Low Testosterone (Hypogonadism) — Causes, Symptoms & Treatment Guide — Symptoms, Causes & Treatment | MyMedicPlus

Testosterone is the principal male sex hormone (androgen), produced by Leydig cells in the testes under stimulation by LH (luteinising hormone) from the pituitary gland, which in turn is regulated by GnRH from the hypothalamus. Testosterone is responsible for male sexual development, maintenance of libido, sperm production, bone mineral density, muscle mass and strength, red blood cell production, fat distribution, mood, cognitive function, and energy. Low testosterone (hypogonadism) refers to clinical and/or biochemical evidence of androgen deficiency. Normal total testosterone in adult men: approximately 10-35 nmol/L (280-1000 ng/dL). Hypogonadism is classified as primary (testicular failure — raised LH and FSH due to loss of negative feedback) or secondary (hypothalamic-pituitary dysfunction — low or normal LH and FSH with low testosterone). The Endocrine Society defines hypogonadism requiring treatment as total testosterone below 10.4 nmol/L (300 ng/dL) consistently on two morning samples combined with characteristic symptoms. Testosterone levels decline physiologically with age — approximately 1-2% per year from age 30. Biochemical hypogonadism (testosterone below 11 nmol/L) affects 20-40% of men over 45 years; true symptomatic hypogonadism requiring treatment affects 6-12% of men over 50. The TRAVERSE trial (2023) — the largest RCT of TRT (5,246 men, 33 months) — confirmed that testosterone replacement did not increase cardiovascular events but did increase pulmonary embolism, atrial fibrillation, and acute kidney injury.

Primary hypogonadism (testicular failure): Klinefelter syndrome (47XXY — the most common genetic cause, affecting 1 in 650 male births — small firm testes, azoospermia, gynaecomastia, tall stature); testicular trauma, torsion, or orchidectomy; chemotherapy or radiation therapy causing gonadotoxicity; autoimmune orchitis; mumps orchitis (bilateral orchitis causes permanent testicular damage in 13-20% of post-pubertal males); myotonic dystrophy and other genetic conditions. Secondary hypogonadism (hypothalamic-pituitary causes): Kallmann syndrome (congenital GnRH deficiency with anosmia — failure to enter puberty); hyperprolactinaemia (prolactin excess from pituitary adenoma suppresses GnRH pulse generator — measure prolactin in all men with hypogonadism); other pituitary tumours; haemochromatosis (iron deposition in the pituitary — gonadotropin deficiency); pituitary apoplexy; head trauma; opioid use (exogenous opioids suppress GnRH in a dose-dependent manner — approximately 75% of men on long-term opioids develop hypogonadism); and glucocorticoid excess (Cushing's syndrome or exogenous corticosteroids). Functional (reversible) hypogonadism: obesity (aromatase in adipose tissue converts testosterone to oestradiol — hypoandrogenism; adipose tissue also produces inflammatory cytokines suppressing Leydig cell function); type 2 diabetes; obstructive sleep apnea (nocturnal hypoxia suppresses testosterone); severe chronic illness (critical illness, CKD, cirrhosis, heart failure); malnutrition; and anabolic steroid abuse (exogenous androgens suppress the hypothalamic-pituitary-testicular axis — often profoundly so).

Symptoms of hypogonadism reflect the multiple physiological roles of testosterone across different body systems. Sexual symptoms (most androgen-sensitive): reduced libido (the most common presenting complaint); erectile dysfunction (ED — testosterone deficiency impairs both desire and nocturnal erections; however most organic ED is vascular, not hormonal — measure testosterone in all men with ED); and infertility and azoospermia (FSH-driven — primary hypogonadism causes oligo-azoospermia). Metabolic symptoms: increased body fat (particularly visceral abdominal fat — testosterone inhibits adipogenesis); reduced muscle mass and strength (sarcopaenia — testosterone stimulates protein synthesis and myogenesis); decreased bone mineral density (osteoporosis — testosterone is converted to oestradiol in bone for mineralisation — fracture risk increased); and anaemia (testosterone stimulates erythropoiesis via EPO production). Psychological and cognitive symptoms: fatigue; mood disturbance (depression, irritability, low mood — testosterone has neuropsychological effects); reduced energy; difficulty concentrating; and reduced self-confidence. Physical signs: reduced facial and body hair; gynaecomastia (breast tissue enlargement — from relative oestrogen excess); small soft testes (primary hypogonadism); delayed puberty (congenital/adolescent hypogonadism — small testes, eunuchoid body proportions, lack of secondary sexual characteristics); and hot flushes (sudden heat sensations — more common in acute testosterone deficiency). It is critical to recognise that these symptoms are non-specific and overlap with depression, sleep disorders, chronic illness, and normal aging. Symptoms alone are not sufficient to diagnose hypogonadism — biochemical confirmation is essential.

