Use of Testosterone and Anabolic Steroids in Patients Who Have HIV

[Nelson Vergel]

Introductory Article:

Anabolic Steroids: A Practical Guide


Use of Androgens in Patients Who Have HIV/AIDS: What We Know About the Effect of Androgens on Wasting and Lipodystrophy

Permission by author:
Donald Abrams, MD
AIDS Read. 2001 Mar;11(3):149-56.

Abstract

Decreases in energy, sense of well-being, libido, muscle strength, and muscle mass occur often in patients who have chronic diseases, such as HIV infection. When these symptoms were first recognized in HIV-positive patients, they were thought to be manifestations of HIV infection but may possibly be associated with hypogonadism. Most HIV-infected patients who have hypogonadism have secondary or central hypogonadism, not primary testicular failure. In HIV-infected hypogonadal men, administration of testosterone appears to increase fat-free mass, muscle mass, and quality of life (increased libido, erectile function, and sense of well-being). Similarly, anabolic steroid hormones appear to increase lean body weight and decrease fat content. Although androgens have been used for the treatment of HIV-related wasting and for hypogonadism, many questions remain unanswered, including those regarding the long-term effects, if any, of suppression of luteinizing hormone and follicle-stimulating hormone, as well as the long-term possibilities of malignancy of the prostate and of hepatocellular cancer. Appropriate doses of the various preparations of testosterone and anabolic steroids have not been determined

Introduction

For several years, androgens -- particularly testosterone -- have been used for the treatment of HIV-related wasting. Despite a substantial body of literature on the topic, there remain a large number of unanswered questions. Perhaps the best place to begin a review of the role of androgens in counteracting wasting is to recall the normal physiology of testosterone.

Control of Testosterone Secretion

The testes have 2 principal functions -- spermatogenesis and the secretion of testosterone. Spermatogenesis is a function of the Sertoli cells and is stimulated by follicle-stimulating hormone (FSH), which is secreted by the pituitary gland. Negative feedback on the pituitary gland to control the release of FSH is provided by the hormone inhibin, which is thought to be secreted by either the Sertoli cells or the cells of the spermatogenic tubules.[1]

The synthesis of testosterone begins with the mobilization of cholesterol by the steroid acute regulator protein. The dominant steps involved in synthesizing testosterone from cholesterol are the formation of pregnenolone, 17- -hydroxypregnenolone, dehydroepiandrosterone (DHEA), androstenedione, and testosterone. A less dominant pathway involves the formation of progesterone from pregnenolone, followed by 17- -hydroxyprogesterone, androstenedione, and testosterone.[1]

Regardless of the pathway, the rate-limiting step in the synthesis of testosterone is the initial formation of pregnenolone from cholesterol. This step is catalyzed by the enzyme P-450[SUB]scc[/SUB] (cholesterol side-chain cleavage enzyme) and is inducible by luteinizing hormone (LH) secreted by the pituitary gland. Once released from the testes, testosterone may be converted to dihydrotestosterone (DHT) in various target cells by the enzyme 5 -reductase. Testosterone may also be converted to estradiol by the enzyme P-450 arom (aromatase).[1,2]

Testosterone regulates the secretion of LH through a negative feedback mechanism. Under normal circumstances, the pituitary gland is very sensitive to the feedback provided by testosterone. In patients who have low blood levels of testosterone, blood levels of LH are increased. Testosterone also acts on the hypothalamic-pituitary axis to suppress the stimulating action of gonadotropin-releasing hormone on the pituitary release of LH.[2]

Actions of Testosterone (Part 2 below)

 

[Nelson Vergel]

Part 2:

Actions of Testosterone

The actions of testosterone in peripheral tissues are mediated by the action of DHT on androgen receptors. Testosterone accounts for sexual differentiation and maturation and the development of secondary sex characteristics at puberty. In addition to its action on the hypothalamic-pituitary axis, testosterone acts on the cerebral cortex. Many of the behavioral characteristics that we associate with maleness are, to some extent, the result of the action of either testosterone or DHT on the brain. For example, in the limbic system, testosterone and DHT stimulate libido. These hormones also increase skeletal muscle mass, cardiac muscle mass, and the formation and mineralization of bone, and they stimulate erythropoiesis. In short, testosterone and DHT have far-reaching effects, which extend beyond sexual differentiation and fertility.

