INTRODUCTION — Hypogonadism was recognized early in the HIV epidemic as being relatively common. Low serum testosterone levels in males with HIV may be associated with a variety of manifestations including fatigue, decreased libido and erectile dysfunction, weight loss, muscle wasting, and bone loss .
Hypogonadism in a male refers to a decrease in one or both of the two major functions of the testes: testosterone production and spermatogenesis. These abnormalities can result from disease of the testes (primary hypogonadism) or malfunction of the hypothalamus or pituitary gland (secondary hypogonadism). (See 'Determining the etiology' below.)
This topic addresses hypogonadism in males with HIV infection. General information about male hypogonadism is discussed elsewhere. (See "Clinical features and diagnosis of male hypogonadism" and "Testosterone treatment of male hypogonadism".)
EPIDEMIOLOGY — The observed prevalence of hypogonadism in males with HIV decreased following the advent of potent antiretroviral therapy (ART) and adoption of early treatment.
Earlier studies of endocrine dysfunction among patients with HIV showed that 30 to 50 percent of symptomatic males had low total testosterone levels, often in association with weight loss and CD4 lymphocyte depletion, and that this finding was much more common than abnormalities in thyroid or adrenal function [2-5]. Studies conducted in the ART era suggest prevalence rates similar to those in males without HIV, although symptom burden may be higher. A systematic review including 41 studies reported a 26 percent prevalence of testosterone deficiency in males with HIV . No significant difference in total testosterone levels was observed between patients with HIV and controls, though higher sex hormone-binding globulin and lower free testosterone levels were seen in persons with HIV. In another multicenter, cross-sectional study of males over 50 years of age, patients with HIV had similar prevalence of testosterone deficiency (34 percent) but higher burden of symptoms compared with the control group . Other observational trials of males with HIV report hypogonadism prevalence of 6 to 10 percent [8,9].
Age and comorbidities — The prevalence of hypogonadism increases with advancing age regardless of HIV serostatus  (see "Approach to older men with low testosterone") In the general population, hypogonadism is often related to chronic disease and frailty, and these associations have also been demonstrated in those with HIV .
In the Cohort of HIV at-risk Aging Men's Prospective Study (CHAMPS) cross-sectional cohort study, testosterone levels were assessed in 502 men ≥49 years old with or without HIV infection . Overall, 54 percent of participants had laboratory evidence of hypogonadism (defined in the study as serum testosterone <300 ng/dL), but it was no more common in individuals with HIV.
Obesity and insulin resistance — A predisposing factor to hypogonadism in patients with HIV is the development of obesity and insulin resistance, especially in patients with visceral adiposity [13,14]. Some may develop these conditions as part of lipodystrophy syndrome. (See "Epidemiology, clinical manifestations, and diagnosis of HIV-associated lipodystrophy".)
HIV-specific factors — Serum testosterone concentrations have been observed to be lower among patients with HIV who are symptomatic.
In the era before potent antiretroviral therapy (ART), gonadal function was evaluated in 70 men with HIV who were categorized as: a) asymptomatic; b) having mild symptoms and signs of HIV infection (eg, thrush, lymphadenopathy); or c) having AIDS . The mean serum testosterone concentrations were higher in the asymptomatic subjects compared with the other two groups. Of the hypogonadal men, 18 of 24 (75 percent) had secondary hypogonadism. Although CD4 cell counts were not available in that study, the relationship between advancing immunodeficiency and low testosterone levels was inferred by the clinical stage of disease.
Antiretroviral therapy — Some small studies have demonstrated that initiation of ART can restore testosterone levels to normal in males with hypogonadism, but others have shown no effect [8,16]. In a trial of 213 ART-naïve asymptomatic men with HIV, initiation of ART generally resulted in increased testosterone levels over the 64-week study period . A cross-sectional study also demonstrated that patients on ART had higher levels of testosterone compared with those who were not on it .
