HIV and Testosterone in Men

 

Sensitivity (%)

Specificity (%)

NPV (%)

PPV (%)

R(+)

R(−)

Diag. OR

TT

25.0

100

89.6

100

Infinite

0.75

Infinite

FT (RIA)

33.3

96.2

90.4

57.1

8.76

0.69

12.7


Calculated free testosterone (CFT) <0.22 nmol/L (6.36 ng/dL) used as the reference for diagnosis of hypogonadism

NPV negative predictive value; PPV positive predictive value; R(+) positive likelihood ratio; R(−) negative likelihood ratio; Diag. OR diagnostic likelihood ratio; TT diagnosis of hypogonadism as total testosterone <10.4 nmol/L (3 ng/mL); FT (RIA) diagnosis of hypogonadism as measured free testosterone <0.031 nmol/L (9 pg/mL)



The results of these studies collectively suggest that measurement and calculation of bioavailable testosterone in HIV positive persons is a more accurate way of detecting biochemical hypogonadism, particularly in those with borderline low free or total testosterone levels.

In recent years, since the introduction of effective treatment for HIV in the form of HAART, studies have sought associations between ARV treatment and hypogonadism in HIV positive males.



HAART Era


The effect of ARV therapy on testosterone levels is unclear. Studies looking at the effect of ARV on androgen levels have shown conflicting results.

A study performed in 2007, Crum-Cianflone et al. aimed to establish the prevalence and risk factors for hypogonadism amongst a modern cohort of HIV-infected men [9]. Three hundred HIV positive men were enrolled in this study, 60% of which were on ARV with generally good immune function (mean CD4 cell count of 522 cells/mm3). All had mean age of 39 and included a mixture of ethnicities. Seventeen percent (50/296) of the men were hypogonadal (as defined by a morning total testosterone level <300 ng/dL), and a further 16% had a borderline testosterone level (300–400 ng/dL) [9]. In multivariate analysis, increasing age and a higher body mass index (BMI) were positively associated with hypogonadism, while smoking was negatively associated (OR 0.44, p  =  0.02). A subset of participants with low testosterone had luteinizing hormone (LH) and FSH measured, all of which were found to be low, suggesting secondary hypogonadism. There was no association observed between hypogonadism and current, past, or cumulative use of HIV medications.

Wunder et al. demonstrated a high prevalence of low free testosterone levels amongst an untreated HIV positive cohort and studied the effect of ARV therapy on androgen levels over time [10]. Data were derived from stored serum samples from the Swiss HIV Cohort Study (SHCS), which is an ongoing multicenter research project. Ninety-seven participants had serum levels of LH, FSH, and FT measured at baseline, and again, after 2 years of successful HAART. At baseline, 68 patients (70%) had subnormal FT levels based on an age-adjusted normal range. Of these, LH levels were low in 44%, normal in 47%, and high in 9%, indicating a mainly secondary hypogonadism in this group. There was a trend for association between lower CD4+ T-cell counts and hypogonadism, but no other associations were found for age, BMI, sexuality, duration of HIV disease, or plasma HIV viral load. No significant changes in free testosterone, LH, or FSH were observed after 2 years of successful ARV therapy. Overall, >60% remained hypogonadal at this point. Twenty-four percent of those who were originally hypogonadal returned to normal levels, and 32% of those originally within normal levels became hypogonadal after 2 years of therapy. All participants on the ARV regime were on the nucleoside reverse transcriptase inhibitors (NRTI) zidovudine and lamivudine. Sixty-three percent were also on a boosted protease inhibitor (bPI) as the third agent, and the remaining 37% were on a non-nucleoside reverse transcriptase inhibitor (NNRTI). The authors acknowledged that the use of stored serum samples was a limiting factor in the interpretation of these findings, as the samples were not consistently morning levels; therefore, this may have led to higher rates of reported hypogonadism.

Effective treatment with ARV has been shown to increase lean body mass (LBM), particularly in individuals with low CD4 counts at initiation of treatment [11]. In a study looking at the effect of some older ARVs on LBM and testosterone levels, Dube et al. noted increases in free testosterone after initiation of ARV, along with an increase in fat-free mass [12]. The rise appeared to be more marked with certain types and classes of ARV, with greater increases at 64 weeks among zidovudine–lamivudine recipients than among stavudine–didanosine recipients, and among efavirenz (an NNRTI) recipients than among nelfinavir (a bPI) recipients [12]. It is worth noting that in recent years, usage of stavudine, nelfinavir, and to a lesser degree didanosine has declined in parts of the world with access to newer ARV agents, due to the high levels of toxicities observed, including lipodystrophy.

