Residency · Residency · Urology

Male Hypogonadism and Testosterone Replacement Therapy

Introduction

Male hypogonadism is a clinical syndrome characterized by the failure of the testes to produce physiologic levels of testosterone and/or a normal number of spermatozoa. This failure results from disruption at one or more levels of the hypothalamic-pituitary-gonadal (HPG) axis. The condition affects an estimated 2-6% of adult males, with its prevalence increasing significantly with advancing age and the presence of comorbid conditions such as obesity, type 2 diabetes, and metabolic syndrome.

Classification of Hypogonadism

Primary Hypogonadism (Hypergonadotropic)

Primary hypogonadism arises from testicular failure and is marked by elevated levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The most common genetic cause is Klinefelter syndrome (47,XXY), which affects approximately 1 in 600 males. Other causes include bilateral orchitis, such as mumps orchitis, which damages Leydig and Sertoli cells; cryptorchidism, where prolonged undescended testes lead to germ cell and Leydig cell dysfunction; and testicular torsion or trauma resulting in bilateral testicular loss. Chemotherapy and radiation can cause dose-dependent gonadal toxicity, with alkylating agents being the most gonadotoxic. Additionally, myotonic dystrophy is associated with progressive testicular atrophy.

Secondary Hypogonadism (Hypogonadotropic)

Secondary hypogonadism results from dysfunction at the hypothalamic or pituitary level, leading to low or inappropriately normal gonadotropin levels. Kallmann syndrome is a notable cause, characterized by GnRH deficiency with anosmia due to failed migration of GnRH neurons. Pituitary adenomas, particularly prolactinomas, suppress gonadotropin secretion. Hyperprolactinemia induced by medications such as antipsychotics and metoclopramide inhibits GnRH pulsatility. Chronic opioid use suppresses LH pulse amplitude, with hypogonadism prevalence ranging from 50-90% among chronic users. Anabolic steroid abuse leads to suppression of the HPG axis via negative feedback. Obesity and metabolic syndrome contribute by increasing aromatase activity, which converts testosterone to estradiol. Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by isolated GnRH deficiency without anosmia.

Late-Onset Hypogonadism (Age-Related)

Late-onset hypogonadism involves a gradual decline in testosterone levels of approximately 1-2% per year after age 30. It features mixed primary and secondary components, with a relative increase in sex hormone-binding globulin (SHBG). This form of functional hypogonadism is often associated with comorbidities rather than organic pathology of the HPG axis.

Clinical Presentation

Sexual Symptoms

The most sensitive symptom of testosterone deficiency is decreased libido. Erectile dysfunction is common but multifactorial, and testosterone replacement alone may not restore function. Patients may also report decreased morning erections and reduced ejaculate volume. Infertility may present with oligospermia or azoospermia.

Physical Signs

Physical examination may reveal decreased muscle mass and strength accompanied by increased body fat, particularly visceral fat. Gynecomastia can occur due to relative estrogen excess. There is often decreased body hair and slowed beard growth. Testicular atrophy is suggested by a testicular volume less than 12 mL on orchidometry. Osteoporosis or low bone mineral density is common, as testosterone deficiency is a leading cause of male osteoporosis.

Psychological Symptoms

Patients frequently experience fatigue and decreased energy, depressed mood, irritability, cognitive decline, and poor concentration.

<image>Diagram of the hypothalamic-pituitary-gonadal axis showing GnRH release from hypothalamus, LH and FSH from anterior pituitary, and testosterone and inhibin B feedback loops from the testes, with labeled sites of disruption in primary and secondary hypogonadism</image>

Diagnostic Evaluation

Biochemical Assessment

Total testosterone should be measured in the early morning (before 10 AM) in a fasting state, with two measurements on separate days required to confirm diagnosis. The normal range is 300-1000 ng/dL (10.4-34.7 nmol/L), and values below 300 ng/dL on two occasions confirm biochemical hypogonadism. Free testosterone, calculated or measured by equilibrium dialysis, provides a more accurate assessment when conditions altering SHBG are present. SHBG levels can be elevated by aging, hepatic disease, hyperthyroidism, and anticonvulsants, while decreased levels occur in obesity, hypothyroidism, and nephrotic syndrome. Measurement of LH and FSH helps distinguish primary hypogonadism (elevated gonadotropins) from secondary hypogonadism (low or inappropriately normal gonadotropins). Prolactin levels should be checked to exclude prolactinoma if secondary hypogonadism is confirmed. Estradiol measurement is indicated if gynecomastia is present. Iron studies and ferritin levels are important because hemochromatosis is an underrecognized cause of secondary hypogonadism. Semen analysis is performed if fertility is a concern.

Imaging

Pituitary MRI is indicated when secondary hypogonadism is accompanied by total testosterone levels below 150 ng/dL, prolactin elevation, or visual field deficits. Dual-energy X-ray absorptiometry (DEXA) scans are recommended for men with documented hypogonadism to assess bone mineral density.