Older studies suggested that ART, particularly protease inhibitors (PIs), may be associated with male sexual dysfunction, independent of testosterone level . In a study of 90 stable men with HIV, 53 percent reported erectile dysfunction; duration of PI use was a risk factor .
Other medications/substances — Medications can affect sex hormones through different mechanisms. For example, systemic glucocorticoid therapy and megestrol acetate can cause hypogonadism by suppressing the hypothalamic-pituitary-gonadal axis. Ketoconazole, particularly at higher doses (eg, 400 mg/day), directly inhibits steroidogenesis. Psychotropic medications can lead to hyperprolactinemia, which may result in testosterone deficiency . The suppression of testosterone is sometimes seen in patients on methadone maintenance therapy; buprenorphine suppresses plasma testosterone to a lesser extent . The chronic use of alcohol, marijuana, anabolic steroids, and opiates  can also impair testosterone production. (See "Causes of primary hypogonadism in males" and "Causes of secondary hypogonadism in males".)
Liver disease — Chronic hepatitis C infection has been associated with low testosterone levels in males with HIV, which is consistent with other studies showing a relationship between chronic liver disease and hypogonadism in the general population [12,23]. (See "Clinical manifestations and natural history of chronic hepatitis C virus infection".)
CLINICAL MANIFESTATIONS — Patients with HIV who are hypogonadal present with symptoms and signs of androgen deficiency similar to those in the general population [12,24,25]. These include fatigue, decreased libido and erectile dysfunction, weight loss, muscle wasting, and bone loss . In addition, there may be loss of body hair, hot flashes, gynecomastia, anemia, and infertility in some patients. (See "Clinical features and diagnosis of male hypogonadism", section on 'Clinical features'.)
Establishing the diagnosis — The approach to the evaluation of testosterone deficiency in patients with HIV is the same as that in the general population and is discussed in detail elsewhere (see "Clinical features and diagnosis of male hypogonadism", section on 'Diagnosis'). Testing for hypogonadism is only indicated if there are suggestive symptoms or signs but not in asymptomatic individuals. Small atrophic testicles may be present on physical examination in both secondary and primary hypogonadism. (See 'Determining the etiology' below.)
Checking testosterone level — Males with HIV who have signs or symptoms suggestive of hypogonadism should undergo testing to determine the free testosterone level, either directly by an equilibrium dialysis assay or calculated from total testosterone, sex hormone-binding globulin (SHBG), and albumin concentrations (the calculation is typically performed by the laboratory) [26-28]. Testing should be performed 8 to 10 in the morning while fasting, and an abnormal level should be confirmed prior to treatment, as recommended in the Endocrine Society guidelines . (See "Clinical features and diagnosis of male hypogonadism", section on 'Free testosterone' and 'Interpretation of testosterone levels' below.)
This is distinct from the general population, in whom measurement of serum total testosterone concentration (free plus protein bound fractures) is usually the initial test of choice. However, total testosterone concentrations can be misleading in males with HIV, who may have low free testosterone levels, despite normal total testosterone levels [8,29,30]. The discrepancy between total and free testosterone levels in this population may be explained by higher levels of SHBG [29-31].
Morning levels are preferred, since testosterone concentrations in males demonstrate diurnal variation, with peak levels in the morning. Measurement of serum testosterone is not advised during an acute illness when androgen levels may transiently decline. Testosterone levels may also be suppressed by food or glucose intake .
Interpretation of testosterone levels — The clinical suspicion of hypogonadism in males with HIV is supported by a serum free testosterone level below the lower limit of normal for the assay used on two separate occasions.
If total testosterone levels were checked, repeated low values also support the diagnosis of hypogonadism. The normal range for total testosterone in adult males in most laboratories is about 300 to 800 ng/dL.
Determining the etiology — Once a patient has laboratory evidence of hypogonadism, further evaluation is necessary to determine if it is secondary or primary. The first step is to check luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels (see "Clinical features and diagnosis of male hypogonadism", section on 'Additional testing to determine etiology'). In patients with HIV on antiretroviral therapy (ART), androgen deficiency is more often a consequence of secondary, rather than primary, hypogonadism, but the pathogenesis is unclear in many cases [2,33].
