37-Year-Old Man With Fatigue and Erectile Dysfunction

Abstract

A 37-year-old man presented to the primary care clinic with fatigue, subjective muscle weakness, erectile dysfunction, and decreased libido of several months' duration. These symptoms had progressively worsened over several months. He also reported poor morning erections, decreased motivation, loss of interest in activities he previously found enjoyable, depression, anxiety, sleep disturbance, and snoring. He reported no weight changes, headaches, or vision changes. His medical history was notable for generalized anxiety, gastroesophageal reflux disease, and long-standing obesity. On physical examination, his blood pressure was 133/86 mm Hg, heart rate was 73 beats/min, and body mass index was 39 kg/m2. His weight had increased 7 kg over 2 years but had been stable for 6 months. Cardiovascular, respiratory, abdominal, and neurologic (including cranial nerve, strength, and sensory) examination results were unremarkable. Neck circumference was 45 cm, and the oropharynx was rated as Mallampati class II. The thyroid gland was nonenlarged, nontender, and had no palpable nodules. The testicles were nontender with normal firmness and size and measured 20 cc bilaterally, with no testicular masses or inguinal hernias noted. The patient's prostate gland was normal in size and morphology. His score on the Patient Health Questionnaire-9 depression screen was 11, indicating moderate depression. Laboratory evaluation revealed the following (reference ranges provided parenthetically): hemoglobin, 14.3 g/dL (13.2-16.6 g/dL); hematocrit, 43.2% (38.3%-48.6%); hemoglobin A1c, 5.2% (4.0%-5.6%); and creatinine, 0.9 mg/dL (0.74-1.35 mg/dL). Results of liver function testing and a lipid panel were normal. The total testosterone level, checked at 8:20 am, was 168 ng/dL (240-950 ng/dL). On further questioning, the patient described decreased body hair with less frequent shaving over the preceding several months. He reported normal onset of puberty and development and had 2 biologic children who were conceived with no difficulty. He had no anosmia, previous testicular injury, mumps, local radiation, or current/recent opioid, anabolic steroid, or supplement use. The patient and his wife were not planning to have more children.1.Which one of the following would be the best next step in the diagnostic evaluation of this patient's symptoms?a.Thyrotropin measurementb.Karyotype determinationc.Total and bioavailable testosterone evaluationd.Total testosterone measuremente.No further testing The body hair loss, erectile dysfunction, decreased libido, fatigue, and depression are consistent with testosterone deficiency (hypogonadism).1Araujo A.B. Esche G.R. Kupelian V. et al.Prevalence of symptomatic androgen deficiency in men.J Clin Endocrinol Metab. 2007; 92: 4241-4247Crossref PubMed Scopus (541) Google Scholar, 2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar Diagnosis of male hypogonadism requires signs and/or symptoms of hypogonadism and confirmation of low testosterone levels twice on laboratory testing.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 3Mulhall J.P. Trost L.W. Brannigan R.E. et al.Evaluation and management of testosterone deficiency: AUA guideline.J Urol. 2018; 200: 423-432Crossref Scopus (330) Google Scholar If hypogonadism is confirmed, additional testing, including thyrotropin measurement or karyotype determination, may be indicated. However, these tests are premature at this point in the evaluation. Circulating testosterone can be free or bound to albumin, sex hormone–binding globulin (SHBG), or other binding proteins.4Mammi C. Calanchini M. Antelmi A. et al.Androgens and adipose tissue in males: a complex and reciprocal interplay.Int J Endocrinol. 2012; 2012: 789653Crossref PubMed Scopus (72) Google Scholar Bioavailable testosterone includes free testosterone and testosterone bound with low affinity, primarily to albumin. Sex hormone–binding globulin binds testosterone with high affinity and is affected by a variety of health conditions; measuring bioavailable and/or free testosterone in addition to total testosterone is therefore necessary to establish the diagnosis of hypogonadism.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 5Saboor Aftab S.A. Kumar S. Barber T.M. The role of obesity and type 2 diabetes mellitus in the development of male obesity-associated secondary hypogonadism.Clin Endocrinol (Oxf). 