Biochemical diagnosis requires two fasting morning blood samples (testosterone peaks in the morning and falls by 25-40% by the afternoon) showing consistently low total testosterone. Measurement: total testosterone (by immunoassay or liquid chromatography-mass spectrometry — LC-MS/MS is more accurate); the Endocrine Society recommends measurement by accurate assay (LC-MS/MS preferred). Normal: above 10.4 nmol/L (300 ng/dL); borderline: 8-10.4 nmol/L (230-300 ng/dL); definite deficiency: below 8 nmol/L (230 ng/dL). SHBG (sex hormone binding globulin) level: elevated SHBG (in cirrhosis, hyperthyroidism, ageing) binds more testosterone, reducing free testosterone — calculate free testosterone in men with borderline total testosterone and elevated SHBG. Free testosterone (calculated or measured): below 220 pmol/L (63 pg/mL) indicates deficiency. LH and FSH: elevated LH and FSH indicates primary hypogonadism (testicular failure); low or normal LH and FSH with low testosterone indicates secondary (central) hypogonadism requiring pituitary imaging (MRI pituitary — exclude pituitary tumour). Prolactin: elevated in hyperprolactinaemia (pituitary adenoma) — causes secondary hypogonadism by suppressing GnRH. Serum ferritin and transferrin saturation (haemochromatosis). Karyotype (suspected Klinefelter syndrome). Semen analysis (fertility evaluation). Haemoglobin, haematocrit (baseline before TRT — polycythaemia is a TRT side effect). PSA (prostate-specific antigen), digital rectal examination (prostate assessment before TRT in men over 40). DEXA scan (bone mineral density in chronic hypogonadism). Pituitary MRI (macroadenoma, haemochromatosis, structural lesion) if secondary hypogonadism confirmed.

TRT is indicated in men with both biochemical hypogonadism (consistently low total testosterone on two morning samples) AND symptomatic hypogonadism (sexual, psychological, or physical symptoms), after excluding reversible causes. TRT is contraindicated in: active prostate cancer; breast cancer; desire for fertility (TRT suppresses sperm production by suppressing FSH — men wishing to preserve fertility should use clomiphene or gonadotropin therapy); haematocrit above 54% (polycythaemia risk); untreated obstructive sleep apnea; and severe heart failure. Formulations and routes: Topical testosterone gels (Testogel 1% — 50-100mg daily; Tostran 2% — applied to inner thigh or abdomen; Axiron — axillary application): convenient daily use; steady testosterone levels; skin transfer risk to partners (wash hands, cover application site); most widely prescribed in primary care. Intramuscular injections (Sustanon 250 — mixed testosterone esters — 3-weekly; Nebido — testosterone undecanoate — 10-14 weekly after loading): less frequent administration; Nebido maintains stable levels; Sustanon causes peaks and troughs. Transdermal patches (Androderm): daily; causes skin irritation in 30-40%. Subcutaneous pellets (Testopel — US): 3-6 monthly implantation. Buccal system (Striant): twice-daily application to gum. Monitoring after TRT initiation: testosterone (target 15-25 nmol/L — mid-normal range) at 3 months, then annually; haematocrit (target below 54% — reduce dose or stop if polycythaemia develops); PSA (at 3 months, then annually — any rise above 1.4 ng/mL per year warrants urological review); symptoms assessment; and DEXA at 2 years. TRAVERSE trial (2023): in men 45-80 with pre-existing or high cardiovascular risk, TRT did not increase MACE but increased VTE (pulmonary embolism), atrial fibrillation, and acute kidney injury — safety must be carefully considered. TRT improves libido, sexual function, mood, muscle mass, bone density, and energy in genuinely hypogonadal men. For secondary hypogonadism in men seeking fertility: clomiphene citrate (off-label — stimulates endogenous LH/FSH) or gonadotropin therapy (hCG + FSH) to stimulate testicular testosterone and sperm production.

