced bone mass peak, and altered body composition.

Age of onset

• Prepubertal (absent puberty), pubertal (arrested), and postpubertal (adult-onset) hypogonadism differ in manifestations and in treatment aims.

Male

• Prepubertal: small testes (below 4 mL), absent virilisation, eunuchoid proportions (arm span exceeding height by 5 cm or more), delayed bone age, gynaecomastia, sparse hair, high-pitched voice.
• Adult: low libido, erectile dysfunction, infertility, small or soft testes, loss of body hair, reduced muscle mass, central adiposity, osteopenia, hot flushes, anaemia, depression and fatigue.
• Klinefelter: tall stature, long legs, small firm testes, gynaecomastia, learning difficulties, azoospermia.

Female

• Primary amenorrhoea with absent breast development (Tanner stage 1 at 13 years or lack of menarche by 15 years).
• Secondary amenorrhoea or oligomenorrhoea, infertility, vasomotor symptoms, vaginal dryness, dyspareunia, low libido, osteoporosis, and mood disturbance.
• Turner syndrome: short stature, webbed neck, shield chest, wide-spaced nipples, cubitus valgus, low hairline, lymphoedema, coarctation, bicuspid aortic valve, horseshoe kidney, and learning difficulties.
• Premature ovarian insufficiency: menstrual irregularity and hot flushes under age 40.

Clues to central causes

• Anosmia or hyposmia (Kallmann), headache, visual field defects (chiasmal compression), galactorrhoea (prolactinoma), features of other pituitary hormone deficiencies (hypothyroidism, adrenal insufficiency, growth hormone deficiency), eating disorder, excessive exercise, weight loss, and history of head trauma or radiation.

Clues to primary causes

• Prior chemotherapy or radiotherapy, mumps orchitis, cryptorchidism, autoimmune disease, family history of early menopause or fragile X disorder, and syndromic features.

Red flags: visual impairment, severe headache, hypopituitarism with adrenal crisis risk, hypercalcaemia, rapid weight loss, and bone fragility fractures.

Confirm hypogonadism biochemically, then determine level and cause.

Initial tests

• Males: early morning fasting total testosterone on at least two occasions (low if below 8 nmol/L or 230 ng/dL, with borderline values 8 to 12 nmol/L requiring free testosterone, SHBG and repeat). LH and FSH, prolactin, TSH, CBC, iron studies, HbA1c, and semen analysis in fertility concerns.
• Females: pregnancy test, FSH (above 25 to 40 IU/L on two samples 4 weeks apart supports ovarian insufficiency), LH, oestradiol (low), AMH (low), prolactin, TSH, and testosterone and DHEAS if hyperandrogenism is suspected. Progestogen challenge test (medroxyprogesterone 10 mg for 10 days) to determine oestrogen status where used.

Interpretation

• Low sex steroid with high LH/FSH: primary gonadal failure. Karyotype, FMR1, adrenal and thyroid autoantibodies (21-hydroxylase antibodies), and gonadal imaging.
• Low sex steroid with low or normal LH/FSH: central. Pituitary function testing (morning cortisol, free T4, IGF-1, prolactin), iron studies, and MRI of the hypothalamus and pituitary. Olfactory testing and genetic panel for Kallmann syndrome.
• Distinguish constitutional delay of growth and puberty from permanent hypogonadotropic hypogonadism: basal testosterone, GnRH agonist stimulation (leuprolide 20 micrograms/kg SC with LH at 3 to 4 hours, above 5 IU/L indicates puberty onset), inhibin B and AMH (low in hypogonadotropic hypogonadism), and observation to age 18.

Further assessment

• DEXA for bone density, lipids, glucose, and echocardiography and renal ultrasound for Turner syndrome.
• Testicular ultrasound (volume, microlithiasis, mass). Pelvic ultrasound for uterine size and ovarian volume.
• Genetic counselling and testing as indicated (karyotype, SRY, CFTR, androgen receptor, 5-alpha reductase).

Goals: restore sex steroid levels, induce and maintain secondary sexual characteristics, protect bone and cardiovascular health, support fertility when desired, and address psychosocial aspects.