2013; 78: 330-337Crossref PubMed Scopus (95) Google Scholar The SHBG level may be lowered by obesity, diabetes, anabolic or corticosteroid use, hypothyroidism, and nephrotic syndrome and increased with aging, human immunodeficiency virus, cirrhosis, hepatitis, hyperthyroidism, and some anticonvulsant medications. Because this patient was obese, either free or bioavailable testosterone measurement is necessary to evaluate for hypogonadism. Bioavailable testosterone, if feasible, is preferred because free testosterone measurements can vary widely between laboratories.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar No further testing or repeating total testosterone measurement alone would be insufficient. Repeated total and bioavailable testosterone measurements, checked at 7:45 am, were 136 ng/dL and 53 ng/dL (72-235 ng/dL), respectively, confirming the diagnosis of hypogonadism.2.Which one of the following should be considered as the next step in the evaluation of this patient's low testosterone?a.Luteinizing hormone (LH) and follicle-stimulating hormone (FSH)b.Semen analysisc.Prolactind.Iron saturatione.Overnight oximetry After confirming a diagnosis of hypogonadism, the next step is to determine whether it is primary or secondary,2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 3Mulhall J.P. Trost L.W. Brannigan R.E. et al.Evaluation and management of testosterone deficiency: AUA guideline.J Urol. 2018; 200: 423-432Crossref Scopus (330) Google Scholar which is achieved by measuring LH and FSH concentrations. Notably, these hormones can be artificially elevated or decreased by biotin; supplements containing biotin should be discontinued 72 hours before testing.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar If there are fertility concerns, semen analysis should be obtained on 2 occasions several weeks apart.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar Because this patient was not concerned about fertility and had no evidence of prior infertility, semen analysis is unnecessary. Primary hypogonadism is caused by disorders of the testes and presents with elevated LH and FSH levels. Causes include Klinefelter syndrome, other chromosomal abnormalities, cryptorchidism, anorchia, testicular radiation, chemotherapy, testicular trauma/torsion, aging, and androgen synthesis inhibitors.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 6Grossmann M. Matsumoto A.M. A perspective on middle-aged and older men with functional hypogonadism: focus on holistic management.J Clin Endocrinol Metab. 2017; 102: 1067-1075Google Scholar Therefore if LH and FSH levels are elevated, a karyotype should be obtained.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar Additional testing should be guided by patient history and risk factors. In secondary hypogonadism, LH and FSH concentrations are low or inappropriately normal. Secondary hypogonadism can be idiopathic or caused by pituitary tumor, iron overload, infiltrative hypothalamic/pituitary disease, hyperprolactinemia, systemic illness, excessive exercise, obesity, sleep disorders, organ failure, and a wide range of medications, drugs, and supplements such as opioids, anabolic or corticosteroids, alcohol, and cannabis.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 6Grossmann M. Matsumoto A.M. A perspective on middle-aged and older men with functional hypogonadism: focus on holistic management.J Clin Endocrinol Metab. 2017; 102: 1067-1075Google Scholar Initial evaluation of secondary hypogonadism includes measurement of serum prolactin level and iron saturation and/or ferritin concentration to evaluate for hyperprolactinemia and iron overload, respectively.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 3Mulhall J.P. Trost L.W. Brannigan R.E. et al.Evaluation and management of testosterone deficiency: AUA guideline.J Urol. 2018; 200: 423-432Crossref Scopus (330) Google Scholar Measurement of other pituitary hormones and other work-up is guided by history and examination. This patient's LH and FSH values were 1.4 IU/L (1.3-9.6 IU/L) and 2.9 IU/L (1.2-15.8 IU/L), respectively. We therefore proceeded with further evaluation for causes of secondary hypogonadism. Prolactin, ferritin, transferrin, and morning cortisol levels were normal, and human immunodeficiency virus and hepatitis B and C were absent. Polysomnography revealed mild obstructive sleep apnea (OSA). Pituitary magnetic resonance imaging (MRI) should be performed if pituitary hormone or visual field abnormalities exist. It is also indicated if the total testosterone level is less than 250 ng/dL for men younger than 40 years old or less than 150 ng/dL for men 60 years or older if there is no apparent cause of secondary hypogonadism.