<image>Clinical photograph comparison showing physical features of male hypogonadism including eunuchoid body proportions, sparse body hair, gynecomastia, and small testicular volume versus normal male phenotype</image>

Testosterone Replacement Therapy (TRT)

Indications

Testosterone replacement therapy is indicated for symptomatic hypogonadism with confirmed low testosterone on two morning samples. The American Urological Association (AUA) guidelines recommend TRT for men with total testosterone below 300 ng/dL who exhibit symptoms. Contraindications include a desire for fertility, breast or prostate cancer, hematocrit above 54%, untreated severe obstructive sleep apnea, uncontrolled heart failure, and recent myocardial infarction or stroke within the past six months.

Formulations

TRT is available in various formulations. Intramuscular injections include testosterone cypionate or enanthate at doses of 100-200 mg every 1-2 weeks, and testosterone undecanoate (Aveed) at 750 mg intramuscularly every 10 weeks after an initial loading phase. Transdermal gels such as AndroGel and Testim, available in 1% or 1.62% concentrations, are applied daily and provide steady-state levels but carry a risk of transference to partners or children. Transdermal patches (Androderm) deliver 2-4 mg per day but commonly cause skin irritation. Nasal gel (Natesto) is administered as 5.5 mg per nostril three times daily, causing minimal suppression of the HPG axis and potentially preserving spermatogenesis. Subcutaneous pellets (Testopel) are implanted every 3-6 months at doses of 150-450 mg, providing consistent levels but requiring a minor surgical procedure. Oral testosterone undecanoate (Jatenzo) is taken at 158-396 mg twice daily with food, avoiding hepatic first-pass metabolism through lymphatic absorption.

Monitoring on TRT

Monitoring during TRT includes measuring testosterone levels at 3-6 months and then annually, aiming for mid-normal levels between 450-600 ng/dL. Hematocrit should be checked at 3-6 months and annually thereafter; therapy should be withheld if hematocrit exceeds 54% due to the risk of thromboembolic events. Prostate-specific antigen (PSA) is measured at baseline, 3-6 months, and then according to screening guidelines; a rise greater than 1.4 ng/dL within 12 months warrants urologic evaluation. Annual lipid panels and metabolic parameters should be assessed. Bone mineral density should be re-evaluated at 1-2 years if osteoporosis was present at baseline. Symptom assessment using validated instruments such as the quantitative Androgen Deficiency in the Aging Male (qADAM) or Aging Males' Symptoms (AMS) questionnaire is recommended.

TRT and Fertility Considerations

Exogenous testosterone suppresses spermatogenesis through negative feedback on FSH and LH, effectively acting as a male contraceptive. Recovery of spermatogenesis after cessation of TRT occurs in most men within 6-12 months but may take up to 24 months, and some men may not recover. For hypogonadal men desiring fertility, alternative therapies include clomiphene citrate at 25-50 mg daily or every other day (off-label), which is a selective estrogen receptor modulator that increases LH and FSH secretion. Human chorionic gonadotropin (hCG) at 1500-3000 IU subcutaneously two to three times per week mimics LH and maintains intratesticular testosterone. Anastrozole at 1 mg daily (off-label) is an aromatase inhibitor useful in obese men with elevated estradiol. Combined therapy with hCG and FSH (or human menopausal gonadotropin) is used for severe hypogonadotropic hypogonadism with azoospermia.

<image>Comparison chart of testosterone replacement therapy formulations showing route of administration, dosing frequency, pharmacokinetic profile with serum level curves, advantages, and disadvantages for each delivery method</image>

Key Clinical Pearls

Before diagnosing hypogonadism, it is essential to obtain two morning fasting testosterone levels because testosterone levels fluctuate with illness, sleep, and stress. Exogenous testosterone acts as a contraceptive and should never be prescribed to men actively trying to conceive; instead, clomiphene or hCG should be used. Polycythemia is the most common adverse effect of TRT, so hematocrit must be monitored regularly, and dose reduction or phlebotomy should be considered if hematocrit exceeds 54%. Current evidence indicates that testosterone therapy does not increase the risk of prostate cancer, but PSA monitoring remains standard practice. In cases of secondary hypogonadism, prolactinoma and hemochromatosis should always be ruled out before initiating TRT. Functional hypogonadism related to obesity often improves with weight loss, making lifestyle modification the first-line therapy.

References

1. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744.
2. Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and management of testosterone deficiency: AUA guideline. J Urol. 2018;200(2):423-432.
3. Corona G, Goulis DG, Huhtaniemi I, et al. European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males. Andrology. 2020;8(5):970-987.
4. Schlegel PN, Sigman M, Collura B, et al. Diagnosis and treatment of infertility in men: AUA/ASRM guideline part I. Fertil Steril. 2021;115(1):54-61.

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