In the Massachusetts Male Aging Study, rates of hypogonadism amongst HIV negative men were reported as between 6 and 12% amongst 40–69-year-old American males [13]. Reported prevalence of hypogonadism in HIV positive men varies widely, and rates reported depend on the type of testosterone measurement used; however, it seems clear that prevalence of hypogonadism is higher in HIV positive compared to HIV negative males.

While studies show there are high levels of biochemical hypogonadism in clinical practice, a diagnosis of testosterone deficiency is usually made in conjunction with consistent clinical symptoms and signs [14]. Testosterone deficiency can cause nonspecific symptoms such as fatigue, depressed mood, weakness, and sexual dysfunction, all of which are also frequently associated with many chronic illnesses, HIV virus, ARV therapy, and opportunistic infections. Careful history, examination, and appropriate investigation are essential when trying to ascertain whether biochemical hypogonadism is clinically relevant in an individual.


HIV Wasting and Testosterone


The US Centers for Disease Control and Prevention (CDC) classification system for HIV disease staging and classification defines HIV wasting syndrome as involuntary weight loss >10% of baseline body weight, in association with either chronic diarrhea or chronic weakness and documented fever for ≥1 month. Wasting is further identified as an indicator for the AIDS condition [15]. In the developed world, wasting amongst HIV positive persons taking ARV is now less common and frequently reverses quickly with appropriate HIV viral control and nutritional supplementation. However, even in the era of HAART, HIV-associated weight loss remains prevalent. A large retrospective observational study of a contemporary managed care population in the United States observed that even amongst a modern cohort of HIV, almost one in ten had evidence of HIV-associated weight loss [16].

In a study presented in 2000, by Desyatnik et al., the association between clinical wasting and hypogonadism was investigated [17]. A retrospective review of 88 male patients with HIV infection who had been on HAART for at least 6 months was performed. Hypogonadism was defined as serum-free testosterone <15 pg/mL and was observed in 20% of participants. Wasting was defined as weight loss >5% of ideal body weight and was observed in 42% of the subjects. The investigators observed that testosterone deficiency in these males did not correlate with wasting.

The same year a paper was published by Rietschel et al. looking specifically at androgen levels in a group of HIV positive men with wasting [18]. Seventy percent of participants were receiving ARV therapy. The authors found that in this population with wasting, 21% of patients receiving HAART had hypogonadism compared with 15% of those not on HAART. The prevalence of hypogonadism was not related to any particular class of ARV. Comparison was also made with a control group of HIV positive men without wasting, and total and free testosterone levels were not significantly different for subjects with wasting and subjects without wasting.

In the context of the developing world, wasting syndromes are commonly encountered and may have multiple etiologies including lack of appropriate ARV, concomitant infections, such as parasitic infection and tuberculosis, and lack of nutritional intake and food security. In this instance, the appropriate remedy of the any exacerbating underlying cause of wasting would be indicated in the first place before consideration of testosterone replacement.


Testosterone, Cytokines, and Wasting


The contributions of catabolic cytokines to HIV-associated wasting and weight loss, in a group of HIV positive men, were investigated by Roubenoff et al. [19]. The authors studied a group of 172 men, 43% of which were on HAART. They found that both TNF-α and IL-1β production by peripheral blood mononuclear cells predicted loss of LBM, and that serum-free testosterone was inversely associated with TNF-α production. However, serum-free testosterone alone was not an independent predictor of either LBM or resting energy expenditure after adjustment for cytokine production. The authors suggested that the inverse relationship between testosterone and cytokine production might be due to testosterone acting as a modulator of the effect of TNF-alpha and IL-1beta and not as a direct determinant of body composition or metabolic rate.