●Secondary hypogonadism – Normal or low levels of LH and FSH in the setting of a low testosterone level suggest secondary hypogonadism. Such patients should be evaluated for possible reversible etiologies of gonadotropin deficiency, such as hyperprolactinemia and hemochromatosis, by checking serum prolactin and iron studies, although frequently no specific disorder is identified. We also evaluate other hormones that reflect anterior pituitary function (eg, free T4, thyroid-stimulating hormone [TSH], cortisol, insulin growth factor [IGF]-1). (See "Causes of secondary hypogonadism in males".)
We recommend performing a pituitary/hypothalamic magnetic resonance imaging (MRI) scan in patients with HIV with advanced immunodeficiency (CD4 cell count <200/microL), in whom secondary hypogonadism may rarely result from opportunistic infections (eg, Cryptococcus neoformans, Toxoplasma gondii) affecting the pituitary gland or hypothalamus , as well as in patients who have serum testosterone <150 ng/dL, persistent hyperprolactinemia, other anterior pituitary hormone deficiency(ies), or symptoms or signs suggestive of tumor mass effect (eg, headache, visual field defect) regardless of immune status .
●Primary hypogonadism – Increased LH and FSH levels in a patient with low serum testosterone suggest primary hypogonadism. In such cases, physical examination may show small atrophic testicles. If the primary hypogonadism is longstanding, a karyotype to exclude Klinefelter syndrome, which is the most common congenital cause of hypogonadism, is warranted. (See "Causes of primary hypogonadism in males".)
In patients with HIV and primary hypogonadism, a scrotal ultrasound should be performed if there is concern about an infectious process, which would be suspected in untreated patients with HIV and advanced immunodeficiency (CD4 cell count <200/microL) who have testicular pain, fever, or constitutional symptoms. Testicular opportunistic infections rarely occur in the setting of viral suppression .
Assessment for other contributing factors — Because the clinical manifestations of hypogonadism are nonspecific, further evaluation may be warranted in patients to determine if there are other contributing factors:
●Decreased libido or erectile dysfunction – Decreased libido or erectile dysfunction may be related to neurologic or vascular diseases, drug toxicity, or psychosexual issues. A review of medications and screening for depression are advised in this setting. (See "Epidemiology and etiologies of male sexual dysfunction".)
●Fatigue or weight loss – Fatigue or weight loss without localizing abnormalities may be the result of an opportunistic infection in patients with advanced immunodeficiency (CD4 cell count <200/microL), an occult neoplasm, another underlying medical condition, or depression. A complete blood count, chemistries (including thyroid function), and inflammatory markers (eg, sedimentation rate, C-reactive protein) are advised in this setting. Additional evaluation may be warranted in patients with advanced immunodeficiency based upon presenting symptoms and signs. Age- and sex-appropriate cancer screening studies should be updated as appropriate. (See "Approach to the adult patient with fatigue" and "Approach to the patient with unintentional weight loss".)
●Bone loss – Patients with HIV are at increased risk of bone loss. Contributing factors may include cigarette smoking, vitamin D deficiency, and history of tenofovir disoproxil fumarate (TDF) therapy. All patients should be screened for vitamin D deficiency, those who smoke should be provided assistance with smoking cessation, and those on TDF should be switched to a tenofovir alafenamide formulation if possible. (See "Bone and calcium disorders in patients with HIV".)
If any of these contributing factors coexist with hypogonadism, testosterone supplementation may be delayed pending determination of whether there is a symptomatic and/or biochemical response to appropriate treatment for those conditions.
