Male hypogonadism

Male hypogonadism is a condition caused by reduced function of the testes, leading to decreased production of testosterone. It is classified as primary male hypogonadism or secondary male hypogonadism based on the underlying cause. Primary male hypogonadism is characterized by elevated gonadotropin (LH and FSH) levels and caused by disorders or abnormalities affecting the testes, including damage to the testes (e.g., due to orchitis, radiation, trauma, or torsion) and congenital conditions (e.g., Klinefelter syndrome). Secondary male hypogonadism is characterized by gonadotropin deficiency and caused by disorders of the hypothalamus and/or pituitary gland (e.g., tumors, infiltrative diseases, head trauma, congenital conditions such as Kallmann syndrome). Clinical features may include decreased bone and muscle mass and gynecomastia. Certain features depend on the time of onset (i.e., prepubertal or postpubertal): Prepubertal manifestations include microphallus and eunuchoidal proportions, and postpubertal manifestations include loss of morning erections, low energy, and hot flashes. Low fasting morning total testosterone levels on two separate occasions confirms the diagnosis. Once the diagnosis is established, additional laboratory and/or imaging studies should be obtained to determine the etiology. Functional male hypogonadism is managed with lifestyle modifications and/or treatment of the underlying condition. Testosterone therapy is indicated for patients with low testosterone levels due to testicular disorders (e.g., genetic causes), pituitary gland disorders (e.g., tumors), and brain disorders. Use of testosterone for age-related testosterone decline is off-label. There are multiple testosterone formulations; the formulation used depends on drug availability, cost, and patient preference. Patients taking testosterone therapy require regular monitoring to assess for complications and response to treatment.

• Primary male hypogonadism: hypogonadism due to disorders or abnormalities affecting the testes, characterized by elevated gonadotropin levels
• Secondary male hypogonadism: hypogonadism due to disorders of the hypothalamus and/or pituitary gland, characterized by gonadotropin deficiency (due to decreased secretion of GnRH or LH/FSH)
• Mixed male hypogonadism: hypogonadism resulting from both disorders of the testes (primary) and the hypothalamus and/or pituitary gland (secondary) ^[2]
• Organic male hypogonadism: hypogonadism due to often irreversible hypothalamic-pituitary-testicular axis pathology
• Functional male hypogonadism: hypogonadism due to often reversible suppression of the hypothalamic-pituitary-testicular axis (e.g., due to obesity)

Acquired causes of primary (hypergonadotropic) and secondary (hypogonadotropic) hypogonadism are further classified as organic vs. functional. See “Etiology of male hypogonadism” for examples.

Primary male hypogonadism ^[1][2][3]

Acquired

• Organic
  • Orchitis (e.g., due to gonorrhea, mumps virus infection)
  • Bilateral orchiectomy
  • Testicular radiation
  • Chemotherapy
  • Testicular trauma
  • Testicular torsion
  • Hemochromatosis ^[4]
  • Older age ^[5]
• Functional
  • Medications (e.g., ketoconazole)
  • Varicocele

Congenital

• Klinefelter syndrome
• Down syndrome
• Cryptorchidism
• Congenital anorchia (vanishing testes syndrome)
• Y chromosome microdeletions
• LH and FSH receptor genetic variants
• Myotonic dystrophy

Secondary male hypogonadism ^[1][3]

Acquired

• Organic
  • Damage to the pituitary gland (e.g., due to tumors, infiltrative diseases such as sarcoidosis or hemochromatosis, or infection)
  • Head trauma
• Functional
  • Critical systemic illness
  • Hyperprolactinemia
  • Medications (e.g., opioids, GnRH agonists, GnRH antagonists, glucocorticoids)
  • Cannabis use ^[4][5]
  • Anabolic steroid use
  • Obesity
  • Excessive calorie restriction
  • Excessive exercise
  • Sleep deprivation and other sleep disorders (e.g., OSA) ^[5][6]

Congenital

• Kallmann syndrome
• Normosmic congenital hypogonadotropic hypogonadism
• CHARGE syndrome
• Waardenburg syndrome
• Congenital adrenal hypoplasia
• Septo-optic dysplasia

Mixed male hypogonadism ^[1][2]

• Acquired
  • Heavy alcohol use
  • Chronic diseases (e.g., HIV, IBD, post-COVID-19 condition, celiac disease)
  • Organ failure (e.g., heart failure, chronic kidney disease, cirrhosis)
• Congenital
  • Congenital adrenal hyperplasia
  • Prader-Willi syndrome

The clinical presentation of hypogonadism is complex and influenced by various factors, including age and underlying health conditions.

Prepubertal onset ^[1][3]

The following features are unique to prepubertal onset.

• Microphallus
• Cryptorchidism
• Eunuchoidal proportions (e.g., arm span exceeding height by ≥ 6 cm) ^[1]
• High-pitched voice
• Absence of scrotal rugae
• Scrotal hypopigmentation

Onset-independent ^[1]

Features listed here are suggestive of postpubertal onset male hypogonadism but may also manifest in individuals with prepubertal onset.

• Decreased male-type body hair (e.g., facial, chest); often severe
• Decreased libido
• Loss of morning erections
• Hot flashes
• Gynecomastia
• Azoospermia or oligospermia
• Reduction in height of > 6 cm ^[1]
• Osteoporotic fractures
• Unexplained anemia

Non-specific features ^[1]

• Erectile dysfunction
• Decreased muscle mass
• Gynoid fat distribution (e.g., around the hips and buttocks)
• Fatigue or low energy
• Depressed mood

Approach ^[1]

• Obtain a fasting morning total serum testosterone level in individuals with clinical features of male hypogonadism.
  • Confirm the diagnosis with a repeat level if the first level is low.
  • Measure LH and FSH levels in individuals with confirmed hypogonadism.
• Evaluate medical and family history to assess for possible causes (see “Etiology of male hypogonadism”).
• Perform additional laboratory and/or imaging studies to determine the cause.
• Consult an endocrinologist for patients with equivocal initial studies.

