Male hypogonadism: treatment and what hCG and kisspeptin show

Complete guide: Sexual health peptides: a complete guide to PT-141

What is male hypogonadism and how is it diagnosed?

Male hypogonadism is insufficient production of testosterone, sperm or both because of failure of the testis (primary) or of the hypothalamic-pituitary axis that drives it (secondary or hypogonadotropic). The ICD-10 code for testicular hypofunction is E29.1. The Endocrine Society guideline recommends diagnosing it only in men with symptoms and signs consistent with testosterone deficiency and unequivocally and consistently low serum testosterone¹.

Per that guideline, the initial test is fasting morning total testosterone using an accurate and reliable assay, and the diagnosis is confirmed by repeating the measurement; if total testosterone is near the lower limit or sex hormone-binding globulin is altered, measuring or estimating free testosterone is recommended¹. Once deficiency is established, further evaluation to find the cause is recommended¹. The 2018 American Urological Association (AUA) guideline likewise centres on accurate total testosterone measurement, symptoms and signs².

The threshold is debated in older men. In the European Male Ageing Study (EMAS), a survey of 3,369 men aged 40 to 79, only three sexual symptoms (poor morning erection, low sexual desire and erectile dysfunction) had a syndromic association with low testosterone, and late-onset hypogonadism was defined by at least three of them together with total testosterone below 11 nmol/L (3.2 ng/mL) and free testosterone below 220 pmol/L⁴. The authors began from the premise that the link between ageing, testosterone deficiency and this syndrome was a controversial concept⁴.

Standard treatment today: what the guidelines recommend

In men with symptomatic deficiency, the Endocrine Society recommends testosterone therapy to induce and maintain secondary sex characteristics and correct symptoms, after discussing benefits, risks and monitoring, aiming for mid-normal concentrations¹. It recommends against starting it in men planning fertility in the near term or with breast or prostate cancer, a palpable prostate nodule or induration, PSA above 4 ng/mL, elevated hematocrit, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled heart failure, myocardial infarction or stroke within 6 months, or thrombophilia¹. It advises monitoring symptoms, adverse effects, testosterone, hematocrit and prostate cancer risk during the first year¹. The 2022 UK Society for Endocrinology guideline is another reference for testosterone replacement in male hypogonadism³.

What treatment adds in older men was tested in the Testosterone Trials: 790 men aged 65 or older with testosterone below 275 ng/dL received testosterone gel or placebo for 1 year. There was a moderate benefit in sexual function and some benefit in mood and depressive symptoms, but none in vitality or walking distance, and the sample was too small to assess risks⁵. For congenital hypogonadotropic hypogonadism, a European consensus statement covers pathogenesis, diagnosis and treatment¹¹.

Exogenous testosterone has a well-known effect on fertility: it lowers gonadotropins and intratesticular testosterone and impairs spermatogenesis, leading to azoospermia in about 40% of patients, as framed in one urology study¹³. The AUA guideline includes specific statements for men who wish to preserve fertility². This is where hCG and GnRH research comes in.

What research on peptides and related hormones has shown

The male reproductive axis is switched on when the hypothalamus releases gonadotropin-releasing hormone (GnRH), a decapeptide, in pulses; the pituitary answers with LH and FSH and the testis with testosterone and sperm. The history of the class is summarised in A hundred years of therapeutic peptides and its use in ovarian stimulation in Infertility: treatment and what GnRH peptide research shows.

hCG (human chorionic gonadotropin). It is a glycoprotein hormone, not a small peptide, and acts on the LH receptor. The label of a US hCG product lists, in males, prepubertal cryptorchidism not due to anatomical obstruction and selected cases of hypogonadotropic hypogonadism (hypogonadism secondary to a pituitary deficiency), and states that hCG has not been demonstrated to be effective adjunctive therapy in the treatment of obesity¹⁰. The best evidence is a review of 42 cases: 21 patients with idiopathic hypogonadotropic hypogonadism or Kallmann syndrome treated with GnRH or hCG/hMG, and 21 with hypopituitarism treated with hCG/hMG; across 57 treatment courses, testicular volumes doubled within 5 to 12 months, sperm appeared in the ejaculate in 54 of 57 courses, and pregnancies occurred in 26 of 36 courses aimed at conception¹². There were no significant differences between GnRH and hCG/hMG in time to sperm or pregnancy rates¹². This is an observational series, not a randomized trial.

hCG alongside testosterone. In 29 randomized healthy men, testosterone enanthate alone cut intratesticular testosterone by 94% (from 1,234 to 72 nmol/L) and suppressed LH and FSH to 5% and 3% of baseline; adding hCG every other day maintained intratesticular testosterone in a dose-dependent manner¹⁴. In a retrospective review of 26 hypogonadal men (mean age 35.9, mean follow-up 6.2 months) on testosterone plus low-dose hCG, none became azoospermic, semen parameters did not change over more than 1 year, and 9 of 26 contributed to a pregnancy with their partner¹³. The authors conclude it may preserve fertility, not that it has been shown to¹³.