It follows, then, that the symptoms and signs of testosterone deficiency, whether associated with AIDS or with other chronic diseases, include decreases in:

1. Energy.
2. A sense of well-being.
3. Libido.
4. Muscle strength.
5. Muscle mass.
6. Erythropoiesis.
7. Bone Mineralization.

Early in the course of the AIDS epidemic, these symptoms were considered to be manifestations of AIDS, but some astute investigators recognized that they could be associated with a deficiency of testosterone.

Testosterone Transport and Blood Levels

About 60% of testosterone in the circulation is bound to sex hormone-binding globulin (SHBG); 38% is bound to albumin, and only 2% is unbound, or free. Testosterone that is bound to SHBG does not easily dissociate, but that bound to albumin can dissociate.

The laboratory assay for free testosterone is more expensive than that for total testosterone. Thus, many laboratories determine only the latter unless they are specifically requested to assay the former. The normal serum value for total testosterone in males is 280 to 1100 ng/dL (9.7 to 38.2 nmol/L); the normal serum level of free testosterone is 50 to 210 pg/mL (174 to 729 pmol/L).

Hypogonadism

Male hypogonadism is defined as the failure of spermatogenesis and the failure of synthesis of normal levels of testosterone by the testes. Two principal types of male hypogonadism -- primary (testicular failure) and secondary (failure of the hypothalamic-pituitary axis, also called central hypogonadism) -- exist. The differentiation between primary and secondary hypogonadism is relatively simple but is not made on the basis of the level of testosterone. In both conditions, the serum levels of testosterone will be low. Instead, the measurement of the levels of the gonadotropins FSH and LH can help differentiate between primary and secondary hypogonadism. Serum levels of both FSH and LH will be normal or reduced in secondary hypogonadism but increased in primary testicular failure.


Hypogonadism in HIV-Infected Patients


The early studies of HIV-infected patients indicated that most patients who had hypogonadism had secondary, or central, hypogonadism. Only rarely found to be a result of primary testicular failure, hypogonadism usually occurred because of opportunistic infection. In a study of 70 HIV-positive men seen at a Johns Hopkins University clinic, 19 were asymptomatic, 42 had AIDS, and 9 had what used to be called AIDS-related complex. Of the 42 patients who had AIDS, 66% reported decreased libido, 33% had erectile dysfunction, and 50% were found to have low serum levels of testosterone. Even asymptomatic, HIV-positive patients were found to have decreased serum levels of testosterone. Seventy-five percent of the hypogonadal men had hypogonadotropic hypogonadism.

 

[Nelson Vergel]

Part 3:

Routes of Administration and Doses of Testosterone


Testosterone may be given orally, sublingually, intramuscularly, or transdermally. The available sublingual preparation is generally not used. Both the oral and intramuscular preparations of free testosterone are rapidly absorbed and metabolized so that androgenic effects are minimal. To prolong the action, various esters of testosterone are used in intramuscular formulations. In increasing order of duration of effect, the esters of testosterone are propionate, enanthate, cypionate, and buciclate. The doses and frequency of administration vary with the particular ester of testosterone. These esters are hydrolyzed to testosterone, which, in turn, is metabolized in a manner identical to that of endogenous testosterone.


A major unresolved question is that of the most appropriate dose of testosterone and, in the case of intramuscular preparations, the frequency of administration. Some clinicians have recommended so-called supraphysiologic doses of testosterone as high as 600 mg weekly. However, the pharmacology textbooks recommend 25 to 50 mg of the propionate ester 2 or 3 times weekly or 50 to 400 mg of the enanthate or cypionate esters every 2 to 4 weeks. It is difficult to know what the physiologic dose is.[5] Consensus among HIV care providers seems to have settled on a treatment dosage of 200 mg injected every 2 weeks.

If the dose of testosterone is too large and the injections are given every 3 weeks, the patient may well have testosterone levels that are higher than normal during the first week and lower than normal during the third week. In fact, relatives and caregivers of patients who receive testosterone by intramuscular injection have remarked that patients often display more aggressiveness and hostility during the first few days after an injection of testosterone, as a result of supraphysiologic levels.