Prevalence of Hypogonadism in Any Chronic Disease


Hypogonadism has been observed in the presence of many common acute and chronic illnesses in men such as chronic liver and renal disease, cancer, and sepsis. In the case of depressed testosterone in HIV disease, the symptoms and signs observed are often nonspecific and may be attributed to the underlying disease or treatment. Low levels of testosterone may cause loss of LBM, bone mass density, and produce symptoms such as depressed mood, loss of energy, and sexual dysfunction. The mechanisms explaining hypogonadism and various systemic diseases are incompletely understood, but these conditions are likely caused by a combination of stress, nonspecific weight loss, inflammation, and medication [20].


Metabolic Syndrome


The metabolic syndrome (MS) is a term used to describe the clustering of risk factors for cardiovascular disease, including abnormal lipids, hypertension, insulin resistance, and intra-abdominal obesity. In HIV positive cohorts, diagnosed prevalence has been shown to vary according to the diagnostic criteria used [21] and has been reported in between 7 and 45% of individuals [22].

The reasons why high rates of metabolic syndrome are seen in HIV positive individuals are not fully elucidated, but are thought to be related to both treatment and disease factors, and several mechanisms have been suggested. HIV protease inhibitor mediated blockade of glucose transport and NRTI mediated mitochondrial ­toxicity have been well characterized. Additional cellular effects, including the induction of endoplasmic reticulum and oxidative stress, altered adipocytokine secretion. Lipotoxicity has been implicated in the development of metabolic ­syndrome in this cohort [23]. In HIV negative cohorts, metabolic syndrome is associated with low levels of testosterone [24, 25].

A recent study by Monroe et al. compared HIV-uninfected men with HIV-infected men and found that had they had lower FT, higher SHBG, and more insulin resistance and DM [26]. Lower FT and lower SHBG were associated with insulin resistance regardless of HIV serostatus. The authors suggested that sex hormones play a role in the pathogenesis of glucose abnormalities among HIV-infected men.


Lipodystrophy


Lipodystrophy syndrome has been reported in as many as 41% of people with HIV and comprises changes in body fat distribution including both fat loss (lipoatrophy) and fat accumulation (lipohypertrophy) [27]. Mitochondrial toxicity and dysfunction have been implicated as a cause for the adverse metabolic toxicities of ARV treatments, including lipodystrophy and insulin resistance. Toxicity caused by the ARV is drug class specific and in the case of NRTI have been attributed to the drugs, causing an inhibitory effect on DNA polymerase gamma enzyme [28].

Sex hormones including testosterone may play a role in altered fat distribution and insulin sensitivity of male patients with HIV lipodystrophy.


Gynecomastia and Hypogonadism


A study by Biglia et al. found that 40 out of 2,275 (1.8%) men with HIV have gynecomastia. Mean free testosterone index (ratio of total testosterone divided by SHBG) was significantly lower in those patients with gynecomastia compared to a control group without gynecomastia. The authors conclude that gynecomastia in this group is associated with hypogonadism. Duration of exposure to ARV was not associated with gynecomastia [29]. The finding of lower free testosterone index and bioavailable testosterone levels in patients with gynecomastia has been observed in subsequent studies and the effect of certain ARV treatments. In particular, the NNRTI, efavirenz, has also been associated with gynecomastia in HIV positive men [30, 31].


Abnormal Testosterone Metabolism and Raised Estradiol


There is evidence that men on ARV develop low sexual desire that can be associated with raised estradiol levels. It has been suggested that abnormal metabolism seen in HIV positive men results in increased aromatization of testosterone to estradiol [32]. It has been postulated that increased conversion of testosterone to estradiol may result from increased central adipose tissue seen in lipodystrophy/metabolic syndrome. It is one possible explanation why metabolic syndrome/lipodystrophy syndrome and low testosterone frequently coexist in HIV positive men.


Sexual Function and HIV


High rates of sexual dysfunction have been well described amongst men with HIV. In particular, erectile dysfunction (ED) is prevalent, and has been reported to be present in between 9 and 74% of HIV positive men [33]. Guaraldi et al. studied 133 HIV positive men and found a prevalence rate of erectile dysfunction in 55 and 65% of men aged less than or more than 50 years old, respectively. Comparison of total and free testosterone was made in those with and those without ED, and no significant differences were observed.

In the large study by Crum-Cianflone, ED was reported in 175/285 (61%) [9]. In this study, rates of hypogonadism were not significantly different between those with and those without ED. Increasing age and depression were associated with ED and high CD4 cell count was observed to be protective. There was also no association between either ED or hypogonadism and the current, past, or cumulative use of HIV medications. Similarly, in a cross-sectional study by Lallemand et al., 111 out of 156 (71%) HIV positive men on ARV reported sexual dysfunction. There was also no association between sexual dysfunction and types of ARV used [34].

