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HIV and Hormones

Summer 2004


Introduction

The term "hormone" broadly refers to any type of chemical messenger, but is most often used to denote chemicals produced by the endocrine glands. Hormones play a key role in maintaining homeostasis (a steady state of equilibrium) and regulating many bodily processes -- everything from growth and metabolism to sexual function and reproduction. Over- or underproduction of endocrine hormones can contribute to a wide variety of medical conditions. Diseases such as HIV that affect the whole body can interfere with proper endocrine function, and hormones, in turn, can affect HIV disease progression.


The Endocrine System

While exocrine (e.g., sweat, salivary, digestive) glands secrete chemicals directly to their site of action, endocrine (or ductless) glands release hormones into the bloodstream to be transported throughout the body. The major endocrine glands are the hypothalamus, pituitary, thyroid, parathyroids, adrenal glands, Islets of Langerhans in the pancreas, and the gonads (testes in males and ovaries in females); see illustration below. Other cells (for example, in the gastrointestinal tract and the brain) also secrete chemicals that exert endocrine effects.


HIV and Hormones

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The Hypothalamus and Pituitary

The hypothalamus, located in the lower middle part of the brain, is the primary link between the endocrine system and the nervous system. The hypothalamus relays information about the body's external and internal environment from the brain to other glands. The hypothalamus secretes releasing hormones that direct the pituitary to increase or decrease production of its own hormones, which in turn stimulate subsidiary glands such as the thyroid, adrenal glands, and gonads. The major hypothalamic hormones are growth hormone-releasing hormone (GHRH), thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH), gonadotropin-releasing hormone (GnRH), and prolactin-releasing hormone (PRH).

The pituitary, a pea-sized gland located at the base of the brain, is often called the body's "master gland." The anterior (frontal) lobe of the pituitary produces growth hormone (GH, also called somatotropin), which promotes normal growth and development (especially in children) and regulates metabolism; thyroid-stimulating hormone (TSH, or thyrotropin), which controls the activity of the thyroid gland; adrenocorticotropic hormone (ACTH, or corticotropin), which stimulates the adrenal cortex; two gonadotropins -- follicle-stimulating hormone (FSH) and luteinizing hormone (LH) -- which regulate the activity of the testes and ovaries; and prolactin, which stimulates mammary gland development and milk production. The posterior (rear) portion of the pituitary secretes antidiuretic hormone (ADH, or vasopressin), which helps regulate the body's fluid balance, and oxytocin, which triggers uterine contractions during labor and the release of milk.


The Thyroid and Parathyroid Glands

The thyroid, a butterfly-shaped gland located at the base of the neck, produces triiodothyronine (T3) and thyroxine (T4), two hormones that regulate basal metabolic rate. These hormones increase heart rate and blood vessel dilation, affect mood and metabolism, and are necessary for reproduction; they also play an important role in growth and development in children. Overproduction of thyroid hormones (hyperthyroidism) causes rapid metabolism, insomnia, anxiety, weight loss, and heat intolerance. Conversely, underproduction (hypothyroidism) is characterized by slow metabolism, fatigue, depression, weight gain, muscle and nerve dysfunction, and cold intolerance. The thyroid also secretes calcitonin, which helps regulate the body's calcium and phosphorus balance.

Located near the thyroid are four small parathyroid glands, which secrete parathyroid hormone (PTH). Along with calcitonin, PTH helps regulate levels of calcium, which is required for proper neural transmission and muscle function. PTH increases the concentration of calcium in the blood by promoting the release of calcium from bones, decreasing calcium excretion by the kidneys, and enhancing calcium absorption in the intestines. Calcitonin, in contrast, inhibits the release of calcium from bones and increases its excretion in the urine.


The Adrenal Glands

The two adrenal glands sit on top of each kidney. These glands are comprised of two parts, the medulla (inner part) and the cortex (outer part). The adrenal medulla produces two complementary hormones, epinephrine (adrenaline) and norepinephrine (noradrenaline). In response to physiological or psychological stress, the medulla releases epinephrine, which prepares the body for the "fight or flight" response by increasing heart and breathing rate, enhancing muscle contraction, and stimulating the release of fatty acids and glucose (sugar) for energy. In general, norepinephrine has the opposite effects.

The adrenal cortex produces three types of hormones: mineralocorticoids, glucocorticoids, and androgens. Mineralocorticoids such as aldosterone help regulate the body's fluid and electrolyte balance. Glucocorticoids such as cortisol are often called the body's "stress hormones." Cortisol depresses the immune system and influences glucose and lipid (fat) metabolism, promoting the delivery of glucose to cells to supply energy. Finally, the adrenal cortex produces androgens in both men and women (see the "Sex Glands" section, below).


