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Endocrinology - Male Hypogonadism - Fast Facts | NEJM Resident 360

Male hypogonadism refers to a decrease in one or both major functions of the testes — sperm production and testosterone production. The condition reflects the disruption of the hypothalamic–pituitary–gonadal axis: Pulsatile release of gonadotropin-releasing hormone (GnRH) every 60–90 minutes stimulates pulsatile release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary into the blood stream. These hormones then stimulate production of testosterone (LH on Leydig cells) and spermatogenesis (FSH on Sertoli cells). Normally, the testes produce approximately 3–10 mg of testosterone daily. In male hypogonadism, the body does not produce enough testosterone or sperm. In this review, we discuss:

• Classification

• Presentation

• Diagnosis

• Treatment

Classification

Classification of hypogonadism is important when determining appropriate treatment and assessing fertility status. Hypogonadism can be classified as:

• primary hypogonadism or hypergonadotropic hypogonadism (testes are primarily affected)

• secondary hypogonadism or hypogonadotropic hypogonadism (pituitary axis is affected)

Causes of Hypogonadism

	Primary Hypogonadism	Secondary Hypogonadism
Inherited

• Klinefelter syndrome (most common)

• Y-chromosome microdeletions

• Cryptorchidism

|

• Anosmic idiopathic hypogonadotropic hypogonadism (Kallmann syndrome)

• Normosmic idiopathic hypogonadotropic hypogonadism

• Prader–Willi syndrome

• Laurence–Moon syndrome (autosomal recessive), mutations in leptin +/– receptor

| | Acquired |

• Infectious (mumps, echovirus)

• Radiation

• Medications (ketoconazole, spironolactone, glucocorticoids, alkylating chemotherapy)

• Varicocele

• Trauma

• Hemochromatosis

• Alcohol intake

|

• Stress, critical illness

• Radiation

• Malnutrition

• Excessive exercise

• Hyperprolactinemia

• Obesity

• Hemochromatosis

• Chronic opioids

• Trauma

|

Presentation

Clinical signs and symptoms of hypogonadism are nonspecific and include:

• decreased libido

• decreased spontaneous erections

• fatigue

• hot flashes

• depressed mood

• difficulty with concentration

• decreased muscle mass

Diagnosis

• Diagnosis is based on clinical signs and symptoms of hypogonadism.

• Low serum testosterone should be checked in the morning and repeated on two occasions to confirm low levels:

• • Testosterone secretion peaks in the morning but is blunted in men aged 60 years and older.

  • Total serum includes testosterone bound to albumin, sex hormone–binding globulin, and free testosterone (0.5%–2%).

  • Bioavailable testosterone includes testosterone loosely bound to albumin and free testosterone.

• Men should not be routinely screened for hypogonadism without clinical signs and symptoms.

Diagnosis of Male Hypogonadism

(Source: Male Hypogonadism. Lancet 2014.)

Treatment

• In patients with confirmed hypogonadism, testosterone replacement therapy can be initiated to maintain secondary sexual characteristics, sexual function, and quality of life.

• Before starting treatment, patients should be assessed clinically for prostate cancer risk and obstructive sleep apnea symptoms. Laboratory evaluation should include prostate-specific antigen (PSA) and hematocrit.

• Choosing a testosterone formulation will depend on patient preference.

Examples of Testosterone-Replacement Therapy

Drug	Advantages	Disadvantages	Cost (per month)
Injectable
Testosterone cypionate
and
Testosterone enanthate	Inexpensive,
corrects hypogonadal symptoms,
usually self-administered	Highly variable
pharmacokinetics,
fluctuations in libido
and mood,
coughing episodes
after injection,
polycythemia (mainly in
elderly men),
contraindicated in patients
with bleeding disorders	<$100
Testosterone undecanoate	Administered every 3 months,
stable levels,
corrects hypogonadal
symptoms	Risk of pulmonary oil microembolism,
needs administration in
a healthcare setting,
polycythemia,
contraindicated in patients
with bleeding disorders,
only available to certified
prescribers through a REMS
program because of the
risk of serious pulmonary
oil microembolism reactions
and anaphylaxis	$100–1000
Implant
Testosterone	Corrects hypogonadal symptoms	Requires surgical incision,
possibility of infection,
risk of spontaneous
pellet extrusion,
fibrosis	$100–1000
Transdermal
Testosterone gel
(1%, 1.62%, 2%)	Convenient,
mimics circadian rhythm,
corrects hypogonadal symptoms,
good skin tolerability	Potential transfer to
partners or children,
skin irritation
(but affects <10% of men),
supraphysiological
dihydrotestosterone
concentrations,
need to cover application
site and wash hands
after application	$100–1000
Testosterone patch	Convenient,
mimics circadian rhythm,
corrects hypogonadal
symptoms	Problems with adherence
due to sweating,
skin irritation
(up to 66% of men)	$100–1000
Testosterone solution	Corrects hypogonadal symptoms,
physiological testosterone
concentrations achievable	Skin irritation,
erythema 5–7% of men	$100–1000
Intranasal
Testosterone gel	Corrects hypogonadal symptoms,
no injection,
no concern for transfer,
rapid absorption and
avoidance of first-pass
metabolism	Nasal irritation,
administration 2 or 3 times daily,
limited ability to adjust dose to
achieve therapeutic testosterone levels	$100–1000
Oral
Testosterone undecanoate	Oral administration,
corrects hypogonadal
symptoms	Twice-daily dosing,
worsening of hypertension,
liver abnormalities
(with older oral testosterone formulations)	$100–1000

(References: Jatenzo – An Oral Testosterone for Hypogonadism. The Medical Letter 2021 and Male Hypogonadism. Lancet 2014.)

• The effect of testosterone on cardiovascular events is uncertain due to limited randomized controlled data.

• Testosterone therapy causes erythrocytosis through several mechanisms: It stimulates bone-marrow production and erythropoietin production, and it suppresses hepcidin, which increases iron availability.

• The prostate is an androgen-dependent tissue, but no association has been reported between testosterone therapy and prostate cancer.

• Testosterone therapy inhibits spermatogenesis. This should be considered in men with low testosterone who are interested in starting a family in the near future.

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