The study by Moreno-Perez et al. revealed that 100% (12/12) of patients with hypogonadism, as measured by calculated free testosterone (CFT), had ED, but only a quarter of all patients with ED were hypogonadal [7].

Using CFT or bioavailable testosterone levels to diagnose hypogonadism is an accurate way of identifying ED related to or worsened by low testosterone levels. However, the cause of ED is often multifactorial; thus, the use of biochemical hypogonadism to investigate ED is a valuable part of the diagnostic armory available when investigating HIV positive patients with ED.


Age


Hypogonadism is associated with increasing age. Total testosterone decreases year-on-year in HIV negative populations as they move through their fourth and fifth decades of life [13, 35]. Within developed countries, we are now caring for an aging cohort of HIV positive individuals, and it is predicted that as prognosis continues to improve for individuals living with HIV, there will be increasing numbers of older people living with HIV [36, 37]. We may reasonably expect that the numbers of HIV positive men with late onset hypogonadism increase in the future. In 2005, Klein et al. set out to examine the prevalence and association of hypogonadism in males at risk of or living with HIV aged over 50 years old [38]. In a sample of over 500 men, aged >49 years, of which 275 were HIV positive, the authors noted that hypogonadism was prevalent. The HIV positive group was associated with high HIV viral load, but not with CD4 count or disease stage. Raised total testosterone was associated with HIV positivity, but free androgen index (FAI) was not associated with HIV status. Both low, free androgen index and low androgen levels were correlated with clinical findings suggestive of hypogonadism.

There is a growing body of literature describing a process of accelerated aging in HIV-infected individuals. Chronic immune activation and inflammation are observed, along with thymic dysfunction and gut microbial translocation. All act together to drive early senescence in HIV infection [39]. Among the HIV positive women, early loss of ovarian function and early menopause have been described in some study populations [4042] as well as an unexpectedly high numbers of HIV positive women reaching menopause very early [40, 43]. It may be that men living with HIV infection are more prone to a syndrome of late onset androgen deficiency or an “early andropause,” heralded by dysregulation of the hypothalamic–pituitary axis as part of a process of accelerated physiological aging [44].


Bone Mineral Density and Testosterone


High rates of osteopenia and osteoporosis have been reported in HIV-infected cohorts. Prevalence rates range between 22–71% and 3–33%, respectively [45]. Loss of bone mineral density (BMD), in the context of HIV, is likely to be multifactorial, and contributing factors include ARV treatments (particularly implicated is the widely used NRTI, tenofovir), vitamin D deficiency, alcohol and drug use, smoking, low BMI, and HIV infection. Hypogonadism may be an additive risk factor for low BMD and should be managed appropriately, because part of the osteoporosis management includes measures to improve calcium and vitamin D nutrition, increase weight-bearing exercise, and specific pharmacologic therapy, including, in some cases, testosterone replacement [46].


Recreational Drug Use


Intravenous drug use is a risk factor for HIV acquisition, and recreational drug use is not uncommon among HIV-infected cohorts. Marijuana, opiates, anabolic steroids, and alcohol can all inhibit gonadal function [47]. A study on androgen levels, by Wisniewski, showed that free T concentrations were lower in men who used cocaine and/or opiates, irrespective of HIV status [48].


Treatment of Hypogonadism and Wasting Syndrome in HIV Positive Men


There are various treatments available for hypogonadism and wasting syndrome in HIV positive men. The literature is wide ranging on the multitude of therapy options and benefits seen in HIV men. Treatment of hypogonadism and wasting syndrome in HIV positive men has been shown to help with LBM, weight loss, depression, fatigue, libido, and BMD.

Therapy ranges from testosterone replacement to synthetic analogues such as anabolic steroids as well as growth hormone, dronabinol, megestrol acetate, and insulin-like growth factor I. In this section, treatment for hypogonadism and wasting syndrome in HIV positive men will be reviewed. The review will include various types of treatments, methods of delivery, benefits, and side effects.