Several transdermal testosterone systems are marketed and have release rates varying from 2.5 to 6 mg/24 h. The original patches, marketed as Testoderm and Testoderm with Adhesive, were designed to be placed on the scrotum, because the skin of the scrotum is extremely thin. Thus, absorption would be facilitated. Although these transdermal systems were designed for scrotal use, they could also be used by women by placing them on an upper extremity or the trunk. In women, the normal level of testosterone is much lower than that in men. Absorption of testosterone from a transdermal patch that was designed for application to the thin skin of the scrotum would be much less if the patch were placed on, say, the skin of an upper extremity. Theoretically, in that situation, the serum level of testosterone would be more in keeping with the normal level of testosterone in women.

Two transdermal systems that do not have to be placed on the scrotum have been marketed -- Androderm and Testoderm TTS. A testosterone gel is now available for transdermal use.


Relationship Between Wasting and Hypogonadism

In a survey of HIV-infected patients published several years ago, it was found that those who displayed evidence of wasting were more likely to have low serum levels of testosterone than were several other groups of patients, including those who hadMycobacterium avium complex infection, those whose CD4 lymphocyte counts were less than 200/µL and who were not wasting, and those whose CD4 lymphocyte counts were greater than 200/µL.[6] Therefore, it appeared that there was a correlation between wasting and hypogonadism in HIV-infected men.

In an unpublished survey conducted in the San Francisco Bay Area before the availability of protease inhibitors (PIs), approximately 70% of 46 physicians reported prescribing testosterone for their HIV-infected patients, but most of the physicians surveyed did not first measure serum levels of testosterone. These physicians reported that their patients who received testosterone noted improved libido, increased energy, improved erectile function, and a better quality of life. It appears that most physicians who treat HIV-infected patients believe that the patients benefited from the administration of testosterone. However, fewer than 25% of physicians reported that their patients who received testosterone gained weight or had increased appetite.

Therefore, 2 questions arise. First, are there any data substantiating that administration of testosterone benefits patients who have wasting by increasing lean body mass (LBM)? Second, does administration of testosterone to HIV-infected patients improve various measures of quality of life, such as libido, erectile function, energy, and sense of well-being?

 

[Nelson Vergel]

Part 4:

Studies of the Effects of Testosterone


Two studies -- 1 of intramuscular testosterone, the other of transdermal testosterone (Androderm) -- have shown gains in LBM.[7,8]On the other hand, 2 additional studies -- 1 of intramuscular testosterone and the other of a different transdermal formulation (Testoderm scrotal patch) -- showed no evidence of gain in fat-free body mass.

Fifty-one HIV-positive men were enrolled in a randomized, double-blind, placebo-controlled study of intramuscular testosterone. These patients experienced wasting -- defined as a body weight less than 90% of ideal body weight or a loss of weight greater than 10% of baseline weight -- and a serum level of free testosterone below 42 pmol/L (normal range for men in the patients' age group, 42 to 121 pmol/L). The men received either placebo or testosterone enanthate, 300 mg IM, every 3 weeks for 6 months.

In this study, the treated patients had a mean increase of 2 kg (4.4 lb) of fat-free body mass, compared with a weight loss of 0.3 kg (0.7 lb) in the patients who received placebo. This difference was statistically significant. Similarly, LBM increased by a mean of 1.9 kg (4.2 lb) in the treated patients but did not change in the patients who received placebo. Muscle mass increased by 2.4 kg (5.3 lb) in the treated patients but decreased by 0.8 kg (1.8 lb) in the patients who received placebo. (Table 1)

The testosterone-treated patients reported that they felt better, experienced improved quality of life, and had improved appearance, compared with patients who received placebo. However, there was no difference in overall weight, fat mass, total body water content, or exercise capacity between the 2 groups.

More recently, the effects of resistance exercise combined with testosterone use on fat-free body mass have been studied. Early in 2000, a study of the effects of testosterone with and without resistance exercise was published. This placebo-controlled, double-blind, randomized clinical trial was conducted from September 1995 through July 1998 in HIV-positive men. The study began before the introduction of PIs. The criteria for enrollment included a serum level of testosterone below 12.1 nmol/L together with a weight loss of more than 5% within the previous 6 months. The patients were assigned to 1 of 4 groups: placebo and no exercise, placebo plus exercise, testosterone and no exercise, and testosterone plus exercise. In the 2 groups receiving active drug, testosterone enanthate, 100 mg/wk, was administered intramuscularly.

