In the era of HAART, hypogonadism persists in men with HIV

Before the introduction of highly active antiretroviral therapy, patients with HIV were commonly diagnosed with hypogonadism — likely an effect of “wasting” and chronic illness associated with their disease.

Now, years later, data continue to reveal an increased prevalence of hypogonadism among patients with HIV, although the rates are not as high since the introduction of highly active antiretroviral therapy (HAART).

Todd T. Brown, MD, PhD, said studies defining the frequency of hypogonadism in the era of HAART are needed to determine who is at highest risk.

Reprinted with permission from: Marge Ewertz, RN

The cause of hypogonadism in HIV is unknown. Researchers continue to investigate the reasons behind the increased incidence of hypogonadism, as well as ways to improve and standardize diagnosis and treatment and to determine which patients with HIV are at highest risk for hypogonadism.

“Hypogonadism among men infected with HIV is nothing new and was very common before there was effective ART,” Todd T. Brown, MD, PhD, associate professor of medicine in the division of endocrinology and metabolism at Johns Hopkins University, told Endocrine Today. “Testosterone replacement was an important treatment for AIDS-related wasting before there was effective ART. Now we’re seeing sort of a different ‘flavor’ because most people are on effective ART, but the question remains about what’s happening to their testosterone levels.”

In an interview with Endocrine Today, Steven K. Grinspoon, MD, professor of medicine at Harvard Medical School and director of the program in nutritional metabolism and clinical director of the neuroendocrine clinical center at Massachusetts General Hospital, said in the early days of HIV, before ART, patients with HIV were often chronically ill with opportunistic infections and low weight, and were often hypogonadal.

“It was unclear if the hypogonadism was related to HIV per se or associated illness, but the prevalence was fairly high — typically around 50%,” Grinspoon said in an interview. “More recent data suggest that the prevalence is about 20%, but we’re not 100% sure what the number is.”

In a 1988 study published in the American Journal of Medicine, Adrian Dobs, MD, MHS, of Johns Hopkins School of Medicine, and colleagues observed a 50% incidence of hypogonadism among men with HIV. A 2011 study published in PLoS One, conducted by researchers in Italy, suggested that the current prevalence of hypogonadism is about 16%.

“The frequency of hypogonadism has changed over the years,” Dobs told Endocrine Today. “For AIDS patients, it may be as high as 50%, and in patients without AIDS who are HIV-positive, the numbers are much lower, probably about 15% to 20%.”

Causes of hypogonadism

AIDS wasting was long-thought to be the culprit behind hypogonadism in these patients. AIDS wasting refers to when patients with AIDS lose 10% or more of their body weight. It is often accompanied by diarrhea, extreme weakness and fever that are not related to an infection. In severe cases, including AIDS wasting, the illness suppresses hypothalamic gonadotropin-releasing hormone and pituitary secretion of luteinizing hormone and follicle-stimulating hormone, which in turn results in reduced testosterone production and hypogonadism.

Marc Hellerstein

However, the incidence of AIDS-related wasting has subsided, and the essential question is why hypogonadism persists in current patients, even with ART, according to Marc Hellerstein, MD, PhD, professor of human nutrition at the University of California at Berkeley and professor of endocrinology, metabolism and nutrition at the University of California at San Francisco.

“My best guess is that it is related to the chronic ongoing inflammation due to immune activation,” Hellerstein said. “Starvation or infection/inflammation, for example, are well understood to be associated with hypogonadism. This might be a reflection of ongoing inflammation, but we really don’t know.”

According to Grinspoon, the reasons that hypogonadism is common in people with HIV are multifactorial. Chronic disease itself is associated with hypogonadism, especially if associated with weight loss and severe illness. Grinspoon also said there may be some effects of excess inflammatory cytokines on gonadal function, and that HIV medications may also have an effect on gonadal function.

There are several other mechanisms that may be related to hypogonadism, according to Dobs. There could be an infection related to AIDS that directly affects either the pituitary gland or the testes. In addition, HIV and AIDS are related to a number of inflammatory factors, and these are associated with decreased production of testosterone due, in part, to interference with several of the enzymes in the pathway to testosterone production, Dobs said.

Conflicting data

Since the introduction of HAART, studies have shown varying numbers for the incidence of hypogonadism in men. For example, in a 2000 article published in Clinical Infectious Diseases, Grinspoon and colleagues found that 21% of men with HIV receiving HAART had low free testosterone levels. Based on these data, the researchers concluded that hypogonadism remains relatively common in men with AIDS wasting despite treatment with HAART.