TESTOSTERONE REPLACEMENT THERAPY
Indications — Testosterone replacement therapy is indicated in patients with HIV who have a low serum testosterone level (confirmed on at least two occasions in the morning without concurrent acute illness) and any of the following :
●Symptoms of androgen deficiency (eg, fatigue, hot flashes/sweats, decreased libido, erectile dysfunction)
●Unexplained weight loss
●Low bone mineral density
Patients with HIV who have hypogonadal symptoms and a low testosterone level and who are initiating antiretroviral therapy (ART) can be monitored before making a decision about whether to start supplemental testosterone, since ART may lead to increased testosterone levels . It is reasonable to reevaluate such patients for hypogonadism after they have achieved normal immune function and weight.
Testosterone therapy should not be prescribed in patients without laboratory evidence of hypogonadism. Patients who have a low testosterone level in the absence of any of the above symptoms or signs do not necessarily warrant treatment and may be monitored, but they do warrant evaluation for etiology of the hypogonadism (see 'Determining the etiology' above). If no specific cause is found, we typically reevaluate these patients both clinically and with a testosterone level in three to six months.
Efficacy — Evidence regarding the effectiveness of testosterone therapy in this patient population is limited. Seventy-four patients with HIV and hypogonadal symptoms were enrolled in a double-blind, placebo-controlled, six-week trial with biweekly testosterone injections (400 mg); testosterone responders and placebo recipients were then offered an additional 12 weeks of open-label testosterone therapy . Among the 70 men who completed the trial, libido improved in a higher proportion of those taking testosterone compared with placebo (74 versus 19 percent). Testosterone therapy was also associated with improvement in fatigue and mood disturbance. Improvement of all parameters was maintained during subsequent open-label treatment, although no long-term follow-up was reported.
Supplemental testosterone has also been effective in promoting weight gain, increased lean body mass, and higher bone mineral density in males with HIV, including those with HIV wasting syndrome [6,38,39]. In one randomized trial of 54 eugonadal men with HIV wasting syndrome, testosterone supplementation led to higher bone mineral density in the lumbar spine [39,40]. However, whether increased bone mineral density results in lower fracture risk is still unknown.
Pretreatment evaluation — Before initiating testosterone replacement therapy, we recommend obtaining a complete blood count, glucose, renal and hepatic function, and lipid panel. Patients should be informed of the benefits and risks of screening for prostate cancer (see "Screening for prostate cancer") and engaged in shared decision-making regarding whether to perform a digital rectal examination and measure prostate-specific antigen (PSA) prior to testosterone supplementation. Guidelines support screening and monitoring candidates on testosterone treatment aged 55 to 69 years who have a life expectancy greater than 10 years . African-American males and those with first-degree relatives with diagnosed prostate cancer are at greater risk for high-grade cancers and should start screening at age 40 years. (See "Screening for prostate cancer", section on 'Approach to screening'.)
Additional evaluation may be warranted based upon the clinical manifestations. (See 'Assessment for other contributing factors' above.)
The management of patients with HIV who have osteoporosis is discussed elsewhere. (See "Bone and calcium disorders in patients with HIV".)
Preparations — As in the general population, drug selection for testosterone replacement therapy in patients with HIV depends primarily on patient preference . (See "Testosterone treatment of male hypogonadism", section on 'Choice of testosterone regimen'.)
We generally advise one of the transdermal approaches (eg, patch, gel, or solution) as first-line treatment because of their ease of administration, lack of wide fluctuations in testosterone levels, and fewer adverse effects compared with periodic injections (table 1). The testosterone patch is applied daily over the skin of the back, thigh, or upper arm. There are now several different testosterone gel formulations, which are applied daily over a covered area of nongenital skin.
If the patient prefers an intramuscular injection, testosterone enanthate or testosterone cypionate may be used; a long-acting injectable agent, testosterone undecanoate in oil, is also available. Injections can be self-administered or administered in a medical setting. The dosing depends on the formulation:
●For testosterone enanthate or cypionate, we generally start with either 200 mg every two weeks or 100 mg every week. The initial dose can then be titrated based on testosterone levels that are measured midway between injections, with the goal of achieving a level in the mid-normal range.