It is interesting that 230 patients were screened for the study but that only 133 were eligible. Of these 133 patients, 61 were enrolled and randomized, with 31 assigned to no exercise (placebo, 14; testosterone, 17) and 30 assigned to exercise (placebo, 15; testosterone, 15). Because of dropouts, only 49 patients completed the study: 27 in the no-exercise group (placebo, 12; testosterone, 15) and 22 in the exercise group (placebo, 11; testosterone, 11) (Table 2).

The baseline characteristics of the 4 groups were similar. The principal measures of outcome in this study were muscle strength, body weight, thigh muscle volume, and LBM.

Among men who did not exercise, mean body weight increased significantly, by 2.6 kg (5.7 lb) in those who received testosterone (P< .001 compared with zero change; P < .01 compared with placebo). In contrast, mean body weight decreased by 0.5 kg (1.1 lb) in those who received placebo.

Among men who exercised, mean body weight increased by 0.7 kg (1.5 lb) in those who received testosterone. However, in those who received placebo, it increased by 2.2 kg (4.8 lb) (P = .02 compared with zero weight change).

In the no-exercise group, muscle volume increased significantly in men who received testosterone (P < .001 compared with zero change; P < .01 compared with placebo), with no significant change in those who received placebo.

In the exercise group, both the patients who received placebo and those who received testosterone experienced significant increases in muscle volume (P = .003 for placebo compared with zero change; P = .001 for testosterone compared with zero change).

Thus, either testosterone alone or exercise alone significantly increased weight compared with baseline, but the effects of testosterone were not additive to those of exercise. In other words, based on the results of this study, exercise is a potent anabolic activity.

 

[Nelson Vergel]

Part 5:

Other findings noted in this study were that maximum muscle strength increased in all 3 treatment groups but did not increase in the group that received placebo and did not exercise. LBM increased in the patients who received testosterone alone and in those who received testosterone and exercised. Also, as would be expected, hemoglobin increased in patients who received testosterone.

A multicenter, randomized, double-blind, placebo-controlled, 12-week trial of the transdermal scrotal preparation of testosterone enrolled 133 hypogonadal, HIV-infected men. The diagnosis of hypogonadism was based on either a serum level of total testosterone below 400 ng/dL (44% of enrolled patients) or a level of free testosterone below 16 pg/mL (75% of enrolled patients). An additional criterion for enrollment was a weight loss of 5% to 20%. The mean CD4 lymphocyte count was 162/µL.

Patients who used the transdermal scrotal testosterone patch experienced reversal of hypogonadism, with morning levels of testosterone increasing by 277 ± 45 ng/dL at week 12 of the study. However, no significant changes in weight, body cell mass, quality of life, CD4 lymphocyte counts, or HIV-RNA were noted between the 2 groups. Nevertheless, overall health and cognitive functioning were perceived as improved.

Anabolic Steroid Hormones

Anabolic steroids were developed in an attempt to maximize the anabolic effects of testosterone and minimize its androgenic effects. All currently available anabolic steroids are derivatives of testosterone. They help achieve positive nitrogen balance, providing that the intake of calories and protein is adequate, and their androgenic effects are less than those of testosterone.

The orally active anabolic steroids are produced by alkylation at the C-17 position of the D-ring of testosterone. These anabolic steroids are oxymetholone (Anadrol-50), stanozolol (Winstrol), and oxandrolone (Oxandrin). These hormones have a short duration of action (short half-life) and an increased resistance to inactivation in the liver. With current methods of assay, these drugs are difficult to detect in body fluids.

The anabolic steroids that are not orally active and are administered parenterally are 17-a esterified derivatives of testosterone. These derivatives are nandrolone phenylpropionate (Durabolin) and nandrolone decanoate (Deca-Durabolin). The parenterally active anabolic steroids are highly lipid soluble, are slowly absorbed from injection sites, and have a prolonged duration of action. They are also more easily detected in body fluids than are the orally active anabolic steroids.

Effects of Anabolic Steroids on Lean Body Mass

In subjects taking either oral or parenteral anabolic steroids, weight gain occurs because of enhanced synthesis of protein, which is secondary to stimulation of anabolic receptors in muscle cells. However, some of the weight gain associated with their use is the result of retention of sodium and water.

