Hypogonadism, Male

Essentials of Diagnosis

• Diminished libido and erections

• Fatigue, depression, reduced exercise endurance

• Decreased growth of body hair

• Small or normal testes; low serum total testosterone or free testosterone level

• Luteinizing hormone (LH) and follicle-stimulating hormone (FSH)

  • Low or normal in hypogonadotropic hypogonadism (insufficient gonadotropin secretion by pituitary)

  • Increased in testicular failure (hypergonadotropic hypogonadism)

General Considerations

• Caused by deficient testosterone secretion by the testes

• In hypogonadotropic form, FSH and LH deficiency may be isolated or accompanied by other pituitary hormone abnormalities

Hypogonadotropic hypogonadism (Low testosterone with normal or low LH)

• Causes (Table 26–12) can be primary (failure to enter puberty by age 14) or acquired

• Causes of acquired hypogonadotropic hypogonadism include

  • Pituitary or hypothalamic tumors

  • Granulomatous diseases

  • Lymphocytic hypophysitis

  • Cushing syndrome

  • Adrenal insufficiency

  • Thyroid hormone excess or deficiency

  • Hemochromatosis

  • Estrogen-secreting tumor (testicular, adrenal)

  • Chronic illness or malnourishment

  • Kallmann syndrome

  • Idiopathic or associated with normal aging or obesity

Hypergonadotropic hypogonadism (Testicular Failure with high LH)

• Causes (Table 26–12)

  • Male climacteric (andropause)

  • Klinefelter syndrome: at least one Y chromosome and at least two X chromosomes (47,XXY et al)

  • Orchitis, eg, mumps, gonorrhea, tuberculosis, leprosy

  • Testicular failure secondary to radiation therapy or chemotherapy

  • Autoimmune, uremia, testicular trauma or torsion, lymphoma, myotonic dystrophy, androgen insensitivity

Symptoms and Signs

• Delayed puberty if congenital or acquired during childhood

• Decreased libido with acquired hypogonadism in most

• Erectile dysfunction, hot sweats, fatigue, or depression

• Infertility, gynecomastia, headache (if pituitary tumor)

• Decreased body, axillary, beard, or pubic hair but only after years of severe hypogonadism

• Loss of muscle mass and weight gain due to increased subcutaneous fat

• Testicular size, as assessed with orchidometer, may decrease but usually remains normal in length (> 6 cm) in postpubertal hypogonadotropic hypogonadism

• In Klinefelter syndrome, manifestations are variable

  • Generally, testes normal in childhood, but usually become small, firm, fibrotic, and nontender in adolescence

  • Normal onset of puberty, variable degree of virilization, gynecomastia at puberty, tall stature with increased arm span

  • Patients with > 2 X or > 1 Y chromosomes are more prone to mental deficiency, clinodactyly, synostosis, poor social skills

• Testicular mass (Leydig cell tumor), trauma, infiltrative lesions (eg, lymphoma), or chronic infection (eg, leprosy, tuberculosis)

• Osteoporosis and fractures in chronic hypogonadism

Differential Diagnosis

• Erectile dysfunction due to other cause

  • Diabetes mellitus

  • Atherosclerosis

  • Stroke

  • Drugs

• Male infertility due to other cause

  • Cryptorchism

  • Retrograde ejaculation

• Gynecomastia due to other cause

  • Puberty

  • Chronic liver disease

  • Drugs

  • Malignancy

• Hypothyroidism (may also cause hypogonadism)

• Depression

Laboratory Tests

• Normal ranges for serum testosterone have been derived from nonfasting morning blood specimens, which tend to be the highest of the day

• Later in the day, serum testosterone levels can be 25–50% lower

• Therefore, a serum testosterone drawn fasting or late in the day may be misleadingly below the "reference range"

• Testosterone highest at age 20–30 years, slightly lower at 30–40 years; falls gradually but progressively after age 40

• After age 40, serum total testosterone declines variably by an average of 1–2% annually; serum free testosterone levels decline even faster, since sex hormone–binding globulin increases with age

• Check serum LH and FSH levels if serum testosterone is low or borderline low

• LH and FSH high in hypergonadotropic hypogonadism and low or inappropriately normal in hypogonadotropic hypogonadism