Wunder and colleagues in 2007 reported that 70% of treatment-naive men with HIV in their study had subnormal free testosterone levels, which did not improve after 2 years on combination ART.

Michael P. Dubé

Conversely, also in 2007, Michael P. Dubé, MD, and colleagues reported a subnormal free testosterone level among 6% of treatment-naive patients at baseline before receiving ART. Dubé, professor of medicine in the division of infectious diseases at Keck School of Medicine at the University of Southern California, said this number is not significantly higher than in the general population.

The varied numbers, according to Grinspoon, may be due to differences in screening techniques. In Wunder and colleagues’ study, for example, Grinspoon said the researchers did not strictly assess free testosterone levels in the morning, which is a recommended technique.

“The conclusion by Wunder and colleagues of a 70% incidence may be somewhat overstated,” he said. “But, the data showing that there was no increase in testosterone levels after combination ART are interesting and suggest factors intrinsic to HIV disease may contribute to an increased prevalence of hypogonadism.”

Dubé said he and colleagues in their 2007 paper measured free testosterone by dialysis.

“When studies select out people such as individuals with wasting, who are more likely to display abnormalities, you’re going to find a higher frequency for that group just by definition,” he said.

Testing in HIV population

Assessing hypogonadism among patients with HIV is often difficult for a number of reasons. First, according to Grinspoon, patients with HIV often have increased sex hormone-binding globulin (SHBG) levels, which can affect the total testosterone level. The Endocrine Society recommends generally assessing morning total testosterone, except for in men in whom SHBG abnormality is suspected.

Adrian Dobs

“If you assess the total testosterone, you may get slightly elevated or falsely reassuring results, so most experts agree that assessing the free or bioavailable testosterone is more valid in the HIV population,” Grinspoon said.

Dobs also said the evaluation should include two separate blood samples, both drawn early in the morning. In addition, Brown said the algorithm for calculating testosterone levels must be validated.

“This algorithm involves obtaining total testosterone from a reliable methodology and then calculating the free testosterone using an equation that’s well established in the general population,” he said. “Whether or not this equation holds up in HIV-infected men who have very high levels of SHBG hasn’t been determined yet.”

Another issue is the assay used to assess the levels.

“The equilibrium dialysis method is the most robust, but not everyone uses that assay or assesses the bioavailable testosterone,” Grinspoon said. “To add an additional wrinkle because of a diurnal rhythm, in which testosterone is highest in the morning and then low in the afternoon and evening, the morning level should be checked and confirmed with a second assessment. There’s some precision that’s needed to make this diagnosis, and the real prevalence in a very large population using this algorithm is unknown.”

Dubé said the variability in prevalence results is related to differences in screening methods.

“There’s no good definition of what defines a serum testosterone level that requires intervention,” he said. “It depends on who you talk to, but it’s still not clear what the best screening test is for low testosterone levels in patients with HIV.”

Nonspecific symptoms

Determining whether a patient with HIV has symptoms that warrant assessment for hypogonadism is also difficult. Because of the association of hypogonadism with sarcopenia and low bone density, however, making a diagnosis is important.

“The symptoms and signs of hypogonadism are varied, while some of them are more specific,” Brown said, adding that sexual-type symptoms such as erectile dysfunction and loss of libido should prompt screening. Changes in body composition that accompany hypogonadism, such as increased fat, lower muscle mass and lower BMD, should also serve as red flags.

“Some of these problems are completely unrelated to hypogonadism, but it’s important to keep these things in mind,” Brown said. Unexplained fatigue and depression may also warrant screening, although Grinspoon said he would not test patients for hypogonadism based on just these two symptoms alone, as they are non-specific.

Steven K. Grinspoon

Grinspoon recommended testing patients who present with low bone density and to conversely test for low bone density among men who have been diagnosed with hypogonadism.

“Most important from a medical standpoint is to test those with advanced HIV disease who have wasting because those are the individuals for whom testosterone therapy is likely to be of significant benefit,” Dubé said. “That’s something I think is underutilized — testing for hypogonadism in that particular group. Once you get beyond that, symptoms have not been a reliable indicator of whether or not there are low serum testosterone levels.”

Dobs said it is important to obtain a good medical history and to perform a physical to determine whether the patients are symptomatic for hypogonadism. Some of the questions to be asked include: Does the patient have decreased libido, mild depression or decreased BMD? On a physical exam, what are the size and the consistency of the testes?

“A [DXA] scan may be helpful in this situation because men who have hypogonadism have low BMD, and also, some of the medications that are used for HIV disease are associated with thin bones,” Dobs said.