The effects of anabolic steroids on protein synthesis and nitrogen balance are most evident in hypogonadal men, prepubertal males, and women. In eugonadal men, anabolic steroids produce only a brief period of positive nitrogen balance and no lasting effect on protein synthesis and muscle mass.

Much of what is known about the effects of anabolic steroids has been derived from anecdotes and observational studies. Most of the use of these drugs has been clandestine, and very little controlled research has been done on these compounds.

In a randomized, double-blind, placebo-controlled study of nandrolone decanoate in 29 patients undergoing dialysis, the outcomes measured were weight, LBM, fatigue, grip strength, walking and stair-climbing times, and treadmill performance.[SUP][13][/SUP] Either nandrolone decanoate, 100 mg, or placebo was administered once a week for 3 to 6 months. Lean body weight increased by an average of 4.5 kg (9.9 lb) in the drug group (P < .001 compared with baseline weights), whereas the increase in lean body weight in the placebo group was an average of 1.9 kg (4.2 lb). However, average gain in total body weight was similar in the 2 groups (1.8 kg [4 lb] and 1.4 kg [3 lb], respectively), whereas the decrease in fat content was 2.4 kg (5.3 lb) in the drug group versus 0.4 kg (0.9 lb) in the placebo group. Thus, the patients receiving nandrolone decanoate lost fat and gained LBM, but the patients receiving placebo displayed very little change in fat and LBM. An increase in the average serum level of creatinine was additional evidence suggesting that the patients receiving nandrolone decanoate had achieved an increase in muscle mass. Also, various parameters of functional assessment showed improvement in the drug group.

Why the patients who received placebo experienced weight gain is not known. However, it is a confounding variable that must be taken into consideration in the design of studies of testosterone and the anabolic steroids.

As might be expected, the serum levels of testosterone, FSH, and LH decreased significantly in the patients receiving nandrolone decanoate. This effect occurs because testosterone and the anabolic steroids act on the same receptors in various tissues. Therefore, nandrolone decanoate provided a negative feedback on either the hypothalamus or the pituitary gland, which suppressed the release of FSH and LH.

In a similar, recently reported AIDS Clinical Trials Group study, 33 HIV-positive women with wasting received nandrolone decanoate, 100 mg, every 2 weeks (n = 16) or placebo (n = 17) for 12 weeks.[14] Baseline weight, body composition, and energy intake did not differ between groups. All 16 women receiving the steroid experienced significant increases in weight and LBM compared with those receiving placebo. Median weight gain was 4.6 kg (10.2 lb) versus 0.1 kg (0.2 lb), respectively (P < .001), and mean LBM increase was 3.5 kg (7.7 lb) versus 20.4 kg (20.9 lb) (P < .001). Changes in fat did not differ between groups.

 

[Nelson Vergel]

Part 6

Anabolic Steroids: Possible Gateway to Opioid Use

In a recently published letter, data were presented suggesting that use of the anabolic steroids is a gateway to later dependence on opioids.[SUP][15][/SUP] The authors of the letter work in a drug treatment center. They reported that of 227 men admitted for opioid dependence in 1999, 21 patients (9.3%) had a history of using anabolic steroids. In comparison, in 1990, only 1 of 197 men (0.5%) admitted to a history of using such substances. This difference is statistically significant. None of the 21 patients who were opioid-dependent and had a history of using anabolic steroids had a history of abuse of any other substance before using these steroids.

Eighteen of the 21 opioid-dependent men used opioids to counteract insomnia or irritability associated with the use of anabolic steroids, and 14 used opioids to self-treat depression they experienced with withdrawal from steroid use.

Other variables may be involved in the higher incidence of opioid use in men who have used anabolic steroids, but the data, including anecdotal reports, suggest that the use of these steroids may lead to later abuse of other substances. There is also evidence that these drugs may cause psychological dependence. The problem is that the extent to which the anabolic steroids affect the CNS, particularly the opioid receptors in the brain, is not known.

The step from the use of anabolic steroids to use of opioids could also be related to a particular culture. For instance, 17 of the 21 opioid-dependent men who were previous users of these hormones purchased the opioids from the dealer who supplied them with the hormones. Fourteen men were introduced to the use of opioids by fellow bodybuilders.