There are several other testosterone preparations available including oral testosterone undecanoate, subcutaneous testosterone pellets, and a nasal testosterone gel. These formulations have been less well studied than those discussed above and have not been specifically evaluated in males with HIV; thus, we do not favor these alternative approaches.
Duration of treatment — For each of the indications described above, we continue testosterone replacement therapy as long as there is clinical benefit and no significant adverse effects. If there is no effect on symptoms after three months of testosterone replacement and/or adverse effects occur, an alternative testosterone preparation can be tried or the treatment discontinued.
In clinical practice, sometimes patients presenting for care are on testosterone therapy for unclear indications. Checking luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in a patient receiving exogenous testosterone is not useful since gonadotropins will be suppressed. Because there are no evidence-based guidelines regarding whether to continue testosterone in this setting, the decision must be individualized, taking into consideration the risks and benefits of treatment as well as patient preference. If testosterone is discontinued in these patients, it may take months for endogenous gonadal function to resume and may not be well tolerated.
Adverse events — Testosterone replacement therapy can cause acne and emotional lability in some patients. With chronic administration, patients can also develop erythrocytosis and testicular atrophy. Preexisting sleep apnea may also worsen.
The patch or gel methods can be associated with skin irritation, and injections may cause injection-site reactions. (See "Testosterone treatment of male hypogonadism", section on 'Potential adverse effects'.)
There are no important interactions with any antiretroviral drugs.
Contraindications and cautions — Although testosterone treatment has been associated with clinical benefits in males with hypogonadism, many questions remain unanswered including the long-term effects of suppression of the hypothalamic-pituitary-gonadal axis, as well as the possibility of promoting or unmasking malignancy of the prostate  and increasing the risk of cardiovascular disease  and venous thromboembolism . Patients should be counseled regarding these uncertainties before initiating treatment.
●History of metastatic prostate or breast cancer
●Unevaluated prostate nodule or induration
●PSA >4 ng/mL or >3 ng/mL in males at high risk for prostate cancer (eg, African Americans or males with first-degree relatives with prostate cancer) without urologic evaluation
●Hematocrit >48 percent (>50 percent for males living at high altitude)
●Severe lower urinary tract symptoms
●Uncontrolled or poorly controlled heart failure
●Desire for fertility in the next 6 to 12 months
Exogenous testosterone may cause suppression of spermatogenesis and should not be given to men who desire fertility in the near term.
Testosterone should be used with caution in patients who have thrombophilia, underlying cardiovascular disease, or multiple cardiovascular risk factors. This is especially relevant for persons with HIV because cardiovascular risk factors and comorbidities are more prevalent in this population . (See "Testosterone treatment of male hypogonadism", section on 'Venous thromboembolism' and "Testosterone treatment of male hypogonadism", section on 'Cardiovascular risks'.)
Patients who use topical testosterone gel should be made aware of the risk of unintentional transfer of drug by skin contact, particularly to female partners or children, who may become virilized as a result. Secondary exposure can be avoided by washing hands after application, covering the application site, and allowing the gel to completely dry before any direct skin-to-skin contact (see "Testosterone treatment of male hypogonadism", section on 'Secondary exposure: Minimal risk with precautions'). The relative advantages and disadvantages of the different formulations are discussed elsewhere. (See "Testosterone treatment of male hypogonadism", section on 'Choice of testosterone regimen'.)
Monitoring patients — Clinical effectiveness, testosterone levels, and adverse drug effects should be monitored at three to six months, 12 months, and annually thereafter (see "Testosterone treatment of male hypogonadism", section on 'Monitoring'). The target goal should be attainment of morning serum testosterone levels in the mid-normal range. Patients receiving testosterone injections should have levels checked midway between injections.
The hematocrit should be checked at baseline, after three to six months of therapy, and annually thereafter, since testosterone therapy can be associated with erythrocytosis. Identification and management of erythrocytosis in the setting of testosterone therapy is discussed elsewhere. (See "Testosterone treatment of male hypogonadism", section on 'Erythrocytosis'.)