Body Composition and Muscle Wasting


Body composition may undergo drastic changes in HIV positive patients with losses in LBM, muscle mass, and associated wasting syndrome. The latter is defined by the CDC as the involuntary loss of more than 10% of baseline body weight in the previous 12 months [49, 50]. Body cell mass (a component of LBM) [50] represents metabolically active tissue, and men with HIV wasting may show losses in body cell mass and LBM prior to overall changes in body weight and fat mass [5153]. These measured changes are a better indicator of wasting syndrome and malnutrition in men with HIV. Losses of LBM and muscle mass have been shown to correlate with androgen levels in hypogonadal men with HIV, and research has focused on different treatment options to counteract this loss [54].

Androgen replacement therapy in this population has been extensively studied and includes different forms of synthetic testosterone, in addition to metabolic steroids. The literature has focused on men with HIV with and without wasting, HIV positive eugonadal men and hypogonadal men. In addition to androgen replacement, other treatment options that have been studied in relation to body composition include megestrol acetate, dronabinol, insulin-like growth factor I, and growth hormone. Resistance training and exercise have also been studied along with testosterone replacement as well as whether there are additive effects when used in combination.


Types of Therapy



Megestrol Acetate


Megestrol acetate has been shown to benefit men with wasting syndrome. Men randomized to a 12-week randomized controlled study taking either placebo, 100, 400, or 800 mg of megestrol acetate were shown to have significant increases in total weight at 800 mg of megestrol acetate compared to placebo, with overall trends toward increasing weight in a dose-dependent fashion [55]. The total weight gain average in the 800 mg group was 3.54 kg. This was compared to a weight loss of 0.725 kg in the placebo group (p  <  0.001), and average LBM gain of 1.14 kg in the 800 mg group was compared to 0.772 kg weight loss in the placebo group (p  <  0.001). A similar study, which compared dosing of 800 mg of megestrol acetate to placebo, found significant total weight gain in the therapy group compared to placebo; however, this was due to gains in fat content as opposed to LBM, which was not significant between the groups [56]. A recent study compared megestrol acetate therapy to oxandrolone therapy and found similar weight gains between the groups (2.8 kg and 2.5 kg, respectively, p  =  0.80) and LBM (39% and 56% of weight, respectively, p  =  0.38). Adverse events between the groups were not significant (p  =  0.74) [57].


Dronabinol


Dronabinol is an orally active cannabinoid with complex central nervous system effects that increased the appetite of patients with HIV wasting. In a study of 139 patients, randomized to dronabinol or placebo, weight remained stable in the dronabinol group compared to an average weight loss in the placebo group of 0.4 kg. However, increased appetite above baseline and decreased nausea were observed compared to placebo [58]. In an open-label study designed to assess safety and pharmacokinetics of dronabinol and megestrol acetate, alone or in combination in HIV wasting syndrome, dronabinol was found to have no effect on weight (mean weight change −2.0 kg) compared to megestrol acetate alone (6.5 kg) [59].

A more recent retrospective review of 117 patients treated with dronabinol over the course of 3 months to 1 year showed that mean weight gain in patients taking the medicine for 1 year was 3.7 lb. Loss of appetite was also improved as well as nausea [60]. Perhaps, more long-term prospective studies can assess the effect of dronabinol on weight gain and changes in body composition such as LBM.


Growth Hormone


Growth hormone (GH) has been shown to change body composition in HIV positive men. LBM and total weight are increased, although the gains are not often sustained [61]. GH has been approved by the FDA to treat wasting associated with HIV virus, but the cost can be prohibitive [50]. One hundred and seventy-eight men randomized to receive either growth hormone (0.1 mg/kg) or placebo showed significant gains in LBM (3.0 kg, p  =  0.001), total weight (1.6 kg, p  =  0.001), and treadmill work output in the treatment group over the course of 12 weeks. Additionally, body fat differences were observed between the groups with a significant decrease in the treated patients (−1.7 kg, p  <  0.001) [62]. Side effect differences between the two groups were significant and included swelling or puffiness and arthralgias in the treatment arm. Additionally, greater increases in blood glucose and HbA1c were observed in the GH group.