 

[Nelson Vergel]

Part 7

Oral Anabolic Steroids

Of the 3 orally active anabolic steroids, oxandrolone has been studied in HIV-infected patients more extensively than has oxymetholone. Stanozolol is used for the treatment of hereditary angioedema and has not been used for its anabolic effect in this patient population to any great extent.

One of the earlier studies of oxandrolone in HIV-infected patients was begun before the introduction of the PIs. Sixty-three HIV-infected men with a loss of body weight greater than 10% were randomized to receive placebo; oxandrolone, 5 mg/d; or oxandrolone, 15 mg/d. The patients who received 15 mg/d of oxandrolone gained weight throughout the 16-week period, whereas those who received 5 mg/d of oxandrolone maintained their weight. In contrast, the patients who received placebo continued to lose weight.

In a follow-up study, which has not yet been published, patients were randomized to placebo or to 1 of 3 dosages of oxandrolone -- 20 mg/d, 40 mg/d, or 80 mg/d (C. Grunfeld, unpublished data, 1998). The patients in the group who received 40 mg/d had the most statistically significant weight gain. However, both the patients in this group and those who received 80 mg/d showed significant increases in serum levels of liver transaminases.

A study published in 1999 sought to determine whether a regimen of supraphysiologic doses of androgen (testosterone) plus an anabolic steroid (oxandrolone) would improve the LBM and strength gains achieved with progressive resistance exercise in HIV-infected men who had experienced weight loss. A second objective of the study was to determine whether antiretroviral therapy with a PI prevented lean body anabolism.

All subjects in the study participated in supervised progressive resistance exercise for 8 weeks. At the same time, they received testosterone, 100 mg/wk, by intramuscular injection. Twenty-four eugonadal men were then randomized to either placebo or oxandrolone, 20 mg/d. Twenty-two patients completed the study. The results indicated that compared with patients who received placebo, those who received oxandrolone experienced improved nitrogen balance (P = .05); increased LBM (P = .005); and increased muscle strength, as judged by either maximum weight lifted (P = .02 to .05) or dynamometry (P = .01 to .05). The results were similar regardless of whether the patients were taking a PI. However, compared with placebo, oxandrolone was associated with a statistically significant decrease in blood levels of high-density lipoprotein (HDL) cholesterol (P < .001).

Because all patients in the study participated in progressive resistance training and received testosterone, only an additive effect of oxandrolone versus placebo was being determined. Therefore, the study appears to be valid even though the number of patients enrolled was small. On the other hand, had the design of the study called for dividing the patients into multiple groups, so that not all patients received testosterone or participated in progressive resistance exercise, the number of patients required to reach statistical significance would have been much higher -- on the order of 350.

The conclusions that can be drawn from the study are that oxandrolone -- 20 mg/d, added to a program consisting of both progressive resistance exercise and physiologic doses of testosterone -- improved the anabolic and functional responses in patients who showed HIV-related weight loss.

Only 1 study of oxymetholone in HIV-infected patients has been reported. This study was a nonblinded pilot trial that was completed in Germany and reported in 1996. Patients were randomly assigned to receive either oxymetholone (14 patients) or oxymetholone plus ketotifen (16 patients).

Ketotifen is an H1-receptor antagonist (ie, antihistamine) that has been shown to block tumor necrosis factor a. The patients receiving the medications under study were compared with 30 matched control patients who met the same inclusion criteria, such as advanced HIV infection and chronic cachexia.[18]

At entry into the study, all patients had experienced significant weight loss (greater than 12 kg [26.4 lb]). The average weight gain by the patients who received oxymetholone was 8.2 kg (18 lb), a 14.5% increase overweight at entry (P < .001). The average weight gain by the patients who received combination therapy was 6.1 kg (13.4 lb), a 10.9% increase overweight at entry (P < .005). The untreated control patients lost an average of 1.8 kg (4 lb).

Both groups of treated patients showed improvement in the ability to perform activities of daily living (the Karnofsky Index) and in several quality-of-life variables.

Although this study was not a double-blind clinical trial, the investigators believed that the results suggested the need for a randomized, double-blind, placebo-controlled, multicenter trial.

 

[Nelson Vergel]

Part 8


Monitoring Patients Receiving Anabolic Steroids

In women, anabolic steroids may cause virilization. Men and women may develop acne vulgaris. Cardiovascular side effects, such as hypertension, may also occur in all patients, regardless of gender or age. The erythropoietic effect of androgen demands that hemoglobin and hematocrit be measured periodically. In some patients, hematocrit may increase as much as 60%.