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 3Mulhall J.P. Trost L.W. Brannigan R.E. et al.Evaluation and management of testosterone deficiency: AUA guideline.J Urol. 2018; 200: 423-432Crossref Scopus (330) Google Scholar This patient's pituitary MRI revealed no abnormalities.3.Which one of the following is the most appropriate treatment for this patient's condition?a.No treatmentb.Intramuscular testosteronec.Weight lossd.Continuous positive airway pressure (CPAP) devicee.Clomiphene citrate Because this patient has symptomatic hypogonadism, treatment is indicated. Furthermore, hypogonadism can lead to various adverse health outcomes including decreased muscle mass, osteoporosis, anemia, and depression. Testosterone repletion can be accomplished through a variety of delivery methods, including intramuscular, transdermal, and implantable formulations. However, before initiation of testosterone replacement therapy, particularly when hypogonadism is not profound and a potentially reversible cause is identified, the best first course of action is to address the underlying cause(s). This patient was obese and had mild OSA, both of which may cause secondary hypogonadism. Although weight loss has been shown to improve testosterone levels, CPAP use has not.5Saboor Aftab S.A. Kumar S. Barber T.M. The role of obesity and type 2 diabetes mellitus in the development of male obesity-associated secondary hypogonadism.Clin Endocrinol (Oxf). 2013; 78: 330-337Crossref PubMed Scopus (95) Google Scholar, 6Grossmann M. Matsumoto A.M. A perspective on middle-aged and older men with functional hypogonadism: focus on holistic management.J Clin Endocrinol Metab. 2017; 102: 1067-1075Google Scholar, 7Zhang X.B. Jiang X.T. Du Y.P. Yuan Y.T. Chen B. Efficacy of continuous positive airway pressure on testosterone in men with obstructive sleep apnea: a meta-analysis.PloS One. 2014; 9: e115033Crossref Scopus (23) Google Scholar Therefore, weight loss is the best initial approach to this patient's hypogonadism. In addition to testosterone replacement, clomiphene citrate, a selective estrogen receptor modulator, may be an off-label option for functional secondary hypogonadism. It is hypothesized to increase LH and FSH levels, thereby stimulating testosterone production.6Grossmann M. Matsumoto A.M. A perspective on middle-aged and older men with functional hypogonadism: focus on holistic management.J Clin Endocrinol Metab. 2017; 102: 1067-1075Google Scholar, 8Bendre S.V. Murray P.J. Basaria S. Clomiphene citrate effectively increases testosterone in obese, young, hypogonadal men.Reprod Syst Sex Disord. 2015; 4: 155Crossref Google Scholar Prospective and retrospective observational studies of clomiphene citrate use among young men with secondary hypogonadism have found increases in total and free testosterone levels and symptom improvement with no major adverse effects.8Bendre S.V. Murray P.J. Basaria S. Clomiphene citrate effectively increases testosterone in obese, young, hypogonadal men.Reprod Syst Sex Disord. 2015; 4: 155Crossref Google Scholar, 9Katz D.J. Nabulsi O. Tal R. Mulhall J.P. Outcomes of clomiphene citrate treatment in young hypogonadal men.BJU Int. 2012; 110: 573-578Crossref PubMed Scopus (111) Google Scholar However, randomized control trials demonstrating safety/efficacy of clomiphene citrate are lacking, while adverse effects include thromboembolism, decreased libido, and decreased bone mineral density.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar This patient began CPAP therapy but had difficulty losing weight, and his symptoms persisted. We therefore readdressed the risks and benefits of pharmacological treatment for hypogonadism.4.Which one of the following would be an absolute contraindication to initiating testosterone replacement in this patient?a.Moderate OSAb.Family history of prostate cancerc.Cardiovascular diseased.Male pattern baldnesse.Desire for fertility in the near term The Endocrine Society guidelines recommend against testosterone replacement in men with breast or prostate cancer because these conditions carry high risk of serious adverse effects with exogenous testosterone replacement.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar Other contraindications to testosterone administration include unevaluated prostate nodule/induration, unevaluated prostate-specific antigen (PSA) elevation, elevated hematocrit, thrombophilia, untreated severe OSA, benign prostatic hypertrophy with severe lower urinary tract symptoms, uncontrolled heart failure, and myocardial infarction or stroke within the previous 6 months.