Hypogonadotropic hypogonadism

• Check serum prolactin: elevated in prolactinoma

• If gynecomastia, check serum androstenedione and estrone: both elevated in partial 17-ketosteroid reductase deficiency

• Check serum estradiol: elevated in cirrhosis and rare estrogen-secreting tumors (testicular Leydig cell tumor or adrenal carcinoma)

• If no clear cause for hypogonadotropic hypogonadism, check serum ferritin: elevated in hemochromatosis

Hypergonadotropic hypogonadism

• Check karyotyping or measurement of leukocyte X-inactive-specific transcriptase (XIST) for Klinefelter syndrome

Imaging Studies

• Adult men with hypogonadotropic hypogonadism should have an MRI of the pituitary/hypothalamus to search for a mass lesion in presence of one or more of the following:

  • Severe hypogonadism (serum testosterone below 150 ng/mL or 5.2 nmol/L);

  • Elevated serum PRL

  • Other pituitary hormone deficiencies

  • Symptoms of a mass lesion (headaches or visual field deficits)

• Bone densitometry: reduced bone density in long-standing male hypogonadism

Diagnostic Procedures

• Testicular biopsy is usually reserved for younger patients when reason for primary hypogonadism is unclear

• Significant weight loss improves serum testosterone levels when hypogonadotropic hypogonadism is due to morbid obesity

Medications

• Testosterone replacement is usual treatment

  • Reasonable for boys who have not entered puberty by age 14 years

  • Beneficial for most men with primary testicular failure (hypergonadotropic hypogonadism)

  • Warranted for men with severe hypogonadotropic hypogonadism of any etiology with serum testosterone levels < 150 ng/mL (5.2 nmol/L)

  • For other men without elevated serum LH levels and an average of at least two morning serum total testosterone levels below 275 ng/dL (9.5 nmol/L, "physiologic hypogonadism")

  • Consider in men if they have at least three of the following six symptoms:

    • Erectile dysfunction

    • Poor morning erection

    • Low libido

    • Depression

    • Fatigue

    • Inability to perform vigorous activity

  • Due to concerns about cardiovascular outcomes, testosterone therapy should be used for age-related hypogonadism only when low serum total or free testosterone is documented

  • Avoid in men with active breast cancer or prostate cancer

• Screen older men for prostate cancer before initiating testosterone therapy

• Topical testosterone

  • Usually applied once daily in the morning after showering

  • Should not be applied to the breasts or genitals

  • Testosterone topical generic 1% gel

    • Available in packets (12.5 mg/1.25 g, 25 mg/2.5 g, or 50 mg/5g) or tubes (50 mg/5 g)

    • Recommended dose is 50–100 mg/day

  • Testosterone topical generic 2% gel

    • Available in a gel pump (10 mg/0.5 g actuation)

    • Recommended dose is 40–70 mg/day

  • Androgel 1% gel

    • Available in 2.5-g packets (25 mg testosterone) and 5-g packets (50 mg testosterone) and in a pump that dispenses 12.5 mg testosterone per pump actuation

    • Recommended dose is 50-100 mg applied daily to the shoulders

  • Androgel 1.6% gel

    • Available in a pump that dispenses 20.25 mg testosterone per pump actuation

    • Recommended dose is 40.5-81 mg daily

  • Testim 1% gel

    • Available in 5-g tubes (50 mg testosterone)

    • Recommended dose is 50–100 mg daily

  • Fortesta 2% gel

    • Available in a pump that dispenses 10 mg testosterone per pump actuation

    • Recommended dose is 40–70 mg daily

  • Testogel

    • Distributed in 5-g sachets (50 mg testosterone)

    • Not available in the United States

  • Axiron 2% solution

    • Available in a pump that dispenses 30 mg per actuation

    • Recommended dose is 30–60 mg applied to each axilla daily

  • Vogelxo 1% testosterone gel

    • Available in packets or tubes (50 mg/5 g) or a gel pump (12.5 mg/1.25 g)

    • Applied to the shoulders in doses of 50–100 mg once daily.