Males

• Testosterone replacement (once fertility is not required): testosterone undecanoate injection 1000 mg IM at weeks 0 and 6 then every 10 to 14 weeks, testosterone enanthate or cypionate 100 to 200 mg IM every 2 weeks (or 50 to 100 mg weekly SC), 1.62% gel 40.5 mg daily, 2% gel 60 mg daily, or patches. Target mid-normal levels (500 to 700 ng/dL, 17 to 24 nmol/L). Monitor at 3, 6 and 12 months, then annually: haematocrit (reduce dose or stop if above 54%), PSA and digital rectal examination over 40, symptoms, blood pressure, lipids, and bone density.
• Puberty induction in boys: testosterone enanthate 25 to 50 mg IM monthly increased by 25 to 50 mg every 6 to 12 months to 200 mg every 2 weeks over 2 to 3 years, or hCG 1000 to 1500 units twice weekly to stimulate testicular growth.
• Fertility treatment in hypogonadotropic hypogonadism: hCG 1500 to 2500 units SC 2 to 3 times weekly, with recombinant FSH 75 to 150 units 3 times weekly added if sperm absent after 6 months, for up to 18 to 24 months. Pulsatile GnRH (5 to 20 micrograms every 2 hours) is an alternative. Sperm output is achieved in most. Testicular volume above 4 mL predicts response. Testicular sperm extraction with ICSI for primary failure (Klinefelter syndrome microdissection testicular sperm extraction recovers sperm in about 40 to 50%).
• Stop contributory drugs (opioids, glucocorticoids, anabolic steroids), treat hyperprolactinaemia (cabergoline 0.25 to 0.5 mg twice weekly), and encourage weight loss, which may restore testosterone in obesity-related hypogonadism.
• Gynaecomastia: tamoxifen 10 to 20 mg daily for painful early disease, or surgery.

Females

• Oestrogen replacement (until about age 50 to 51 in premature ovarian insufficiency and Turner syndrome):
• Puberty induction: start oestradiol at 1/10 to 1/8 of the adult dose (transdermal oestradiol 3 to 7 micrograms/day, or oral 0.25 mg daily), increasing every 6 months over 2 to 3 years to adult dosing (transdermal 50 to 100 micrograms twice weekly, oral oestradiol 2 mg daily). Add a progestogen after 2 years or at the first breakthrough bleeding (micronised progesterone 200 mg for 12 to 14 days monthly, or dydrogesterone 10 mg for 12 to 14 days).
• Adult replacement: transdermal oestradiol 50 to 100 micrograms twice weekly (or 1 to 2 mg orally) with cyclical or continuous progestogen when the uterus is intact, or the levonorgestrel IUD. Combined oral contraceptive is a practical alternative in young women. Higher doses than in natural menopause are used in young women.
• Growth hormone (somatropin 0.045 to 0.067 mg/kg/day, 0.05 mg/kg/day in Turner syndrome) for short stature in Turner syndrome starting early.
• Fertility: oocyte donation for premature ovarian insufficiency and Turner syndrome (with cardiovascular screening before pregnancy, as aortic dissection risk is raised). Ovulation induction in hypogonadotropic hypogonadism: pulsatile GnRH, or FSH 75 to 150 units daily with hCG trigger 5000 to 10,000 units.
• Functional hypothalamic amenorrhoea: restore energy availability, increase caloric intake, reduce training, cognitive behavioural therapy, and transdermal oestradiol for bone health when recovery is slow.
• Hyperprolactinaemia and pituitary tumours: cabergoline, surgery for non-responders.

Bone health and general care

• Calcium 1000 to 1200 mg daily, vitamin D 800 to 2000 IU daily (target 25-hydroxyvitamin D above 30 ng/mL), weight-bearing exercise, DEXA every 1 to 2 years, and bisphosphonate (alendronate 70 mg weekly) for established osteoporosis after sex steroid replacement.
• Cardiovascular risk modification, smoking cessation, and screening for autoimmune and associated conditions (thyroid disease, Addison disease, diabetes, coeliac disease in Turner syndrome).
• Psychological support, counselling for body image and fertility, and peer support groups. Genetic counselling for hereditary forms.

Follow-up

• Review at 3 to 6 months after initiation, then annually in a specialist clinic. Lifelong replacement is required in permanent hypogonadism. Adolescents transition to adult services with continued monitoring.