Management of hypogonadism

Dobs said most HIV doctors are comfortable with treating hypogonadism, as it is a fairly common issue among their patients. If there are questions about why the patient has hypogonadism, or how the patient is responding to treatment, then the patient should be referred to an endocrinologist.

Patients with HIV and hypogonadism are treated similarly to those without HIV — testosterone replacement therapy received intramuscularly or through newer types of preparations such as gels and patches.

“The disadvantage of the intramuscular injection is that you get a spike in the testosterone level right after the injection … whereas with the gels and the patches, it’s more steady state,” Grinspoon said. “Some people worry that the high levels achieved in association with IM injections may do more to stimulate prostate growth or result in increased testosterone conversion to estrogen through aromatization.”

He said, in any instance, patients must be followed appropriately when receiving testosterone to ensure that levels are not too high and that there is no increase in blood counts or prostate-specific antigen or prostate growth.

Grinspoon and colleagues have shown that testosterone treatment has several benefits. They reported in 1998 that patients who received testosterone saw an increase in fat-free mass, lean body mass and muscle mass, and they also improved quality of life. They also reported in 2000 that testosterone administration led to significant improvements in depression scores.

However, Grinspoon said he advises against the use of anabolic steroids in treating hypogonadism, as these are associated with significant adverse health consequences and may further suppress endogenous testosterone production.

“Anabolic steroids, particularly the oral ones, can affect the liver and are not particularly healthy,” he said. “There is no advantage to stacking an anabolic steroid on top of testosterone treatment.”

Ongoing research necessary

Moving forward, researchers continue to examine the effects of testosterone on bone density and muscle, quality of life, psychiatric symptoms, sexual function and lipids. Hellerstein said more studies examining quality of life and whether better, more selective androgens can be developed for treating hypogonadism are also needed.

The continuing high prevalence of hypogonadism among men with HIV may be because HAARTs have become so effective that more men with HIV are aging, according to Brown.

“We know that testosterone levels decline with aging and may have downstream consequences,” he said. “There’s a question as to whether or not HIV-infected patients, and in this case men, have accelerated aging and whether gonadal function is one of these things which declines faster among men with HIV, compare with HIV-negative men.”

In the non-HIV world, researchers are already examining the harms and benefits of replacing testosterone due to aging.

“It is necessary to test and demonstrate low testosterone levels before treatment, rather than presuming hypogonadism and treating empirically, based on symptoms or presumed accelerated aging,” Grinspoon said.

Brown called for studies that define the prevalence of hypogonadism in this population of men in the era of HAART to understand which men are at highest risk. He also calls for studies that examine whether there is change in testosterone over time in men with HIV vs. those without.

He also said there is a need for studies examining whether testosterone resolves issues associated with aging that seem to occur more frequently in HIV-infected men, including osteoporosis, low muscle mass, fat redistribution and diabetes. Brown and colleagues recently published data on the cross-sectional association between low testosterone level and insulin resistance and diabetes in HIV-infected men.

Most importantly, however, Dubé said, “An area of needed research is to get some standardization of the assays and a better definition of who is going to benefit from testosterone replacement because it is not without potential side effects.” – by Tina DiMarcantonio and Emily Shafer

For more information:

• Bhasin S. J Clin Endocrinol Metab. 2010;95:2536-2559.
• Choi HH. J Clin Endocrinol Metab. 2005;90:1531-1541.
• Dobs AS. Am J Med. 1988;84:611-616.
• Dolan Looby SE. AIDS. 2009;23:951-959.
• Dolan S. AIDS. 2009;23:951-959.
• Dolan S. Arch Intern Med. 2004;164:897-904.
• Dubé MP. Clin Infect Dis. 2007;45:120-126.
• Grinspoon S. Ann Intern Med. 1998;129:18-26.
• Grinspoon S. J Clin Endocrinol Metab. 2000;85:60-65.
• Herbst KL. Fertil Steril. 2006;85:1794-1802.
• Miller K. J Clin Endocrinol Metab. 1998;83:2717-2725.
• Rietschel P. Clin Infect Dis. 2000;31:1240-1244.
• Rochira V. PLoS One. 2011;doi:10.1371/journal.pone.0028512.
• Wunder DM. Antivir Ther. 2007;12:261-265.

Disclosures: Drs. Brown, Dobs, Dubé, Grinspoon and Hellerstein report no relevant financial disclosures.

Should women with HIV ever be given testosterone replacement therapy if necessary?

The few studies published with small cohorts have shown safety, efficacy.

Several prior studies suggest that women with HIV experience androgen deficiency. Low testosterone levels are associated with reduced bone density, lean muscle and fat mass and impaired muscle function in this population. Additionally, reduced quality of life, including fatigue, has been observed among those with low testosterone levels.

