Deficiency of the male hormone testosterone, also known as hypogonadism, can cause physical symptoms that clinically may appear to be very close to depression: chronic fatigue, loss of interest in sex and food, depressed mood and a general sense of not feeling well. Lack of testosterone can also lead to anaemia and osteopenia (lowered bone mineral density).

Wasting (loss of lean body mass) and hypogonadism are also linked, although differentiating between cause and effect is not easy. For example, Berger and colleagues found no significant relationship between low testosterone and wasting, concluding that having low testosterone levels did not necessarily mean wasting occurred (Berger 1998). Although a systematic review found that testosterone replacement therapy was more likely to increase lean body mass compared to nothing, that does not necessarily mean all wasting is caused by hypogonadism, or that hypogonadism always leads to wasting (Kong 2002).

Clinical experience suggests that individuals do not become symptomatic until their total testosterone level is about 5nM, which is around half of the normal end of the lower range value. Levels of sex hormone binding globulin (SHBG) levels can become increased during a chronic infection, leading to hypogonadism despite normal testosterone levels.

Low testosterone levels have been identified as a risk factor in the breast enlargement occasionally seen as a side-effect of some antiretroviral drug regimens (Biglia 2004). For more information, see Gynaecomastia (breast enlargement) in Symptoms and illnesses: A to Z of illnesses.

Definitions and prevalence

Exactly what constitutes low testosterone levels is open to interpretation. There are two measures of testosterone levels: total and free. Free testosterone measurements are considered more accurate and reliable, but are more expensive to carry out. Consequently, many studies looking at the prevalence and treatment of hypogonadism have only included total testosterone levels.

Additionally, although the normal range of total testosterone in the blood is between 9.7 and 38.2nM, some clinicians feel that testosterone levels need to be interpreted on an individual by individual basis, as 'normal' levels in one individual may be very different to those in another. Before the advent of highly active antiretroviral therapy (HAART), up to 50% of men with AIDS, and 25% of men with HIV were observed to be hypogonadal (Dobbs 1988). Another study found that of 127 HIV-positive men with or without wasting, 17% had total testosterone levels below 6.73nM, well below the lower limit of normal. Interestingly, 32% were on testosterone replacement therapy at the time (Berger 1998). A study of 587 HIV-positive males between August 1997 and January 1999 found that 20% had total testosterone levels below 13.9nM (Kopicko 1999).

However, a 1999 study of 148 HIV-positive men compared with 42 HIV-negative men found that 31% of the HIV-positive men had testosterone levels below 9.7nM. In this study, testosterone levels were generally lower in all HIV-positive men compared to HIV-negative men, and were lowest in HIV-positive men who had lost 2.3kg or more of weight in the preceding twelve months (Arver 1999).

A Swiss study of 97 randomly selected men found that free testosterone levels did not normalise after nearly two years of successful antiretroviral therapy in the 70% of patients who had subnormal levels at baseline.^[1]

Causes of hypogonadism

Low levels of testosterone can occur in both men and women with HIV disease, although much more is know about testosterone deficiency as it relates to men. The majority of testosterone deficiency in HIV disease is not caused by testicular failure (also known as primary hypogonadism), but by secondary hypogonadism. This happens when there is a disruption of hormone secretion between the hypothalamus (located in the brain) and the pituitary gland (located near the brain).

Since the pituitary gland secretes hormones that stimulate the production of testosterone in the testes, a disruption in this hormonal cascade can cause secondary hypogonadism. Arver (1999) discovered that out of the 31% of HIV-positive men with low testosterone in their study, 19% had primary and 81% had secondary hypogonadism. Although both are associated with having low levels of testosterone, in secondary hypogonadism other sex hormones are also found at low levels, including luteinising hormone and follicle-stimulating hormone. In contrast, in primary hypogonadism these other sex hormones are elevated.

HIV-related hypogonadism can be caused by a variety of factors including opportunistic infections, wasting, HIV-associated malignancies and the effects of HIV itself, antiretrovirals and other medications. In general, the risk of testosterone deficiency increases with the length of time a person has been HIV positive and how ill he / she has been.

Replacement therapy

Men produce between 3 and 10mg of testosterone daily, mostly in the morning and again in the evening, while women produce around 10% of this amount. Replacement therapy aims to mimic this level of production. Treatment options include intramuscular injections testosterone (Sustanon), or use of a skin patch (Andropatch). Studies have shown that replacement therapy can reverse wasting and lipodystrophy, as well as reduce fatigue, relieve depression and restore lost libido.