The most important adverse effects associated with anabolic steroids are increases in hepatic transaminases, histologic changes in the liver, and hyperlipidemia. Fortunately, hepatic peliosis -- the development of blood-filled cysts in the liver, which may lead to intra-abdominal bleeding -- is rare. Cholestatic jaundice and hepatocellular carcinoma may also develop. The probability of the development of hepatic damage in association with therapy with an anabolic steroid may be increased if the patient has chronic viral hepatitis (B or C).

The contraindications to the use of anabolic steroids include carcinoma of the prostate, carcinoma of the breast in men, pregnancy, sensitivity to the drug, and severe hepatic dysfunction.

Nonprescription Medications

An intermediate compound in the synthesis of testosterone from cholesterol is DHEA. Early in the HIV epidemic, it was noted that DHEA was reduced or even depleted in HIV-infected patients. Because the side effects of this compound are mild, it was reasoned that patients would benefit from its administration.

An open-label, dose-escalation study of DHEA in 31 mildly symptomatic, HIV-infected patients was reported in 1993. In this study, high doses of DHEA -- ranging from 750 to 2250 mg/d -- were used for 16 weeks. This androgenic steroid was well tolerated, and no dose-limiting side effects were observed. Efficacy was not demonstrated, and no improvement in immune status and no evidence of a decrease in the severity of HIV infection were found.

However, at the time that the study was conducted, HIV-RNA was not available to quantify viral load, so the investigators followed p24 antigen levels.

Another compound that is available without a prescription is androstenedione. As noted previously, androstenedione is a precursor of testosterone in the secondary (ie, less dominant) pathway of synthesis. Androstenedione has been marketed as an alternative to the use of an anabolic steroid and as a means of increasing the level of testosterone. To test these hypotheses, a randomized, double-blind, placebo-controlled, 8-week study of androstenedione was conducted in 30 young men (aged 19 to 29 years) who had normal levels of testosterone, were not taking nutritional supplements or anabolic steroids, and were not participating in resistance exercise training.

 

[Nelson Vergel]

Part 9

The patients were randomized to receive either androstenedione -- 300 mg/d, during weeks 1, 2, 4, 5, 7, and 8 of the study (n = 10) -- or placebo (n = 10). These 20 subjects participated in 8 weeks of whole-body resistance training. The remaining 10 subjects received a single 100-mg dose of androstenedione to determine the acute effect of the compound on the serum levels of testosterone and estrogen.

In this study, the levels of total testosterone and free testosterone were not affected by either the single-dose administration of androstenedione or its intermittent administration over the period of 8 weeks. However, the serum levels of estradiol and estrone were higher after weeks 2 and 8 compared with pre supplementation, baseline values (P < .05).

Knee-extension strength and the mean cross-sectional area of type 2 muscle fibers increased significantly and to a similar degree in both groups. Also, a significant decrease in fat mass and a significant increase in LBM occurred to a similar degree in both groups.

The group who received androstenedione showed a significant decrease in serum level of HDL cholesterol after 2 weeks, and this change persisted through 8 weeks of the study.

The investigators concluded that intermittent supplementation with androstenedione, 300 mg/d, does not increase serum levels of testosterone and does not enhance the adaptation of skeletal muscle to resistance exercise. However, supplementation with androstenedione may have untoward consequences, which may include increased serum levels of estradiol and estrone in young men and decreased serum levels of HDL cholesterol.

Effects on the Hypothalamus and Pituitary Gland

The question arises as to the effects of testosterone; anabolic steroids; and various supplements, such as DHEA and androstenedione; on the hypothalamus and pituitary gland. LH induces the first step -- the rate-limiting step -- in the synthesis of testosterone, which then provides negative feedback to both the hypothalamus and the pituitary, which suppresses the release of LH. It is logical to speculate that administration of various drugs and substances with androgenic actions will suppress LH.