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar Obstructive sleep apnea and benign prostatic hypertrophy are not absolute contraindications to testosterone therapy. Similarly, family history of prostate cancer should not preclude testosterone replacement in hypogonadal patients. The Endocrine Society guidelines recommend discussing prostate cancer risk and screening in hypogonadal men between the ages of 40 and 69 years who are at increased risk of prostate cancer.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar The American Urological Association recommends PSA measurement before initiation of testosterone therapy to avoid treating men with occult prostate cancer.3Mulhall J.P. Trost L.W. Brannigan R.E. et al.Evaluation and management of testosterone deficiency: AUA guideline.J Urol. 2018; 200: 423-432Crossref Scopus (330) Google Scholar Baseline hemoglobin and hematocrit measurements should be obtained before initiating testosterone therapy because high testosterone levels may cause erythrocytosis.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 3Mulhall J.P. Trost L.W. Brannigan R.E. et al.Evaluation and management of testosterone deficiency: AUA guideline.J Urol. 2018; 200: 423-432Crossref Scopus (330) Google Scholar Low testosterone concentration has been associated with increased incidence of major adverse cardiac events, but there has also been concern about increased cardiovascular events with testosterone replacement therapy such that the United States Food and Drug Administration requires labeling regarding possible increased risk.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 3Mulhall J.P. Trost L.W. Brannigan R.E. et al.Evaluation and management of testosterone deficiency: AUA guideline.J Urol. 2018; 200: 423-432Crossref Scopus (330) Google Scholar Currently, there are no randomized controlled trials determining the effect of testosterone replacement on cardiovascular mortality, and cardiovascular disease is not an absolute contraindication to testosterone administration.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 3Mulhall J.P. Trost L.W. Brannigan R.E. et al.Evaluation and management of testosterone deficiency: AUA guideline.J Urol. 2018; 200: 423-432Crossref Scopus (330) Google Scholar Testosterone therapy may also exacerbate male pattern baldness, and this adverse effect should be discussed before treatment initiation.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar However, baldness is not a contraindication to testosterone administration. Exogenous testosterone suppresses spermatogenesis and therefore is contraindicated in men desiring fertility in the near term.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 3Mulhall J.P. Trost L.W. Brannigan R.E. et al.Evaluation and management of testosterone deficiency: AUA guideline.J Urol. 2018; 200: 423-432Crossref Scopus (330) Google Scholar Men who desire future fertility may consider reproductive health evaluation and/or sperm banking because recovery of spermatogenesis after testosterone therapy is not well understood.3Mulhall J.P. Trost L.W. Brannigan R.E. et al.Evaluation and management of testosterone deficiency: AUA guideline.J Urol. 2018; 200: 423-432Crossref Scopus (330) Google Scholar Alternative strategies for patients with fertility concerns also include selective estrogen receptor modulators, aromatase inhibitors, or human chorionic gonadotropin.3Mulhall J.P. Trost L.W. Brannigan R.E. et al.Evaluation and management of testosterone deficiency: AUA guideline.J Urol. 2018; 200: 423-432Crossref Scopus (330) Google Scholar This patient had mild, treated OSA and has no desire for fertility in the future, so he had no absolute contraindications to testosterone replacement therapy.5.If this patient was to initiate testosterone replacement therapy, which one of the following factors or procedures should be monitored or performed?a.Cognitive functionb.Hematocritc.PSAd.Dual-energy x-ray absorptiometrye.Mammography Monitoring after initiation of testosterone replacement includes clinical evaluation at 3 to 12 months to assess response to therapy and adverse effects.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar In this patient, testosterone replacement would be expected to improve libido, erectile function, and lean body mass and may help with depression.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 3Mulhall J.P. Trost L.W. Brannigan R.E. et al.Evaluation and management of testosterone deficiency: AUA guideline.J Urol. 2018; 200: 423-432Crossref Scopus (330) Google Scholar The degree to which testosterone replacement improves cognitive function is uncertain, and since this patient had no cognitive complaints, cognitive monitoring is unnecessary. Adverse effects of testosterone replacement include erythrocytosis.