• Transdermal testosterone patch

  • Androderm

    • 2 or 4 mg/day may be applied at bedtime in doses of 4–8 mg; adheres tightly but may cause skin irritation

    • Applied once daily to different nongenital skin sites

• Parenteral testosterone

  • Testosterone cypionate

    • Usual dose is 200 mg every 2 weeks or 300 mg every 3 weeks intramuscularly

    • Usually injected into the gluteus medius muscle in the upper lateral buttock, alternating sides

    • Adjust dose per patient response

  • Testosterone pellets (Testopel)

    • A long-lasting depot testosterone formulation

    • Available as individual vials containing a single 75 mg implantable pellet in each vial

    • The pellets are injected subcutaneously in doses of 150–450 mg every 3–6 months as an in-office procedure

  • Testosterone undecanoate (Aveed, Nebido)

    • Aveed: vials contain 750 mg/3 mL oily solution; initial injection of 750 mg is followed by another 750 mg injection 4 weeks later and maintenance doses of 750 mg every 10 weeks

    • Nebido: vials contain 1000 mg/4 mL oily solution; initial injection of 1000 mg followed by another 1000 mg injection 6 weeks later and maintenance doses of 1000 mg every 12 weeks

    • Caution: Testosterone undecanoate injections have caused serious pulmonary oil microembolism reactions that present with cough, dyspnea, tight throat, chest pain, and syncope. Anaphylaxis can also occur. Patients must be observed in the healthcare setting for 30 minutes after the injection in order to provide appropriate medical care for the complication

• Testosterone buccal tablets (Striant)

  • Place between the upper lip and gingivae

  • One or two 30-mg tablets are thus retained and changed every 12 hours

  • Tablets should not be chewed or swallowed

• Testosterone nasal gel

  • Self-administered by a metered-dose nasal pump

    • One pump actuation (5.5 mg) into each nostril three times daily

    • Pump needs to be primed by inverting it and pressing the pump 10 times before it is used the first time

  • Should not be used concurrently with intranasal sympathomimetic decongestants

  • Adverse effects include nasopharyngitis, sinusitis, bronchitis, epistaxis, nasal discomfort, and headache

• Oral methyltestosterone

  • Usual dose is 10–50 mg daily, given either once daily or given in divided doses

  • Can produce acute hepatitis and prolonged high-dose use can cause peliosis hepatis, cholestatic hepatitis, and hepatocellular carcinoma

  • Therefore, its use is not recommended and it no longer available in some countries

• Clomiphene citrate

  • Dosing started with 25 mg on alternate days and increased to 50 mg on alternate days if necessary, with a maximum dose of 50 mg daily

  • Men with functional hypogonadotropic hypogonadism usually respond well to doses that are titrated to achieve a serum testosterone level of about 500 ng/dL (17.3 nmol/L)

• Gonadotropins

  • Patients with infertility associated with hypogonadotropic hypogonadism may require therapy hCG 1000 units subcutaneously three times weekly for 6 months

  • If the semen analysis shows inadequate sperm, add FSH 75 units subcutaneously three times weekly

Therapeutic Procedures

• Men with mosaic Klinefelter syndrome (eg, 46,XY/47,XXY) may be fertile

• Otherwise, infertility may be overcome by in vitro intracytoplasmic sperm injection (ICSI) into an ovum

Follow-Up

• Reassess patient clinically and measure serum testosterone after initiation of testosterone replacement

• If clinical response is inadequate or serum testosterone is below normal, increase dose

• Monitor hematocrit due to risk of polycythemia

Complications

• Complication of hypogonadism: osteoporosis

• Complications of Klinefelter syndrome

  • Neoplasms, including breast cancer

  • Chronic pulmonary disease

  • Varicosities of the legs

  • Diabetes mellitus (8%)

  • Impaired glucose tolerance without frank diabetes (19%)

• Side effects of testosterone replacement

  • Acne

  • Gynecomastia

  • Aggravation of sleep apnea

  • Reduced HDL cholesterol

  • Erythrocytosis

• Side effects of oral androgens: cholestatic jaundice (1–2%), and peliosis hepatis or hepatocellular carcinoma rarely with long-term use

Prognosis

• Prognosis of hypogonadism due to pituitary lesion is that of primary disease (eg, tumor, necrosis)

• Prognosis for restoration of virility is good if testosterone replacement is given

• In one large study, cardiovascular risk was reduced in hypogonadal men over age 40 who received testosterone replacement therapy to maintain serum testosterone levels within the normal reference range