Further studies, including usage of lower doses of growth hormone (30–40 μg/kg), have found similar observations with increased LBM, decreased fat mass, and decreased trunk and appendicular fat mass [63, 64]. Significant side effects were seen, as in previous studies, including acute increases in fasting glucose levels [62]. An open-label study, which administered growth hormone at a dose of 6 mg/day for 24 weeks followed by a 12 week washout period and then 4 mg dosing every other day for 24 weeks, found significant decreases in visceral adipose tissue, although the effect was not great for the lower dose (visceral adipose tissue decreased an average of 42% at 12 weeks during the high dose treatment vs. 15% in those who continued another 12 weeks at the lower dose). Forty-three percent (n  =  13) of participants experienced side effects during the trial, and 11 patients in the high dose phase and 3 in the low dose either temporarily or permanently discontinued treatment [65].

Side effects of growth hormone were also highlighted in a comparison study of patients randomized to receive either nandrolone decanoate (150 mg IM biweekly), a metabolic steroid, or placebo in a double-blind study, which was compared to an open-label group of patients receiving growth hormone (6 mg daily). Nandrolone and growth hormone were associated with greater increases in LBM compared to placebo (1.6 and 2.5 kg, not significant) as well as greater gains in fat-free mass. Growth hormone also showed greater decreases in whole body fat mass, as seen in previous studies; however, a greater percentage of patients (47.6%) experienced adverse drug events compared to the nandrolone (4.7%) and placebo (4.8%) groups. Most frequently reported events included edema, arthralgia, and carpal tunnel syndrome [66].

In perhaps the largest study to date, including 757 subjects, a randomized double-blind placebo-controlled trial compared patients who received a maximum of 6 mg of growth hormone daily (DD) or as alternate day (AD) dosing. Body weight was shown to increase by 2.9 kg and 2.2 kg, respectively. The median increase in LBM after 12 weeks was 3.3 kg in the AD group and 5.2 kg in the DD group (for both groups: p  <  0.0001 vs. placebo). Greater decreases were also seen in total fat mass and truncal fat mass compared to placebo, with greater decreases in the daily dosing compared to the alternate dosing regimen [67].

In a meta-analysis of randomized placebo-controlled studies, growth hormone was found to improve LBM by approximately 3 kg compared with placebo, and was associated with improvements in physical endurance. However, as previously reported, adverse events were more common including arthralgias, edema, myalgias, and increases in blood glucose [68].


Insulin-Like Growth Factor I


Insulin-like growth factor I is not effective alone in the treatment of wasting associated with HIV, and is associated with detrimental metabolic effects including hypoglycemia [69, 70]. In combination with growth hormone, decreases in fat-free mass and body fat have been noted, although no significant changes in LBM were observed [71]. Another study documented early increases in weight that were not observed at later time points, as well as transient increases in fat-free mass without an overall significant anabolic effect [72]. LBM was observed to increase with combination therapy in another study which randomized patients to four groups: growth hormone or insulin-like growth hormone I alone, in combination and placebo. The combination treatment group showed the greatest gain in LBM, 3.2 kg (p  <  0.001); this was the only group that showed changes sustained at 12 weeks [69].


Testosterone


Hypogonadism is prevalent in HIV positive men, as high as 50% in some studies, including 25% with primary gonadal failure (although with the advent of HAART, the percentages may be lower) [4, 54]. Additionally, there is a correlation between exercise capacity and testosterone levels that highlight the important anabolic effects of testosterone, and support a potential role in wasting [54]. Although not meeting the technical center for hypogonadism patients experience an acute drop in testosterone levels, when in the normal range may experience symptoms [73]. Testosterone replacement therapy in HIV positive men has been well studied, although many of them have small patient populations and are not uniform in outcome measures. Eugonadal and hypogonadal men as well as men with and without wasting syndrome have been studied for testosterone replacement.

Testosterone has been shown to influence body composition and change LBM, which is the metabolically active component of body composition. The use of ­testosterone in wasting syndrome may be equally efficacious as in men in whom wasting has not occurred, with the added benefit of anabolic effects. Different types of testosterone have been studied including intramuscular formulations, transdermal/transscrotal patches, and testosterone gel.


Intramuscular Testosterone

Although testosterone administration has been shown to have no benefit on weight in one study [74], the majority of studies have shown increases in weight and overall changes in body composition. In a double-blind placebo-controlled trial of 51 HIV positive men with evidence of wasting and hypogonadism, patients were randomly assigned to receive testosterone enanthate 300 mg, every 3 weeks or placebo. Gains in fat-free mass were seen in the placebo vs. treatment group at 6 months (−0.6 and 2.0 kg, p  =  0.36), as well as LBM (0 and 1.9 kg, p  =  0.041) and muscle mass (−0.8 and 2.4 kg, p  =  0.005). Testosterone was tolerated well by patients, and significant benefits were also seen in perceived improved quality of life, improved appearance, and feeling better [75].