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 5Saboor Aftab S.A. Kumar S. Barber T.M. The role of obesity and type 2 diabetes mellitus in the development of male obesity-associated secondary hypogonadism.Clin Endocrinol (Oxf). 2013; 78: 330-337Crossref PubMed Scopus (95) Google Scholar Testosterone and and hematocrit levels should be evaluated at 3 to 6 months, 12 months, and then annually after initiating testosterone replacement.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar If the hematocrit value increases to above 54%, therapy should be discontinued until it decreases to a safe level.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar Prostate cancer monitoring should be decided through shared decision making with the patient, and if decided upon, PSA and a digital rectal examination should be performed 3 to 12 months after therapy initiation and then per standard guidelines.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar This patient was not at elevated risk for prostate cancer and is only 37 years old; thus, PSA monitoring is not obligatory. Testosterone is not an approved treatment for osteoporosis, and hypogonadal men with osteoporosis should be treated with other approved therapies. This patient did not have known osteoporosis; therefore, bone mineral density testing is unnecessary. Similarly, he had no history of breast cancer and does not need a mammogram. Because the cause of this patient's hypogonadism (obesity) was thought to be reversible, clomiphene citrate, 25 mg/d, was initiated. After 1 month of treatment, he reported improved energy levels and return of morning erections. Total and bioavailable testosterone levels increased to 636 ng/dL and 375 ng/dL, respectively. His LH and FSH values normalized, and his weight decreased from 130.8 kg to 125.6 kg over 5 months. Clomiphene citrate was decreased to 25 mg twice weekly, and testosterone levels remained elevated, so clomiphene citrate was titrated down further. Because he had symptom relief and biochemical improvement with clomiphene citrate, testosterone replacement was not pursued. Erectile dysfunction, low testosterone levels, and questions about testosterone therapy are encountered frequently in clinical practice. The estimated prevalence of symptomatic hypogonadism in men is 5.6%, with 6.5 million American men projected to have symptomatic androgen deficiency by 2025.1Araujo A.B. Esche G.R. Kupelian V. et al.Prevalence of symptomatic androgen deficiency in men.J Clin Endocrinol Metab. 2007; 92: 4241-4247Crossref PubMed Scopus (541) Google Scholar Direct-to-consumer advertising of testosterone replacement products has contributed to greater awareness of hypogonadism as well as potentially inappropriate use of testosterone replacement among healthy middle-aged and older men.10Layton J.B. Kim Y. Alexander G.C. Emery S.L. Association between direct-to-consumer advertising and testosterone testing and initiation in the United States, 2009-2013.JAMA. 2017; 317: 1159-1166Crossref Scopus (70) Google Scholar Signs and symptoms consistent with testosterone deficiency include loss of body hair, erectile dysfunction, decreased libido, infertility, small testes, fatigue, decreased motivation, depression, sleep disturbance, breast discomfort, mild anemia, and low bone density.1Araujo A.B. Esche G.R. Kupelian V. et al.Prevalence of symptomatic androgen deficiency in men.J Clin Endocrinol Metab. 2007; 92: 4241-4247Crossref PubMed Scopus (541) Google Scholar, 2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar Loss of body hair and small testes are particularly specific for testosterone deficiency.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar The Endocrine Society guidelines recommend against screening for hypogonadism in asymptomatic men.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar Because testosterone levels vary in a diurnal manner and can be suppressed by glucose, it should be measured in the morning before eating.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 11Wittert G. The relationship between sleep disorders and testosterone.Curr Opin Endocrinol Diabetes Obes. 2014; 21: 239-243Crossref Scopus (44) Google Scholar A single testosterone measurement is not sufficient to diagnose hypogonadism, and up to 60% of patients with low testosterone levels on initial testing can have normal average testosterone levels with serial testing.12Brambilla D.J. O'Donnell A.B. Matsumoto A.M. McKinlay J.B. Intraindividual variation in levels of serum testosterone and other reproductive and adrenal hormones in men.Clin Endocrinol (Oxf). 