GnRH (gonadorelin). This is the native decapeptide. In the 42-case series, the pulsatile GnRH group achieved spermatogenesis with no significant difference compared with hCG/hMG¹².

Kisspeptin. It is the neuropeptide that stimulates GnRH release. In 6 healthy male volunteers, a 90-minute intravenous infusion of kisspeptin-54 raised mean LH to 10.8 U/L (4.2 with saline) and testosterone at 180 minutes to 24.9 nmol/L (21.7 with saline), with a plasma half-life of 27.6 minutes¹⁵. Kisspeptin-10 boluses evoked a dose-dependent LH rise, and a 22.5-hour infusion increased LH pulse frequency and testosterone in healthy men¹⁶. In 13 healthy men, a kisspeptin bolus reset the GnRH pulse generator¹⁷. These are short mechanistic studies in healthy volunteers; the authors suggest therapeutic potential, but no trial exists in men with hypogonadism¹⁶. More context in Kisspeptin: solid science, wrong molecule? and PT-141 and kisspeptin in sexual health: a guide.

Safety: adverse effects and precautions

The TOM trial, in 209 men with a mean age of 74 and limited mobility, was stopped early: 23 subjects on testosterone versus 5 on placebo had cardiovascular-related adverse events⁶. TRAVERSE, in 5,246 men aged 45 to 80 with preexisting or high risk of cardiovascular disease, measured a composite of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke: 182 patients (7.0%) on testosterone and 190 (7.3%) on placebo (HR 0.96; 95% CI 0.78 to 1.17), so it was noninferior; a higher incidence of atrial fibrillation, acute kidney injury and pulmonary embolism was observed with testosterone⁷. In the fracture substudy (5,204 men, median follow-up 3.19 years), a clinical fracture occurred in 91 (3.50%) on testosterone and 64 (2.46%) on placebo (HR 1.43; 95% CI 1.04 to 1.97)⁸.

On 28 February 2025 the FDA announced class-wide testosterone labeling changes: it retained the limitation of use for age-related hypogonadism, required product-specific information on increased blood pressure for products with completed ambulatory blood pressure studies and a new blood pressure warning for those without one; on TRAVERSE it stated there was no increase in the risk of adverse cardiovascular outcomes⁹. The hCG label lists as contraindications precocious puberty, prostatic carcinoma or other androgen-dependent neoplasm, and prior allergic reaction to hCG¹⁰.

Summary by agent

Frequently asked questions

What testosterone level diagnoses hypogonadism? There is no single number: the Endocrine Society asks for compatible symptoms and unequivocally low fasting morning total testosterone on repeat measurements¹. EMAS used below 11 nmol/L (3.2 ng/mL) with at least three sexual symptoms⁴; TRAVERSE and the Testosterone Trials used below 300 and below 275 ng/dL, respectively⁵⁷.

Is hCG a peptide? No, it is a glycoprotein hormone acting on the LH receptor. It is included here because it works on the same axis as GnRH and kisspeptin¹⁰.

Is hCG indicated for male hypogonadism? The label of a US hCG product includes selected cases of hypogonadotropic hypogonadism in males and prepubertal cryptorchidism, and warns it has not been demonstrated effective for obesity¹⁰.

Does testosterone affect fertility? Yes: it lowers gonadotropins and intratesticular testosterone, and in a subset of patients can cause azoospermia¹³. In healthy men, low-dose hCG maintained intratesticular testosterone over 3 weeks¹⁴.

Can kisspeptin treat hypogonadism? This has not been shown. Studies in men are in healthy volunteers and show short-term rises in LH, FSH and testosterone¹⁵¹⁶¹⁷.

Does testosterone raise cardiovascular risk? In TRAVERSE it was noninferior to placebo for major cardiovascular events (HR 0.96), with more atrial fibrillation, acute kidney injury and pulmonary embolism⁷; the small TOM trial in frail men was stopped for more cardiovascular events⁶.