Andrology

The terms androgen deficiency (AD) or testosterone deficiency are preferred over "hypogonadism." Unlike female menopause — a universal, age-related process — the rate of testosterone decline and the symptoms it produces are highly variable between men.

Terminology and Epidemiology

The true prevalence of AD in adult males is unknown because the literature uses inconsistent definitions; population-based studies suggest a prevalence of 2–39%.

Classification and Causes

AD is classified by the site of the defect. Primary (hypergonadotropic) disease reflects testicular failure; secondary (hypogonadotropic) disease reflects disruption of the hypothalamic–pituitary–gonadal (HPG) axis.

Feature	Primary (hypergonadotropic)	Secondary (hypogonadotropic)
Site of defect	Testis	HPG axis (hypothalamus/pituitary)
LH	High	Low or low/normal
Mechanism	Testicular failure	Reduced central gonadotropin drive

Primary causes — congenital causes follow the mnemonic DUNKY XX: Down syndrome, Undescended testis, Noonan's syndrome, Klinefelter syndrome, Y-microdeletions, and XX-male. Acquired primary causes are iatrogenic (bilateral orchiectomy, testicular radiation, chemotherapy), testicular trauma, infection (orchitis), and autoimmune disease.

Secondary causes:

• Congenital — e.g. Kallmann syndrome (congenital GnRH deficiency).
• Pituitary or suprasellar tumours.
• Pituitary infiltrative disorders — haemochromatosis, tuberculosis, sarcoidosis, histiocytosis.
• Pituitary apoplexy.
• Medications — chronic opioid exposure.
• Hyperprolactinaemia.
• Severe chronic illness.

Systemic illnesses associated with AD: diabetes, obesity, HIV, myocardial infarction, stroke, COPD and other respiratory illness, cancer, sepsis, chronic liver disease, chronic kidney disease (renal transplantation appears to reverse the hormonal abnormalities of ESRD), rheumatoid arthritis, burn injury, traumatic brain injury, and surgical stress.

Diagnosis

The clinical diagnosis of testosterone deficiency requires BOTH:

• Low testosterone — total morning testosterone <300 ng/dL on 2 separate occasions, AND
• Symptoms or signs associated with low serum total testosterone.

A patient is considered testosterone deficient and a candidate for therapy only when he meets both criteria. The recommended workup is a history and physical exam plus laboratory confirmation. Validated questionnaires are not recommended for diagnosis.

History and Physical Exam

Symptoms fall into three categories:

• Physical — loss of body hair, reduced lean muscle mass, gynecomastia, fatigue; visual-field changes (bitemporal hemianopsia) and anosmia point to a pituitary/central cause.
• Cognitive — depression, poor concentration and memory, irritability.
• Sexual — erectile dysfunction, decreased libido, infertility/difficulty conceiving.

Many symptoms (e.g. fatigue) are non-specific and may reflect conditions other than low testosterone. The history should also capture risk factors for AD, past medical and surgical history, and medications.

On examination, assess body habitus (BMI/waist circumference), virilisation (androgen-dependent hair pattern), gynecomastia, testicular size and consistency, and the presence of a varicocele.

• Gynecomastia is benign enlargement of male breast tissue occurring when the testosterone/estradiol (E2) ratio shifts (infancy, adolescence, old age) and may signal low testosterone. Causes are pharmacological (risperidone, anti-androgens, marijuana, clomiphene), physiological (neonatal, puberty), or pathological (testicular tumours, Klinefelter syndrome, cirrhosis). With any male breast enlargement, consider carcinoma.
• Varicocele — there is no definitive evidence that a varicocele causes low testosterone, though varicocele ligation may increase serum testosterone.

Laboratory Confirmation

• A morning total testosterone <300 ng/dL is considered low. Measure it by liquid chromatography/tandem mass spectrometry (LC-MS/MS, preferred), radioimmunoassay, or immunometric assay. Assays vary significantly between techniques and laboratories, so use the same laboratory and method for serial measurements.
• Free testosterone is not recommended as the primary diagnostic test. Although the free fraction is the most biologically active, direct measurement is unreliable and labour-intensive, and calculation-derived values are confounded by albumin/SHBG variation. Free testosterone has a role only in highly symptomatic men with low/normal or equivocal total testosterone.
• Some men with total testosterone >300 ng/dL are highly symptomatic and still improve with therapy.
• Diagnose only after 2 early-morning measurements on separate occasions — testosterone peaks in the morning and varies with circadian and circannual rhythm. There is no defined optimal interval between tests. If the first is <300 ng/dL but the second is normal, use clinical judgment about a third confirmatory test. Fasting is not required.

