Testosterone is the primary male sex hormone, produced by Leydig cells in the testes. It is essential for development of male reproductive organs, secondary sexual characteristics, bone density, muscle mass, erythropoiesis, libido, and overall well-being. Production is regulated by the hypothalamic-pituitary-gonadal (HPG) axis.

Testosterone is the primary male sex hormone, essential for reproductive development, muscle mass, bone density, and overall health. Source: Unsplash.

Testosterone Physiology

The hypothalamus releases GnRH, stimulating the pituitary to release LH and FSH. LH stimulates Leydig cells to produce testosterone. FSH stimulates Sertoli cells for spermatogenesis. Testosterone provides negative feedback on the HPG axis — some is converted to estradiol by aromatase (in adipose tissue), which also provides negative feedback.

Testosterone circulates in three forms: free testosterone (1-2%, biologically active), albumin-bound (30-40%, readily dissociates as “bioavailable”), and SHBG-bound (60-70%, not bioavailable). Normal total testosterone levels decline with age: 400-1,000 ng/dL at age 20-30, declining to 150-600 ng/dL by age 70-plus. The decline is gradual at 0.5-2% per year after age 30.

Hypogonadism

Hypogonadism is classified by the location of the defect. Primary hypogonadism (hypergonadotropic) involves a testicular defect — testosterone is low, LH and FSH are high (compensatory), and sperm production is low or absent. Secondary hypogonadism (hypogonadotropic) involves the pituitary or hypothalamus — testosterone is low, LH and FSH are low or inappropriately normal, and sperm production is low. Late-onset (age-related) hypogonadism is mixed.

Primary Hypogonadism

Causes include: Klinefelter syndrome (XXY — small firm testes, gynecomastia, tall stature, learning disability, azoospermia), cryptorchidism (undescended testicles), chemotherapy (alkylating agents are gonadotoxic), radiation therapy, mumps orchitis, testicular trauma or torsion, anabolic steroid abuse (suppresses endogenous production, usually reversible), aging, hemochromatosis (iron deposition in Leydig cells), and autoimmune orchitis.

Secondary Hypogonadism

Causes include: pituitary tumors (prolactinoma — hyperprolactinemia suppresses GnRH), other sellar masses, hemochromatosis (iron deposition in gonadotrophs), severe illness (critical illness, burns, MI — functional suppression), sleep apnea, obesity (aromatization of testosterone to estradiol, leptin resistance), diabetes mellitus, Cushing syndrome, hyperprolactinemia, opioids (suppress GnRH via mu-receptor activation), anabolic steroid withdrawal, Kallmann syndrome (congenital GnRH deficiency), and idiopathic causes.

ⓘ Information

Obesity is one of the most common reversible causes of low testosterone. Adipose tissue contains aromatase, which converts testosterone to estradiol. The resulting increase in estradiol suppresses the HPG axis, further reducing testosterone production. Weight loss of 5-10% of body weight can increase testosterone levels by 30-50%. Lifestyle modification — diet, exercise, and weight loss — is the first-line treatment for men with mild, age-related testosterone decline and obesity. Bariatric surgery can produce dramatic improvements in testosterone levels in morbidly obese men.

Signs and Symptoms

Sexual symptoms include decreased libido, ED, decreased nocturnal/morning erections, and delayed ejaculation. Physical signs include testicular atrophy, decreased muscle mass, increased body fat, reduced body hair, gynecomastia, and hot flashes. Bone effects include osteoporosis and fractures. Cognitive symptoms include difficulty concentrating, memory decline, and “brain fog.” Mood effects include depression, irritability, and anxiety. Metabolic effects include increased abdominal fat, insulin resistance, and dyslipidemia. Hematologic effects include mild anemia.

Diagnosis

Diagnosis requires two morning (8-10 AM) total testosterone measurements. Total testosterone below 300 ng/dL is consistent with hypogonadism. Levels between 300-400 ng/dL are borderline. Free or bioavailable testosterone is measured when SHBG abnormalities are suspected (in obesity, aging, thyroid or liver disease). LH and FSH distinguish primary from secondary hypogonadism. Prolactin is measured in all cases of secondary hypogonadism. Pituitary MRI is indicated if testosterone is low with low/normal LH and no clear cause.

Testosterone Replacement Therapy

TRT is indicated for symptomatic men with documented low testosterone (below 300 ng/dL) and primary or secondary hypogonadism. It is NOT indicated for men with normal testosterone, age-related decline without symptoms, athletic performance enhancement, or ED without hypogonadism.