2007; 67: 853-862Crossref PubMed Scopus (144) Google Scholar Sex hormone–binding globulin levels alter total testosterone levels, and in patients with SHBG-altering conditions, either free or bioavailable testosterone concentrations should be measured in addition to total testosterone to confirm the diagnosis of hypogonadism.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 5Saboor Aftab S.A. Kumar S. Barber T.M. The role of obesity and type 2 diabetes mellitus in the development of male obesity-associated secondary hypogonadism.Clin Endocrinol (Oxf). 2013; 78: 330-337Crossref PubMed Scopus (95) Google Scholar Bioavailable testosterone is preferred if available. Once the diagnosis of hypogonadism is confirmed, LH and FSH should be measured to determine whether it is primary or secondary.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 3Mulhall J.P. Trost L.W. Brannigan R.E. et al.Evaluation and management of testosterone deficiency: AUA guideline.J Urol. 2018; 200: 423-432Crossref Scopus (330) Google Scholar Primary (hypergonadotropic) hypogonadism is caused by disorders of the testes and results in high LH and FSH levels.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 6Grossmann M. Matsumoto A.M. A perspective on middle-aged and older men with functional hypogonadism: focus on holistic management.J Clin Endocrinol Metab. 2017; 102: 1067-1075Google Scholar A karyotype should be obtained to assess for Klinefelter syndrome if primary hypogonadism is diagnosed.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar Low or inappropriately normal LH and FSH levels signify secondary (hypogonadotropic) hypogonadism, which is caused by a wide range of conditions including pituitary disease, iron overload, opioids, anabolic and corticosteroids, sleep disorders, and obesity.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 6Grossmann M. Matsumoto A.M. A perspective on middle-aged and older men with functional hypogonadism: focus on holistic management.J Clin Endocrinol Metab. 2017; 102: 1067-1075Google Scholar If secondary hypogonadism is identified, serum prolactin and iron saturation and/or ferritin should be measured.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 3Mulhall J.P. Trost L.W. Brannigan R.E. et al.Evaluation and management of testosterone deficiency: AUA guideline.J Urol. 2018; 200: 423-432Crossref Scopus (330) Google Scholar Further work-up should be based on clinical context and patient assessment, and pituitary MRI should be obtained in men younger than 40 years old with total testosterone levels less than 250 ng/dL or men older than 60 years with total testosterone levels less than 150 ng/dL.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 3Mulhall J.P. Trost L.W. Brannigan R.E. et al.Evaluation and management of testosterone deficiency: AUA guideline.J Urol. 2018; 200: 423-432Crossref Scopus (330) Google Scholar The best treatment approach for secondary hypogonadism is to address the underlying cause. If testosterone deficiency is not easily reversible and the patient is symptomatic, there are a variety of formulations for testosterone repletion. Transdermal formulations such as gels, patches, and axillary solutions are easy to apply and provide dosing flexibility.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 3Mulhall J.P. Trost L.W. Brannigan R.E. et al.Evaluation and management of testosterone deficiency: AUA guideline.J Urol. 2018; 200: 423-432Crossref Scopus (330) Google Scholar Intramuscular and implantable formulations are also available. Choice of treatment regimen should be individualized based on patient preference, availability, and affordability. Clomiphene citrate has been used off-label for functional secondary hypogonadism and has been reported to be effective in small studies.6Grossmann M. Matsumoto A.M. A perspective on middle-aged and older men with functional hypogonadism: focus on holistic management.J Clin Endocrinol Metab. 2017; 102: 1067-1075Google Scholar, 8Bendre S.V. Murray P.J. Basaria S. Clomiphene citrate effectively increases testosterone in obese, young, hypogonadal men.Reprod Syst Sex Disord. 2015; 4: 155Crossref Google Scholar, 9Katz D.J. Nabulsi O. Tal R. Mulhall J.P. Outcomes of clomiphene citrate treatment in young hypogonadal men.BJU Int. 2012; 110: 573-578Crossref PubMed Scopus (111) Google Scholar However, further trials of its safety and efficacy are needed.