The patient should be counseled regarding the risks and benefits of prostate cancer monitoring in order to determine a plan consistent with his values and preferences. This is discussed in detail elsewhere. (See "Testosterone treatment of male hypogonadism", section on 'Prostate cancer'.)
We suggest repeating bone densitometry after one to two years of testosterone therapy in hypogonadal males with osteoporosis or low-trauma fracture . If it is stable or improved, less frequent monitoring may be performed. (See "Bone and calcium disorders in patients with HIV".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary care of adults with HIV".)
SUMMARY AND RECOMMENDATIONS
●Hypogonadism was recognized as being relatively common early in the HIV epidemic. Low serum testosterone levels in males with HIV may be associated with a variety of manifestations including fatigue, decreased libido and erectile dysfunction, weight loss, muscle wasting, and bone loss. (See 'Introduction' above.)
●The prevalence of treatment for hypogonadism in males with HIV has been observed to be lower (about 10 percent) since the advent of effective antiretroviral therapy (ART) and its earlier initiation in their care. (See 'Epidemiology' above.)
●Risk factors for hypogonadism in males with HIV include increasing age, symptomatic infection, use of certain drugs (eg, systemic glucocorticoids, opiates, megestrol acetate, ketoconazole), and chronic hepatitis C infection. (See 'Risk factors' above.)
●In males with HIV who have signs or symptoms suggestive of hypogonadism, the diagnosis is supported by a low serum free testosterone level, either calculated or measured directly by equilibrium dialysis and confirmed on repeat testing. (See 'Establishing the diagnosis' above.)
●Testing should be performed 8 to 10 in the morning while fasting. Measurement of serum testosterone is not advised during an acute illness when androgen levels may transiently decline. (See 'Checking testosterone level' above.)
●Once a patient has laboratory evidence of hypogonadism, further evaluation is necessary to determine if it is primary or secondary. Normal or low levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the setting of a low testosterone level suggest secondary hypogonadism. Increased LH and FSH levels in a patient with low serum testosterone suggest primary hypogonadism. Additional testing or imaging may be warranted to establish the specific etiology. (See 'Determining the etiology' above.)
●Testosterone replacement therapy is indicated in patients with HIV who have a consistently low serum free testosterone level and symptoms of androgen deficiency (eg, fatigue, hot flashes/sweats, decreased libido, erectile dysfunction), unexplained weight loss, or low bone mineral density. (See 'Indications' above.)
●Before initiating testosterone replacement therapy, we recommend obtaining a complete blood count, glucose, renal and hepatic function, and a lipid panel. For males who choose prostate cancer monitoring after discussion of the associated risks and benefits, a prostate-specific antigen should be checked and a digital rectal examination performed. Additional evaluation may be warranted based upon presenting manifestations. (See 'Pretreatment evaluation' above and 'Assessment for other contributing factors' above.)
●We generally use one of the transdermal approaches (eg, patch or gel) as first-line treatment because of their ease of administration, lack of wide fluctuations in testosterone levels, and fewer adverse effects compared with injections (table 1).The testosterone patch is applied daily over the skin of the back, thigh, or upper arm. There are now several different testosterone gel formulations, which are applied daily over a covered area of nongenital skin. (See 'Preparations' above.)
●Many questions remain unanswered regarding the long-term clinical benefits versus the possible prostate, cardiovascular, and thromboembolic risks with testosterone treatment. These issues should be discussed with patients prior to initiating therapy. (See 'Contraindications and cautions' above.)
●Clinical effectiveness, testosterone levels, and adverse drug effects should be monitored at three to six months, 12 months, and annually thereafter. The target goal should be attainment of serum testosterone levels obtained in the morning in the mid-normal range. (See 'Monitoring patients' above.)
ACKNOWLEDGMENT — UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.
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