Even without symptoms, consider checking total testosterone in men with any of these 11 associations: diabetes; obesity (BMI ≥30) or increased waist circumference (>40 inches); HIV/AIDS; male infertility; chemotherapy exposure; testicular radiation; chronic narcotic use; chronic corticosteroid use; pituitary dysfunction; unexplained anaemia; bone-density loss.

Validated questionnaires (ADAM, quantitative ADAM, Aging Male Survey, MMAS, ANDROTEST) are not recommended to select candidates or monitor response — they are highly sensitive (≈80%) but not specific (<50%).

Adjunctive Testing

The initial adjunct is LH; the remaining tests are obtained before initiating treatment.

• Luteinising hormone (LH) — measure in all men with low testosterone to determine etiology. Low or low/normal LH indicates a secondary (central) defect; high LH indicates a primary testicular defect. When the cause is not obvious, a karyotype may establish Klinefelter syndrome (47,XXY) — characterised by very high LH and FSH with low testosterone, managed with exogenous testosterone for symptoms. With ageing, LH does not decline (testosterone falls from testicular hypofunction rather than central change), and Leydig-cell number remains stable.
• Prolactin — measure when low testosterone is paired with low or low/normal LH to screen for hyperprolactinaemia.
• Hematocrit — in all patients (polycythaemia risk; see below).
• Estradiol — in men with breast symptoms or gynecomastia. E2 commonly rises on therapy (aromatase converts testosterone to E2); refer men with breast symptoms and E2 >40 pg/mL to endocrinology. Symptomatic gynecomastia is an uncommon side effect.
• Reproductive health (testicular exam + FSH) — in men interested in fertility. Reduced testicular volume often accompanies impaired sperm production. Elevated FSH (which targets Sertoli cells) signals impaired spermatogenesis — pursue semen analysis. Elevated FSH with azoospermia or severe oligospermia (<5 million/mL) warrants reproductive genetics (karyotype + Y-chromosome microdeletion analysis); the 2015 CUA azoospermia guidelines recommend the same in testicular failure.
• PSA — measure in men >40, younger men with prostate-cancer risk factors, or any history of prostate cancer. PSA rise on therapy depends on baseline testosterone (lower baseline → greater rise). If baseline PSA is elevated, repeat it; two suspicious values warrant formal evaluation (4K, phi, MRI ± biopsy) before starting therapy.

Hyperprolactinaemia

Prolactin is secreted by the pituitary and is a cause of secondary testosterone deficiency, producing infertility, decreased libido, sexual dysfunction, and gynecomastia (via inhibition of dopaminergic activity in the medial preoptic area, lowering testosterone, plus a direct contractile effect on cavernous smooth muscle).

Causes:

• Medications — dopamine antagonists (most common), antipsychotics, SSRIs, PPIs, calcium-channel blockers, anti-emetics, opiates.
• Chronic conditions — hypothyroidism, renal failure, cirrhosis.
• Stress.
• Tumours — pituitary prolactinomas (benign, managed with bromocriptine or cabergoline), non-lactotroph adenomas (GH, ACTH, chromophobe), cystic adenomas, lesions near the hypothalamus/pituitary that disrupt dopamine delivery (e.g. craniopharyngioma), infiltrative disease (sarcoidosis, haemochromatosis, TB), and metastases.
• Other — elevated estrogen, chest-wall injury.

Evaluation: if prolactin is only mildly elevated (≤1.5× upper limit of normal), repeat a fasting level to exclude a spurious/stress-related result. Persistent elevation without an exogenous cause warrants MRI. Any man with total testosterone <150 ng/dL and low/low-normal LH should have a pituitary MRI regardless of prolactin (non-secreting adenomas). Refer to endocrinology if no etiology is found.

Management depends on the cause. A prolactinoma is treated with dopamine agonists (first-line), reserving transsphenoidal surgery for treatment failure or patient preference over lifelong therapy. Otherwise, treat the underlying driver (e.g. hypothyroidism, offending medication).

Pre-Treatment Bloods

Check hemoglobin/hematocrit before starting and counsel about polycythaemia — the most frequent adverse event of testosterone therapy (androgens stimulate erythropoiesis).

• Polycythaemia (erythrocytosis) = Hct >52%. Injectable testosterone produces the greatest rise. Hb/Hct generally climbs for the first 6 months, then plateaus. Increased viscosity can aggravate coronary, cerebrovascular, or peripheral vascular disease, especially in the elderly.
• If baseline Hct >50%, consider withholding therapy until the cause is explained.
• On therapy, a Hct ≥54% warrants intervention. In men with elevated Hct and:
  • High on-treatment testosterone → dose reduction is first-line.
  • Low/normal on-treatment testosterone → measure SHBG and free testosterone: if free T is high with low SHBG, consider dose adjustment; if free T is low/normal, refer to haematology for evaluation and possible phlebotomy.