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar Before initiating testosterone replacement therapy, clinicians should evaluate baseline hemoglobin and hematocrit levels and discuss prostate cancer and cardiovascular disease risk with their patients.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 3Mulhall J.P. Trost L.W. Brannigan R.E. et al.Evaluation and management of testosterone deficiency: AUA guideline.J Urol. 2018; 200: 423-432Crossref Scopus (330) Google Scholar They should also assess for contraindications to testosterone administration, including prostate cancer, breast cancer, unevaluated prostate nodule/elevated PSA, desire for fertility in the near term, elevated hematocrit, thrombophilia, untreated severe OSA, benign prostatic hypertrophy with severe lower urinary tract symptoms, uncontrolled heart failure, and recent myocardial infarction or stroke.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar Goals for treatment with testosterone replacement should be clearly established before initiation of treatment.6Grossmann M. Matsumoto A.M. A perspective on middle-aged and older men with functional hypogonadism: focus on holistic management.J Clin Endocrinol Metab. 2017; 102: 1067-1075Google Scholar Testosterone repletion in hypogonadal men has been found to improve libido and erectile function.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar Repletion may also improve anemia, bone density, lean body mass, and mood; however, effects on cognitive function, depression, fracture risk, diabetes, cardiovascular health, and lipids are less certain.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 3Mulhall J.P. Trost L.W. Brannigan R.E. et al.Evaluation and management of testosterone deficiency: AUA guideline.J Urol. 2018; 200: 423-432Crossref Scopus (330) Google Scholar After initiating testosterone replacement, clinicians should routinely assess for response to therapy and adverse effects.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar Adverse effects of testosterone replacement include erythrocytosis, acne, breast tenderness, and reduced spermatogenesis.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar Less common adverse effects include gynecomastia, breast cancer, urinary symptoms, and male pattern balding.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 5Saboor Aftab S.A. Kumar S. Barber T.M. The role of obesity and type 2 diabetes mellitus in the development of male obesity-associated secondary hypogonadism.Clin Endocrinol (Oxf). 2013; 78: 330-337Crossref PubMed Scopus (95) Google Scholar Fluctuations in mood and libido may also occur, particularly with intramuscular administration.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar Clinicians should monitor testosterone levels and hematocrit concentration during testosterone replacement.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 3Mulhall J.P. Trost L.W. Brannigan R.E. et al.Evaluation and management of testosterone deficiency: AUA guideline.J Urol. 2018; 200: 423-432Crossref Scopus (330) Google Scholar Guidelines recommend adjusting testosterone replacement to reach middle-tertile levels of total testosterone.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 3Mulhall J.P. Trost L.W. Brannigan R.E. et al.Evaluation and management of testosterone deficiency: AUA guideline.J Urol. 2018; 200: 423-432Crossref Scopus (330) Google Scholar Prostate cancer surveillance should be decided upon through shared decision making.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar Patients receiving testosterone replacement therapy may need urology evaluation if PSA increases more than 1.4 ng/mL above baseline or to above 4.0 ng/mL or if worsening lower urinary tract symptoms occur.2Bhasin S. Brito J.P. Cunningham G.R. et al.Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744Crossref Scopus (750) Google Scholar, 3Mulhall J.P. Trost L.W. Brannigan R.E. et al.Evaluation and management of testosterone deficiency: AUA guideline.J Urol. 2018; 200: 423-432Crossref Scopus (330) Google Scholar Overall, the ultimate goal of testosterone replacement in hypogonadal men is symptom relief. If patients do not experience symptomatic relief with adequate testosterone levels, testosterone replacement should be discontinued and alternative etiologies for the patient's symptoms should be sought.3Mulhall J.P. Trost L.W. Brannigan R.E. et al.Evaluation and management of testosterone deficiency: AUA guideline.J Urol. 2018; 200: 423-432Crossref Scopus (330) Google Scholar The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.