Screening asymptomatic individuals for low testosterone levels is not recommended. ^[1]

Laboratory studies ^[1][5][6]

Initial studies

• Fasting morning total serum testosterone
  • Obtain for all patients within 2 hours of waking.
  • Repeat on two separate occasions for most patients. ^[1]
  • 264 ng/dL is the standard lower limit of normal. ^[1][5]
• Free serum testosterone
  • Obtain for patients with either:
    • Borderline total testostrone levels
    • Factors that affect SHBG levels (e.g., obesity, type 2 DM, chronic liver disease).
  • Reference ranges vary by laboratory; refer to local ranges. ^[5]
• Gonadotropins
  • Obtain for all patients after confirming hypogonadism
  • ↑ LH and ↑ FSH: indicates primary hypogonadism
  • ↓ LH and ↓ FSH (or inappropriately normal LH and FSH): indicates secondary hypogonadism

Additional studies

Obtain the following studies as clinically indicated after confirming hypogonadism.

• CBC: in all patients to assess for normochromic, normocytic anemia. ^[1][5]
• Prolactin: in patients with secondary hypogonadism to rule out hyperprolactinemia
• Karyotyping: in patients with primary hypogonadism (e.g., to rule out Klinefelter syndrome)
• Genetic testing: in patients with a suspected genetic cause based on medical history (e.g., history of anosmia in Kallmann syndrome)
• Iron studies: in patients with clinical features of hemochromatosis or secondary iron overload ^[3]
• Pituitary hormones (e.g., ACTH stimulation test, free thyroxine): in patients with clinical features of hypopituitarism ^[5]
• Semen analysis: in patients with concerns about infertility and/or to assess baseline fertility

Imaging ^[1][5]

• Pituitary MRI in patients with any of the following:
  • Features of mass effect (e.g., visual field defect)
  • Hyperprolactinemia
  • Hypopituitarism or other pituitary hormone abnormalities (in addition to LH and/or FSH)
  • Total serum testosterone < 150 ng/dL ^[1][5]
• Bone densitometry: for patients with organic hypogonadism to assess fracture risk
• Testicular ultrasound: Consider ultrasound if the patient has a palpable testicular mass or if the testes are not palpable.

General principles ^[1]

• Functional hypogonadism is managed with lifestyle modifications (e.g., sleep hygiene) and/or treatment of the underlying condition.
• Testosterone therapy is indicated for patients with organic male hypogonadism; See “Etiology of male hypogonadism.” ^[6][7]
• Use of testosterone for age-related testosterone decline is off-label. ^[7]
• Patients receiving testosterone therapy require frequent follow-up and monitoring.

Functional male hypogonadism is not an approved indication for testosterone therapy.

Testosterone therapy ^[1][5]

Formulations

The formulation used depends on patient preference, drug availability, and cost.

• Injectable (most common), e.g.:
  • Testosterone enanthate
  • Testosterone cypionate
  • Testosterone undecanoate
• Transdermal
  • Testosterone gel
  • Testosterone solution
• Other, e.g.: oral testosterone, buccal tablets, nasal gel, or subcutaneous implants

IM administration of testosterone causes more fluctuations in mood and libido than topical formulas. ^[5]

Contact with topical testosterone can cause virilization in women and children.

Contraindications ^[1][5]

• Prostate cancer
• Palpable prostate nodule
• PSA > 4 ng/mL or > 3 ng/mL in patients with a high risk of prostate cancer
• Breast cancer
• Baseline erythrocytosis or thrombophilia
• Desire for fertility in the next 6–12 months ^[5]
• Uncontrolled heart failure
• Uncontrolled sleep apnea
• Severe lower urinary tract symptoms
• MI or stroke within the past 6 months

Individuals with male hypogonadism who are at increased risk of prostate cancer should weigh the risks and benefits of testosterone therapy using shared decision-making with their physician.

Monitoring during treatment ^[1][5]

• Frequency
  • 3–12 months after initiating therapy ^[5]
  • Then annually ^[5]
• Assess
  • Symptom control
  • Complications of testosterone therapy (e.g., erythrocytosis, ↑ PSA).
  • Total serum testosterone level (target is mid-normal range)

Chronic complications ^[8]

• Osteoporosis
• Infertility
• Erectile dysfunction
• Normocytic anemia
• Depression
• Obesity
• Metabolic syndrome
• Type 2 diabetes
• ASCVD

Complications of testosterone therapy ^[1][5]

• ↑ PSA (i.e., PSA > 4 ng/mL or increase of ≥ 1.5 ng/mL from baseline) ^[5]
  • Monitor PSA and perform a DRE 3 months and 12 months after initiation of testosterone therapy for patients at increased risk of prostate cancer, e.g.: ^[5]
    • Age ≥ 40 years with family history of prostate cancer and/or African American race
    • Age 55–69 years
  • Refer for urological evaluation if PSA levels are elevated or a prostate abnormality is detected on DRE.
  • Resume individualized prostate cancer screening if PSA levels are stable after 1 year of testosterone therapy.
• Erythrocytosis
  • Monitor Hct at baseline, 3–6 months after initiating therapy, and annually thereafter.
  • Hct > 54% ^[5]
    • Withhold therapy until Hct normalizes, and then reduce the dose or decrease the frequency of administration.
    • Assess for other causes of erythrocytosis (e.g., hypoxemia, OSA, smoking, obesity).
• Formulation-specific adverse effects: Assess at every visit.

We list the most important complications. The selection is not exhaustive.