Management

Lifestyle Modification (First-Line)

Weight loss and increased physical activity may raise total testosterone and reduce symptoms, but counsel that gains may not be clinically meaningful — significant testosterone improvement requires losing 5–10% of body weight. Pursue lifestyle change primarily for overall health.

Testosterone Therapy (Second-Line)

"Testosterone therapy" is the preferred term (over "replacement" or "supplementation") and includes exogenous testosterone as well as alternatives such as SERMs (clomiphene citrate), hCG, and aromatase inhibitors.

Indications (Campbell's): hypopituitarism; testicular dysgenesis with AD; delayed puberty (idiopathic, Kallmann syndrome); Klinefelter syndrome with AD; adult men with signs and symptoms of AD; sexual dysfunction with low testosterone; low bone density with AD.

Contraindications (Campbell's — CHEAPS BLUTS):

• Very high risk — metastatic prostate cancer, breast cancer.
• Moderate–high risk — poorly controlled congestive heart failure, hematocrit >50%, elevated PSA, abnormal DRE, unevaluated sleep apnea, severe BPH-associated LUTS (IPSS >19).
• Do not initiate within 3–6 months of a cardiovascular event.

Counselling — potential benefits (7): erectile function, libido, depressive symptoms, anaemia, bone mineral density, lean body mass, and mitigating the cardiovascular risk of low testosterone.

Testosterone therapy for ED — the role of testosterone monotherapy for ED is unclear. When a PDE5 inhibitor already restores erection, adding testosterone gives no further benefit; in PDE5i-refractory ED, testosterone helps only in men with biochemical AD (<300 ng/dL). In young men with symptomatic AD, testosterone is first-line (with PDE5i added if needed); in elderly men with ED, PDE5i is first-line with comorbidity optimisation, reserving testosterone for non-responders with biochemically confirmed AD.

Potential harms (5):

• Polycythaemia.
• Increased prostate size — prostate volume rises in the first 6 months but does not translate into worsening LUTS.
• Sleep apnea.
• Gynecomastia (rare).
• Infertility — do not prescribe exogenous testosterone to men currently trying to conceive; it suppresses spermatogenesis to severely oligospermic/azoospermic states. Most healthy men recover, but data in testosterone-deficient/infertile men are lacking. Stop testosterone before attempting conception: ~two-thirds recover ejaculated sperm within 6 months and 10% not until the second year, and some never recover.

Inconclusive areas:

• Cardiovascular events — low testosterone is itself a risk factor for cardiovascular disease (MI, stroke, possibly cardiovascular mortality), but it cannot be stated whether testosterone therapy raises or lowers cardiovascular risk. In TRAVERSE (Lincoff, 2023), 5,246 men aged 45–80 with established or high cardiovascular risk plus hypogonadal symptoms and two fasting testosterone levels <300 ng/dL were randomised to transdermal testosterone or placebo; over a mean 27-month treatment and 33-month follow-up there was no significant difference in the primary or secondary cardiovascular composite, though the testosterone group had more atrial fibrillation, acute kidney injury, and pulmonary embolism. There is no definitive link to venothrombotic events.
• Evidence is also inconclusive for cognition, energy, fatigue, diabetes measures, lipids, and quality of life — counsel patients about possible improvement nonetheless.
• Prostate cancer — no definitive link. The FDA warning persists, but evidence increasingly argues against a causal link. In men with a prostate-cancer history the risk–benefit ratio cannot be quantified; therapy can be considered after radical prostatectomy with favourable pathology (negative margins, seminal vesicles, and nodes) and undetectable PSA. Post-radiation patients (± prior ADT) do not appear to recur, but allow time for endogenous testosterone recovery first. Evaluate PSA recurrence as in untreated men, and discuss that stopping therapy may lower PSA. Data in active-surveillance candidates are limited.

Administration — available formulations (5): topical gel/patch (counsel about transference), buccal patch, nasal gel, subcutaneous pellets, intramuscular injections (3 types: two short-acting, one long-acting), and subcutaneous injections.

• Oral testosterone should not be prescribed — methyltestosterone is rapidly hepatically metabolised (inconsistent levels, liver toxicity), and oral testosterone undecanoate (absorbed via intestinal lymphatics, avoiding first-pass) is approved in some countries but not the US. Esterification of native testosterone yields the analogues with usable bioavailability.
• Prefer commercially manufactured products over compounded testosterone.
• Use the minimal dose to reach a total testosterone of 450–600 ng/dL (middle tertile of normal). Treatment success = therapeutic testosterone of 450–600 ng/dL plus symptom/sign improvement.