Indeed, the data show that both LH and FSH are suppressed by these hormones and by synthetic derivatives and precursors. LH, FSH, and SHBG have been noted to be decreased significantly in patients who received testosterone or testosterone plus oxandrolone

Summary

In HIV-infected, hypogonadal men, administration of testosterone appears to increase fat-free mass, muscle mass, and quality of life (increased libido, erectile function, and sense of well-being). Intuitively, one would expect exercise to be additive to the effects of testosterone on muscle mass and weight, but the only trial to study this hypothesis does not support that theory. Instead, exercise appears to exert an anabolic effect independent of the effect of testosterone. Even in eugonadal men who have AIDS, supervised exercise effectively increases muscle mass

Both anabolic and androgenic steroids, whether administered orally or intramuscularly, appear to increase LBM and decrease fat content. However, some steroids, eg, testosterone, have not been shown to have an additive effect on the changes produced by resistance training.

Two precursors of testosterone -- androstenedione and DHE -- have not yet been conclusively shown to be effective in increasing lean body weight or in decreasing fat content.

Testosterone, the anabolic steroids, androstenedione, and DHEA have adverse effects on the liver and cardiovascular system. Testosterone and anabolic steroids also decrease serum levels of LH and FSH.

 

[Nelson Vergel]

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8. Bhasin S, Storer TW, Asbel-Sethu N, 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. 1998;83:3155-3162.
9. Coodley GO, Coodley MK. A trial of testosterone therapy for HIV-associated weight loss. AIDS. 1997;11:1347-1352.
10. Dobs AS, Cofrancesco J, Nolten WE, et al. The use of transcrotal testosterone delivery system in the treatment of patients with weight loss related to human immunodeficiency virus infection. Am J Med. 1999;107:126-132.
11. Bhasin S, Storer TW, Javanbakht M, et al. Testosterone replacement and resistance exercise in HIV-infected men with weight loss and low testosterone levels. JAMA. 2000;283:763-770.
12. Grinspoon S, Corcoran C, Parlman K, et al. Effects of testosterone and progressive resistance training in eugonadal men with AIDS wasting: a randomized, controlled trial. Ann Intern Med. 2000;133:348-355
13. Johansen KL, Mulligan K, Schambelan M. Anabolic effects of nandrolone decanoate in patients receiving dialysis: a randomized controlled trial. JAMA. 1999;281:1275-1281.
14. Mulligan K, Zackin R, Clark RA, et al. Nandrolone decanoate increases weight and lean body mass in HIV-infected women with weight loss: a randomized, double-blind, placebo-controlled, multicenter trial. In: Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections; February 4-8, 2001; Chicago. Abstract 641.
15. Arvary D, Pope HG Jr. Anabolic-androgenic steroids as a gateway to opioid dependence. N Engl J Med. 2000;342:1532.
16. Berger JR, Pall L, Hall CD, et al. Oxandrolone in AIDS-wasting myopathy. AIDS. 1996;10:1657-1662
17. Strawford A, Barbieri T, Van Loan M, et al. Resistance exercise and supraphysiologic androgen therapy in eugonadal men with HIV-related weight loss: a randomized controlled trial. JAMA. 1999;281:1282-1290.
18. Hengge UR, Baumann M, Maleba R, et al. Oxymetholone promotes weight gain in patients with advanced human immunodeficiency virus (HIV-1) infection. Br J Nutr. 1996;75:129-138.
19. Dyner TS, Lang W, Geaga J, et al. An open-label dose-escalation trial of oral dehydroepiandrosterone tolerance and pharmacokinetics in patients with HIV disease. J Acquir Immune Defic Syndr. 1993;6:459-465.
20. King DS, Sharp RL, Vukovich MD, et al. Effect of oral androstenedione on serum testosterone and adaptations to resistance training in young men: a randomized controlled trial. JAMA. 1999;281:2020-202

Drugs Mentioned in This Article

Androstenedione
Dehydroepiandrosterone
Ketotifen
Zaditor
Nandrolone decanoate
Deca-Durabolin
Nandrolone
Durabolin
phenylpropionate
Oxandrolone
Oxandrin
Oxymetholone
Anadrol-50
Stanozolol
Winstrol
Testosterone
Testoderm, Testoderm with
Adhesive, Androderm, Testoderm TTS
Testosterone buciclate
Testosterone cypionate
Testosterone enanthate

 

[Nelson Vergel]

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I brought up an issue that is coming up with compounded hormone access.

 

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Daniel Pekic interviews Nelson Vergel, author of health books and activist, about his struggle to survive and overcome 37 years of living with HIV. He explains how those years prepared him to now advocate for men's health and hormone treatments.

 

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