Formulations

Intramuscular testosterone cypionate or enanthate (50-200 mg every 1-4 weeks) is inexpensive and flexible but produces peaks and troughs. Testosterone undecanoate (Aveed) 750 mg IM, given initially, at 4 weeks, then every 10 weeks, provides consistent levels but carries a risk of pulmonary oil microembolism requiring 30-minute observation. Transdermal gel 1%/1.62% (AndroGel, Testim) applied daily provides steady levels but carries a transfer risk to others. The patch (Androderm) causes skin irritation in 30-60%. Nasal gel (Natesto) is applied 2-3 times daily, has no transfer risk, but requires multiple daily doses. Subcutaneous pellets (Testopel) provide consistent levels for 3-6 months but have an extrusion risk of 5%. Oral testosterone undecanoate (Jatenzo, Kyzatrex) taken twice daily with fat provides an oral option without injection but requires a high-fat meal and has variable absorption.

Monitoring

Testosterone levels are checked 3-6 months after initiation and then annually, targeting the mid-normal range (500-800 ng/dL). Hematocrit is monitored at baseline, 3-6 months, then annually — stop or reduce dose if hematocrit exceeds 54%. PSA and DRE follow standard prostate cancer screening guidelines. Lipid panel, bone density, and breast exam are performed annually.

Contraindications

Absolute contraindications include active prostate cancer, breast cancer, palpable prostate nodule, undiagnosed PSA elevation, erythrocytosis (hematocrit over 54%), and desire for fertility (gonadotropin therapy is preferred).

⚠ Clinical Correlation

The relationship between TRT and cardiovascular events remains controversial. Earlier observational studies suggested increased risk of MI in older men with cardiovascular disease. However, more recent randomized trials and larger cohort studies have not confirmed a consistent increase in cardiovascular events. The T Trials (2017) found no increase in major adverse cardiovascular events with TRT over 1 year, but the study was not powered for cardiovascular endpoints. A 2023 meta-analysis of placebo-controlled RCTs found no significant increase in cardiovascular events with TRT. The current consensus: TRT does not appear to increase cardiovascular risk in most men, but caution is warranted in men with established cardiovascular disease, particularly in the first few months of therapy. Men with heart failure, recent MI, or uncontrolled hypertension should be evaluated carefully before starting TRT.

Benefits of TRT

Libido improves within 2-6 weeks. Erectile function shows moderate improvement in 40-60% of men over 3-6 months (PDE5 inhibitors may still be needed). Body composition improves with increased lean mass and decreased fat mass over 3-6 months. Bone density increases by 2-5% at the lumbar spine over 6-12 months. Mood and energy improve within 2-6 weeks. Hemoglobin increases by 1-2 g/dL over 3-6 months.

Risks of TRT

Erythrocytosis (hematocrit over 54%) is the most common adverse effect, occurring in 10-30% of men (higher with injectable formulations). Reduced HDL cholesterol occurs by 10-15%. Acne and oily skin are common. Gynecomastia occurs in 5-10%. Testicular atrophy occurs in 30-50%. Infertility from suppressed spermatogenesis affects 50-90% — men desiring fertility should avoid TRT or use hCG co-administration. Fluid retention and exacerbation of sleep apnea occur in 5-10%. The effect on prostate cancer risk remains controversial — current evidence does not show that TRT causes prostate cancer, but close monitoring is essential.

TRT and Fertility

Men who desire fertility should not start TRT without a plan to preserve spermatogenesis. Options include hCG monotherapy (1,000-3,000 IU 2-3 times per week), combination TRT plus hCG, clomiphene citrate (25-50 mg daily), or anastrozole (1 mg daily). Stopping TRT may restore spermatogenesis, but recovery can take 6-24 months.

TRT Alternatives

For men with mild hypogonadism or those who cannot take TRT, alternatives include: clomiphene citrate (Clomid) — a SERM that blocks estrogen feedback to increase LH and FSH, achieving testosterone levels above 400 ng/dL in 50-70% of men. It preserves fertility and avoids testicular atrophy. Anastrozole (Arimidex) — an aromatase inhibitor that reduces conversion of testosterone to estradiol, increasing testosterone levels. hCG monotherapy preserves or increases testicular volume. Lifestyle modification (weight loss, exercise, improved sleep, stress reduction) can increase testosterone by 30-50% from baseline and is the first-line approach for mild, age-related decline.

Summary

Testosterone is essential for male health. Hypogonadism is classified as primary (testicular failure, high LH/FSH) or secondary (pituitary/hypothalamic, low/normal LH/FSH). Diagnosis requires two morning testosterone measurements below 300 ng/dL with symptoms. TRT is effective for libido, body composition, bone density, and mood, but requires monitoring of hematocrit, PSA, and lipids. TRT suppresses fertility — men desiring children should consider alternatives. Weight loss and lifestyle modification are first-line for mild, age-related testosterone decline.