The above patient population was then followed during an open-label treatment trial where the placebo group crossed over to receive testosterone [76]. Only after crossover did the placebo group show gains in LBM (−0.6 kg at 0–6 months compared to 1.9 kg at 6–12 months; p  =  0.03). Subjects who initially received testosterone and continued in the study continued to gain LBM with greater gains at 1 year compared to subjects who initially received placebo and then crossed over (0–6 months 1.6 kg gained compared to 3.7 kg at 6–12 months; p  <  0.05).

In another study, which looked at testosterone replacement in HIV men with and without hypogonadism (testosterone levels at the lower end of normal), primary end points included low libido, mood, energy, and weight [77]. Men were required to have low sexual desire as inclusion criterion for entry into the study. An open-label design was used with testosterone cypionate 200 mg initially and 400 mg biweekly for 8 weeks of open therapy, followed by an additional 4 weeks of treatment for the responders. They then underwent randomization to a placebo-controlled, double-blind treatment arm. Average weight gain was 3.5 lb (p  <  0.001); however, body composition studies were not performed. Significant improvements were also seen with mood and sexual desire/libido. Of the men in the treatment arm randomized to placebo, only 13% of those in the placebo group maintained their response as compared to 78% in the treatment group. Importantly, men who had low (but within the reference range) levels of testosterone were just as likely to respond as hypogonadal men.

A similar study of men with and without hypogonadism, with inclusion criteria requiring sexual dysfunction (weight loss was not a requirement), was performed in 70 men in a double-blind randomized placebo-controlled trial. Men were assigned to a placebo treatment arm or injections of testosterone cypionate 200 mg initially and 400 mg biweekly. At 12 weeks, the men were assigned to open-label maintenance. Along with improved mood, energy, and libido at the 12-week mark, average weight gain was 2.6 kg (p  <  0.01) in the treatment group with gains in muscle mass of 1.6 kg (p  <  0.001). The increase was greater for men with initial wasting at presentation (2.2 kg, p  <  0.001) [73].

High doses of testosterone enanthate (300 mg/week) were utilized in a randomized, double-blind, placebo-controlled trial of HIV positive men with weight loss. Significant increases in fat-free mass were seen in the testosterone group compared to the placebo group (2.8 kg, p  <  0.0001). Interestingly, serum testosterone levels correlated with the increase. Total body weight also increased within the treatment arm (1.8 kg, p  =  0.003), although it was not significantly different compared to placebo [78].

Two studies compared men in a 2  ×  2 factorial design, combining resistance training with or without testosterone treatment and placebo with or without testosterone treatment to determine if there were additive benefits to changes in body composition [79, 80]. The first study included hypogonadal men with weight loss. Body weight was noted to increase significantly in the testosterone group (testosterone enanthate, 100 mg/week) (2.6 kg, p  <  0.001) and in the exercise group alone (2.2 kg, p  =  0.02), however, not in the placebo group or combined testosterone group.

Maximum strength in various exercises including leg press, leg curls, bench press, and latissimus pulls was found to increase in the testosterone-exercise group, but not in the placebo group. LBM increased by 2.3 kg (p  =  0.004) and 2.6 kg (p  <  0.001), respectively, in the testosterone alone or testosterone-exercise group but not in the placebo group. Testosterone and exercise combined did not produce greater results than either one alone [79].

In a similar trial utilizing testosterone enanthate 200 mg/week in eugonadal men with evidence of wasting [80], men treated with testosterone and testosterone-resistance training were found to have greater increases in LBM compared to placebo or placebo-resistance training alone (4.2 kg, 4.6 kg, 0 kg and 2.3 kg, respectively). Significant increases in LBM (p  =  0.05) and muscle area (p  <  0.05) were observed in the resistance training group alone, gains similar to those seen in low dose testosterone replacement. Similar increases in weight, decreases in fat mass and arm and leg muscle area were observed across groups.

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Apr 6, 2017 | Posted by in UROLOGY | Comments Off on HIV and Testosterone in Men

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