Alternatives for Men Desiring Fertility

Exogenous testosterone suppresses intratesticular testosterone, which is essential for spermatogenesis. To preserve fertility, use agents that promote endogenous production (alone or combined):

• SERMs (clomiphene citrate, tamoxifen) — block estrogen negative feedback on LH at the hypothalamus and pituitary.
• Aromatase inhibitors (anastrozole) — inhibit conversion of testosterone to estrogen.
• Human chorionic gonadotropin (hCG) — acts as an LH agonist, stimulating Leydig-cell testosterone.

Only hCG is FDA-approved in males (for hypogonadotropic hypogonadism); the overall evidence for these agents is limited.

Monitoring and Follow-Up

• Initial on-treatment testosterone, timed to the formulation: gels/patches/intranasal at 2–4 weeks; short-acting IM/SQ after several cycles (once equilibrated). The Endocrine Society advises measuring midway between injections for enanthate/cypionate and at the end of the interval before the next undecanoate dose, targeting the low–mid physiologic range (350–600 ng/dL; 12.1–20.8 nmol/L). Wait longer before checking after anastrozole, clomiphene, or hCG.
• Re-evaluate symptoms within 3 months — most improvement occurs in the first 3 months. If a man remains testosterone deficient despite symptom improvement, stop therapy. If on-treatment testosterone is below target but symptoms are partially relieved, up-titrate; if symptoms fully resolve, no titration is needed. If testosterone normalises but symptoms do not improve, discuss stopping at 3–6 months — unless there is documented bone-density loss or anaemia that improves on therapy.
• Total testosterone every 6–12 months.
• Hematocrit/hemoglobin every 6–12 months (or sooner) to keep Hct <54%.
• PSA — in men without prostate-cancer history, use shared decision-making per the AUA Early Detection of Prostate Cancer guideline; men with prostate cancer follow the same schedule (clinicians may test more often).
• DEXA — if baseline shows bone loss, repeat at 1–2 years (sooner after any low-trauma fracture); if normalised, image again at 2–5 years.

Self-Test

1. List systemic illnesses associated with testosterone deficiency. Diabetes, obesity, HIV, MI, stroke, COPD/respiratory illness, cancer, sepsis, chronic liver disease, CKD (reversible with renal transplant), rheumatoid arthritis, burn injury, traumatic brain injury, and surgical stress.

2. List causes of primary and secondary androgen deficiency. Primary (hypergonadotropic): congenital (DUNKY XX — Down, undescended testis, Noonan's, Klinefelter, Y-microdeletions, XX-male), iatrogenic (orchiectomy, radiation, chemotherapy), testicular trauma, orchitis, autoimmune. Secondary (hypogonadotropic): congenital (Kallmann/GnRH deficiency), pituitary or suprasellar tumours, infiltrative disorders (haemochromatosis, TB, sarcoidosis, histiocytosis), pituitary apoplexy, chronic opioids, hyperprolactinaemia, severe chronic illness.

3. What are the recommended initial investigations in someone suspected of having AD? History and physical exam, confirmation of low total morning testosterone (<300 ng/dL on two occasions), LH to determine etiology, and prolactin if LH is low or low/normal.

4. Describe your history and physical exam. History: physical, cognitive, and sexual symptoms; risk factors; past medical and surgical history; medications. Exam: body habitus, virilisation, gynecomastia, testicular size/consistency, and varicocele.

5. What is required for a diagnosis of AD? Both a low testosterone (total morning testosterone <300 ng/dL on two separate occasions) AND associated symptoms or signs.

6. After confirming the diagnosis, what tests are required, and what is needed before treatment? After diagnosis: LH (etiology) and prolactin if LH is low/low-normal. Before treatment: hematocrit (all), estradiol (breast symptoms/gynecomastia), testicular exam + FSH (fertility interest), and PSA (history of prostate cancer, age >40, or younger with risk factors).

7. What are the signs/symptoms and causes of hyperprolactinaemia? Signs/symptoms: infertility, decreased libido, sexual dysfunction, gynecomastia. Causes: medications (dopamine antagonists, antipsychotics, SSRIs, PPIs, CCBs, anti-emetics, opiates), chronic conditions (hypothyroidism, renal failure, cirrhosis), stress, tumours (prolactinoma and other pituitary lesions), elevated estrogen, and chest-wall injury.

8. What are the treatment options for AD in patients who want to preserve fertility? SERMs (clomiphene citrate, tamoxifen), aromatase inhibitors (anastrozole), and hCG — used alone or in combination to maintain endogenous intratesticular testosterone.