Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 26-29: Male Hypogonadism + Key Features Download Section PDF Listen +++ +++ 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 ++Table Graphic Jump LocationTable 26–12.Causes of male hypogonadism.View Table||Download (.pdf) Table 26–12. Causes of male hypogonadism. Hypogonadotropic (Low or Normal LH) Hypergonadotropic (High LH) Aging Alcohol Chronic illness Congenital syndromes Constitutional delay of growth and puberty Cushing syndrome Drugs Estrogen GnRH agonist (leuprolide) Ketoconazole Marijuana Prior androgens Spironolactone Granulomatous diseases Hemochromatosis Hypopituitarism Hypothalamic or pituitary tumors Hypothyroidism, hyperthyroidism Idiopathic Kidney disease Lymphocytic hypophysitis Major medical or surgical illnesses Malnourishment Obesity (BMI > 30 kg/m2) Aging Autoimmunity Anorchia (bilateral) Chemotherapy Idiopathic Klinefelter syndrome Leprosy Lymphoma Male climacteric Myotonic dystrophy Noonan syndrome Orchiectomy (bilateral or unilateral) Orchitis Radiation or radioisotope therapy Sertoli cell-only syndrome Testicular trauma Tuberculosis Uremia Viral infections (mumps) BMI, body mass index; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone. +++ 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 + Clinical Findings Download Section PDF Listen +++ +++ 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 + Diagnosis Download Section PDF Listen +++ +++ 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 + Treatment Download Section PDF Listen +++ ++ 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 + Outcome Download Section PDF Listen +++ +++ 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 + References Download Section PDF Listen +++ + +Bhasin S et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018 May 1;103(5):1715–44. [PubMed: 29562364] + +Budoff MJ et al. Testosterone treatment and coronary artery plaque volume in older men with low testosterone. JAMA. 2017 Feb 21;317(7):708–16. [PubMed: 28241355] + +Cheetham TC et al. Association of testosterone replacement with cardiovascular outcomes among men with androgen deficiency. JAMA Intern Med. 2017 Apr;177(4):491–9. [PubMed: 28241244] + +Diem SJ et al. Efficacy and safety of testosterone treatment in men: an evidence report for a clinical practice guideline by the American College of Physicians. Ann Intern Med. 2020 Jan 7. [Epub ahead of print] [PubMed: 31905375] + +Dubruyne FM et al. Testosterone treatment is not associated with increased risk of prostate cancer or worsening of lower urinary tract symptoms: prostate health outcomes in the Registry of Hypogonadism in Men. BJU Int. 2017 Feb;119(2):216–24. [PubMed: 27409523] + +Elagizi A et al. Testosterone and cardiovascular health. Mayo Clin Proc. 2018 Jan;93(1):83–100. [PubMed: 29275030] + +Grossmann M et al. A perspective on middle-aged and older men with functional hypogonadism: focus on holistic management. J Clin Endocrinol Metab. 2017 Mar;102(3):1067–75. [PubMed: 28359097] + +Lo EM et al. Alternatives to testosterone therapy: a review. Sex Med Rev. 2018 Jan;6(1):106–13. [PubMed: 29174957] + +Salter CA et al. Guideline of guidelines: testosterone therapy for testosterone deficiency. BJU Int. 2019 Nov;124(5):722–9. [PubMed: 31420972] + +Snyder PJ et al; Testosterone Trials Investigators. Effects of testosterone treatment in older men. N Engl J Med. 2016 Feb 18;374(7):611–24. [PubMed: 26886521] + +Travison TG et al. Harmonized reference ranges for circulating testosterone levels in men of four cohort studies in the United States and Europe. J Clin Endocrinol Metab. 2017 Apr 1;102(4):1161–73. [PubMed: 28324103] + +Yeap BB et al. Testosterone treatment in older men: clinical implications and unresolved questions from the testosterone trials. Lancet Diabetes Endocrinol. 2018 Aug;6(8):659–72. [PubMed: 30017800]