Sustanon 250 is the most common method of testosterone replacement in the United Kingdom. It is made up of four different testosterone esters, providing a total of 176mg testosterone, which affect how quickly or slowly the testosterone is absorbed after injection. It is popular amongst clinicians because it is cheaper than patches. It is administered by deep, and often painful, intramuscular injection into the buttock or thigh every two to three weeks.

Sustanon 100 contains three shorter-lasting testosterone esters (equivalent to a total of 74mg testosterone) requiring more frequent administration. However, these two standardised dosing regimens can create several problems due to high post-injection peaks and low pre-injection trough levels.

Such high doses of testosterone can bring about problematic feelings of aggression (known popularly as 'roid rage'), insomnia or feeling wired, and an abnormally high interest in sex that can become all-consuming, and lead to the possibility of sexual risk-taking.

Andropatch 5mg is an oval, sticky patch applied to the back, stomach, upper arms or thighs which slowly releases 5mg testosterone over 24 hours. The patch is also available in a 2.5g version. This provides a replacement dose close to physiological levels, although it provides a constant flow of testosterone through the skin, rather than mimicking natural diurnal production. However, up to 30% of users experience skin irritation and if sites are not changed frequently, and localised skin reactions can develop. There is also the problem of patch visibility, which may be considered stigmatising.

Testosterone gel is also available, marketed as AndroGel in the United States for a number of years. The German company Schering own the European distribution rights and launched Testogel in the United Kingdom in 2003. The alcohol-based gel comes in 5g pouches, to be applied each morning to the belly, shoulders or inner thighs (but not genitals) and dries within minutes. Preliminary reports from a study of 30 hypogonadal HIV-positive males who had been receiving a stable regimen of intramuscular testosterone who then switched to AndroGel were very promising. The gel was well tolerated due to the fact that it was easy to use and testosterone levels were stable and physiological. Quality of life scores also improved by an average of 10% compared with the intramuscular testosterone.

Two further gel formulations are also currently being developed. Andractim is a dihydrotestosterone (DHT) gel, which may be comparable to testosterone gel, although no studies comparing them exist. It is available in France over-the-counter at a cost of ¬14 a month. Another 1% testosterone gel, Testim was launched in the United States in February 2003, but has not been licensed in Europe. An trial recently found that 30% more testosterone was absorbed per dose in hypogonadal HIV-negative men on Testim compared with AndroGel (Marbury 2003). However, the clinical significance of this is unknown.

Testosterone, depression and fatigue

A recent study on the use of testosterone replacement therapy in 22 depressed HIV-negative men aged 30 and over indicates that hypogonadism may cause more depression than previously thought. Researchers from Harvard Medical School found that 43% of the men who had not responded to antidepressant medications had total testosterone levels below 12.2nM and about a third of the men with these low or low-normal levels who received 10g of 1% testosterone gel daily showed dramatic improvement in mood, anxiety, and other measures of depression after eight weeks, compared with placebo (Pope 2003).

An earlier non placebo-controlled study of hypogonadal HIV-negative men treated with intramuscular or oral testosterone replacement therapy found that significant reductions in anger, irritability, sadness, tiredness and nervousness, and significant improvements in energy levels, friendliness and sense of well-being were seen in all men on therapy compared with being off therapy (Wang 1996).

Grinspoon (2000) found that men with HIV-related wasting and total testosterone levels below 14.8nM were more likely to be depressed than those men with higher total testosterone, and those who received testosterone replacement therapy were less depressed than those received placebo.

Fatigue has also been seen to be greatly alleviated in an open-label trial of testosterone for 108 HIV-positive men with clinical symptoms of hypogonadism and a total testosterone level below 17.4nM: 79% were rated as having much improved energy level by the studys end (Wagner 1998)

Contraindications for replacement treatment

Finding the right method and dose of testosterone replacement may take time. Clinical signs and symptoms should be reported to a clinician, and free and total testosterone levels should be measured to ensure that adequate replacement levels are being reached. Although replacement doses of intramuscular or transdermal testosterone are not as toxic as chronic cycles of supra-physiological doses of either testosterone or anabolic steroids there are still a variety of adverse effects of, and contraindications to testosterone replacement therapy.

Replacement doses of testosterone do not appear to affect HIV viral load or CD4 or CD8 cell counts (Bhasin 1998). However, they should be avoided in people with high red blood cell counts.

Men with prostate cancer or an enlarged prostate gland should also avoid using testosterone replacement therapy. Intramuscular testosterone and testosterone patches caused increases in prostate-specific antigen (PSA) levels in HIV-negative hypogonadal men aged over 40, so it is recommended that PSA levels are tested before and after treatment (Guay 2000).