Few studies have investigated the use of testosterone replacement among women with HIV. Early work from our group established safety and efficacy, with regard to improving weight, quality of life, and muscle strength at an effective dose of 150 mcg per day (during a 3- to 4-day application period; transdermal delivery system).

In a more recent longitudinal investigation, transdermal testosterone replacement at 300 mcg per day (via transdermal delivery system; patch changed twice weekly) during 18 months resulted in an increase in bone mineral density at the hip and greater trochanter, as well as improvement in lean muscle mass and BMI. Moreover, testosterone use was associated with improvement in depressive symptoms and problems affecting sexual function in this population. Of importance, in this 18-month investigation, transdermal testosterone administration to women with HIV and low baseline free testosterone concentrations was very well tolerated and did not result in adverse events, including lipid or liver abnormalities or significant differences in hirsutism or acne.

Other studies have demonstrated testosterone administration at a dose of 300 mcg per day for 6 months is well tolerated and effective in increasing testosterone levels (but not body composition or muscle function) among women with HIV. Moreover, high-normal range testosterone levels achieved during a 6-month period in studies of 300 mcg per day did not negatively impact insulin sensitivity or markers of inflammation/thrombolysis and did not significantly reduce abdominal fat.

In our experience, transdermal testosterone dosing at 300 mcg per day among women with HIV and reduced basal testosterone concentrations improved selected quality-of-life indices, including depression and problems affecting sexual function, in addition to BMD and lean mass. Although these data would suggest a potential benefit of testosterone administration in women with HIV, more data among larger study cohorts of women with HIV are necessary to determine safety and efficacy in this population. Testosterone administration in this population remains a promising therapy in need of further study.

Sara E. Dolan Looby, PhD, ANP-BC, is an instructor in medicine at Harvard Medical School and the Program in Nutritional Metabolism at Massachusetts General Hospital in Boston.

Disclosure: Dr. Dolan Looby reports no relevant financial disclosures.

Data not robust enough and no appropriate preparations are FDA approved.

I would not generally recommend that testosterone be prescribed for women with HIV. The first reason is that the data on the effectiveness of replacement dose testosterone in this group of women are not very robust. There have been several small, randomized, placebo-controlled studies examining the effects of testosterone replacement therapy in women with HIV, all with modest results, and not all with consistent findings.

The first short-term study (4-month duration) in women with AIDS wasting demonstrated a mean increase in weight of 1.3 kg compared with placebo with the lower (150 mcg daily) but not higher (300 mcg daily) testosterone dose, while a second short study (6-month duration) demonstrated an improvement in strength but not weight or lean body mass with the 300 mcg daily dose. A third study, of 6-month duration, demonstrated no increase in weight, lean body mass or muscle strength in those who received testosterone compared with placebo. The only long-term published study (18-month duration) demonstrated modest improvements in lean body mass (by a mean of 1 kg more than the placebo group), BMI (by a mean of 0.8 kg/m² more than the placebo group) and in BMD at the hip, but not spine, as well as an improvement in mood compared with placebo.

Therefore, although there are promising published data on the effectiveness of testosterone replacement in other groups of women — for example, in surgically and naturally postmenopausal women for the treatment of libido and sexual function — the data in support of testosterone use in women with HIV are not compelling.

Moreover, and importantly, in most countries, including the United States, there is no government agency-approved preparation available that raises testosterone within a physiologic range for women, and supraphysiologic dosing is inadvisable.

Karen K. Miller, MD, is an associate professor of medicine at Harvard Medical School and in the neuroendocrine unit at Massachusetts General Hospital in Boston.

Disclosure: Dr. Miller reports no relevant financial disclosures.

Robert W. Rebar

Testosterone replacement therapy is not approved for use in any women, and the use is still very controversial.

It is true that women who’ve had their ovaries removed and women with premature ovarian failure have significantly lower testosterone levels than women of a similar age, or for premature ovarian failure, even than postmenopausal women. However, efficacy of providing exogenous testosterone has not been demonstrated for any product to the satisfaction of the FDA.

The risks of therapy are also unclear. If usage is not yet approved for women who are HIV-negative, then how can it be recommended for women with HIV?

Robert W. Rebar, MD, is an executive director of the American Society for Reproductive Medicine and an Endocrine Today Editorial Board member.

Disclosure: Dr. Rebar is an employee of ASRM and on the editorial board of Journal Watch. He also serves as chair of the NIH RMN network DSMB and on a DSMB of an estrogen trial for postmenopausal women.