Untreated hypogonadism (low testosterone) causes progressive systemic complications beyond sexual dysfunction. Bone mineral density decreases by approximately 2-3% annually in men with untreated hypogonadism — leading to osteoporosis and significantly increased risk of vertebral and hip fractures; testosterone replacement therapy consistently improves BMD in hypogonadal men. Skeletal muscle mass declines (sarcopenia), reducing physical strength, functional capacity, and increasing fall risk in older men with hypogonadism. Metabolic complications include increased visceral adiposity, insulin resistance, type 2 diabetes, and metabolic syndrome — all bidirectionally related to testosterone deficiency. Depression, cognitive impairment (including reduced verbal memory and spatial ability), fatigue, and reduced quality of life are well-documented systemic manifestations. Anaemia (from reduced erythropoiesis — testosterone stimulates erythropoiesis by increasing erythropoietin and iron incorporation) occurs in moderate-to-severe hypogonadism — responding to testosterone replacement. Cardiovascular risk is increased in severely hypogonadal men through endothelial dysfunction, dyslipidaemia, and increased arterial stiffness. In Klinefelter syndrome (XXY) — the most common genetic cause of hypogonadism — complications include infertility (azoospermia in virtually all cases), gynaecomastia, testicular atrophy, increased risk of autoimmune disease, type 2 diabetes, and breast cancer (50-fold elevated risk). Secondary hypogonadism from pituitary adenoma requires tumour monitoring and treatment given risk of visual field defects from optic chiasm compression.

Functional (reversible) hypogonadism is significantly preventable and reversible with lifestyle modification. Weight loss: obesity is the strongest reversible cause of low testosterone — every 1 point BMI reduction increases testosterone by approximately 2.5 nmol/L in obese men. A 15% or more weight loss frequently normalises testosterone without TRT. Regular exercise: resistance training acutely increases testosterone and reduces SHBG long-term; high-intensity interval training (HIIT) provides additional benefit; avoid overtraining syndrome (chronic excessive exercise paradoxically lowers testosterone). Sleep: optimise sleep (7-9 hours/night) and treat sleep apnea (CPAP significantly raises testosterone in OSA patients). Avoid chronic stress (cortisol inhibits GnRH and Leydig cell function). Limit alcohol (acute heavy drinking suppresses testosterone; chronic alcohol use causes testicular damage). Avoid exogenous androgens and prohormone supplements (suppress the HPT axis — can cause lasting hypogonadism). Manage chronic diseases (T2DM, liver disease, CKD) aggressively — all suppress testosterone. Avoid opioid medications where possible; if prescribed long-term, monitor testosterone annually.

See your GP for assessment if you experience: persistent low libido or erectile dysfunction not adequately explained by psychological causes or medications; significant fatigue and low energy that has not improved with adequate sleep and lifestyle measures; reduced muscle mass and strength combined with increased abdominal fat; mood changes — depression or irritability — that are persistent and unresponsive to initial management; and any symptoms of delayed or incomplete puberty in adolescent males. See a specialist (endocrinologist or urologist) urgently for: confirmed low testosterone with infertility concerns (semen analysis and gonadotropin assessment needed); suspected pituitary tumour (secondary hypogonadism with headache, visual field defects, or other pituitary hormonal deficiencies); Klinefelter syndrome features (small testes, gynaecomastia, tall stature); and males with severe osteoporosis or unexplained osteoporotic fractures. Do not start TRT without proper biochemical confirmation — symptoms of low testosterone are non-specific and overlap with many other common conditions. Self-prescribing testosterone without medical supervision carries serious risks including infertility, polycythaemia, and cardiovascular complications.