Since HIV disease and antiretroviral therapy regimens can reduce levels of high-density lipoprotein (HDL; 'good' cholesterol), the additive effect of testosterone on HDL levels should be monitored. A meta-analysis of hypogonadal HIV-negative men on intramuscular testosterone replacement therapy found that it is associated with a small decrease in HDL cholesterol as well as declines in low-density lipoprotein (LDL) and total cholesterol levels (Whitsel 2001).

Liver function problems are not usually seen with replacement levels of testosterone, although acne can be a problem.

Women and testosterone

Although testosterone is considered to be a male hormone, it also occurs naturally in women. A recent study found that 26% of HIV-infected women with significant weight loss had total testosterone levels below the normal range, even in the era of HAART (Huang 2003).

Laboratory diagnosis of testosterone deficiency among women is difficult, however. Total testosterone levels may be increased as a result of increased serum concentrations of SHBG in HIV-positive women, and although testing for free testosterone levels may be more accurate, the normal ranges for women are not standardised.

There has been little research into testosterone replacement in women, so treating low testosterone among women with HIV has received little attention. However, Miller (1998) found that when low-dose testosterone patches were used on women with HIV-related wasting, both weight and quality of life improved and the development of masculine features was not reported. Similarly, a recent placebo-controlled study has shown an increase in muscle strength in women with HIV-related wasting treated with testosterone patches (Dolan 2004).

References

Arver S et al. Serum dihydrotestosterone and testosterone concentrations in human immunodeficiency virus-infected men with and without weight loss. J Androl 20(5): 611-618, 1999.

Berger D et al. Hypogonadism and wasting in the era of HAART in HIV-infected patients. Twelfth International. Conference on AIDS, Geneva, abstract 32174, 1998.

Bhasin et al. Effects of testosterone replacement with a nongenital, transdermal system, Androderm, in human immunodeficiency virus-infected men with low testosterone levels. J Clin Endocrinol Metab 83: 33155-33162, 1998.

Biglia A et al. Gynecomastia among HIV-infected patients is associated with hypogonadism: a case-control study. Clin Infect Dis 39: 1514-1519, 2004.

Cohan GR et al. A prospective study of the safety and efficacy of a topical transdermal testosterone gel versus intramuscular injections of testosterone for the treatment of testosterone deficiency in male HIV-infected patients. 42^nd Interscience, Conference on Antimicrobial Agents and Chemotherapy, abstract H-1912, 2002.

Dobbs AS et al. Endocrine disorders in men infected with human immunodeficiency virus. Am J Med 84 (pt 2): 611-616, 1988.

Dolan S et al. Effects of testosterone administration in human immunodeficiency virus-infected women with low weight: a randomised placebo-controlled study. Arch Intern Med 164: 897-904, 2004.

Grinspoon et al. Effects of hypogonadism and testosterone administration on depression indices in HIV-infected men. J Clin Endocrinol Metab 2000; 85 (1): 60-65

Guay AT et al. Testosterone treatment in hypogonadal men: prostate-specific antigen level and risk of prostate cancer. Endocr Pract 6 (2):132-138, 2000.

Huang JS et al. Reduced testosterone levels in human immunodeficiency virus-infected women with weight loss and low weight. Clin Inf Dis 36(4): 499-506, 2003.

Kong A and Edmonds P. Testosterone therapy in HIV wasting syndrome: systematic review and meta-analysis. Lancet Infect Dis 2(11): 692-699, 2002.

Kopicko JJ et al. Characteristics of HIV-infected men with low serum testosterone levels. Int J STD AIDS 10(12): 817-820, 1999.

Marbury T et al. Evaluation of the pharmacokinetic profiles of the new testosterone topical gel formulation, Testim TM, compared to AndroGel. Biopharm Drug Dispos 24(3): 115-120, 2003.

Miller K et al. Transdermal testosterone administration in women with acquired immunodeficiency syndrome wasting: a pilot study. J Clin Endocrinol Metab 83(8): 2717-2725, 1998.

Pope HG, et al. Testosterone gel supplementation for men with refractory depression: a randomised, placebo-controlled trial. Am J Psychiatry 160: 105-111, 2003.

Wang C et al. Testosterone replacement therapy improves mood in hypogonadal men--a clinical research center study. J Clin Endocrinol Metab 81(10): 3578-3583

Wagner GJ et al. Testosterone as a treatment for fatigue in HIV+ men. Gen Hosp Psychiatry 20(4): 209-213, 1998.

Whitsel EA et al. Intramuscular testosterone esters and plasma lipids in hypogonadal men: a meta-analysis. Am J Med 111(4): 261-269, 2001.