Endocrine Hormones


Hypothalamus

  • CRH: corticotropin-releasing hormone

  • GHRH: growth hormone-releasing hormone

  • GnRH: gonadotropin-releasing hormone

  • PRH: prolactin-releasing hormone

  • TRH: thyrotropin-releasing hormone


Pituitary

Anterior

  • ACTH: adrenocorticotropic hormone (corticotropin)

  • FSH: follicle-stimulating hormone (gonadotropin)

  • GH: growth hormone (somatotropin)

  • LH: luteinizing hormone (gonadotropin)

  • Prolactin

  • TSH: thyroid-stimulating hormone (thyrotropin)


Posterior

  • ADH: antidiuretic hormone (vasopressin)

  • Oxytocin


Thyroid

  • Calcitonin

  • T3: triiodothyronine

  • T4: thyroxine


Parathyroid Glands

  • PTH: parathyroid hormone


Adrenal Glands

Cortex

  • Androgens: e.g., dehydroepiandrosterone sulfate (DHEA-S)

  • Glucocorticoids: e.g., cortisol

  • Mineralocorticoids: e.g., aldosterone


Medulla

  • Epinephrine: adrenaline

  • Norepinephrine: noradrenaline


Islets of Langerhans

  • Glucagon

  • Insulin

  • Somatostatin


Gonads (Sex Glands)

Ovaries (Female)

  • Estrogens: estradiol, estrone, estriol

  • Progesterone

  • Testosterone


Testes (Male)

  • Testosterone


The Endocrine Pancreas

The pancreas as a whole is an exocrine gland that secretes digestive chemicals directly into the small intestine. But patches of tissue within the pancreas called the Islets of Langerhans produce endocrine hormones that regulate the metabolism of glucose and lipids. After a meal, islet beta cells secrete insulin, which enables cells to take up glucose and causes the liver and other tissues to store sugar, thus lowering the blood glucose level. Alpha cells secrete glucagon, which has the opposite effect, causing the release of stored sugar and an increase in blood glucose. Other endocrine cells produce somatostatin, which limits the release of GH and inhibits the secretion of insulin and glucagon. (See "Insulin Resistance and Diabetes," BETA, Winter 2004.)


The Sex Glands

Both men and women produce "male" hormones (androgens) and "female" hormones (estrogens). All steroid hormones, derived from cholesterol, are synthesized through a complex pathway that ultimately leads to estrogen. Androgens (from either the gonads or the adrenal cortex) may be converted to estrogens by an enzyme called aromatase.

The testes, or male gonads, are located in the scrotum. When stimulated by LH from the pituitary, the testes produce androgens including testosterone. Testosterone has two types of effects on the body: anabolic effects, which promote muscle building; and androgenic effects, which promote the development of the male sex organs, expression of male secondary sexual characteristics, and normal libido (sex drive). The gonadotropins LH and FSH also control sperm production in the testes.

The ovaries, or female gonads, are located in the pelvic cavity. These glands secrete estrogens and progesterone, as well as a small amount of testosterone. Estrogens promote the expression of female secondary sexual characteristics such as breast development. The ovaries are also the sites of ovum (egg) maturation. A complex interplay of hormones regulates the menstrual cycle and allows for pregnancy. FSH from the pituitary promotes the maturation of an ovum in an ovarian follicle and the secretion of estrogen, which causes cells lining the uterus to proliferate. The rise in estrogen triggers the secretion of LH, which causes the follicle to burst and release the mature ovum, a process known as ovulation. The remains of the burst follicle form a structure called the corpus luteum, which secretes progesterone. If fertilization occurs, the placenta continues to produce progesterone throughout pregnancy. If not, the progesterone level drops, menstruation occurs, and the cycle begins anew.


Drugs that Can Affect Hormone Levels

Carbamazepine (Tegretol)
Increases metabolism and clearance of cortisol

Interferon-alpha, pegylated interferon (Pegasys, Peg-Intron)
Can cause autoimmune thyroid disease, leading to either hyper- or hypothyroidism

Ketoconazole (Nizoral)
Inhibits synthesis of adrenal corticosteroids; inhibits production of sex hormones by the gonads

Marijuana (cannabis)
May decrease testosterone level; may increase estrogen level

Megestrol acetate (Megace)
Decreases testosterone production; decreases cortisol production; may cause adrenal insufficiency if abruptly discontinued; may cause hyperglycemia

Opiates (including heroin, methadone)
Decrease adrenal gland response to ACTH stimulation; decrease pituitary production of gonadotropins (LH, FSH); increase prolactin production

Pentamidine
Toxic to beta cells of the pancreas; may cause hypoglycemia followed by hyperglycemia and type 2 diabetes

Phenytoin (Dilantin)
Increases metabolism and clearance of cortisol

Rifampin (Rifadin, others)
Increases metabolism and clearance of cortisol


How Do Hormones Work?

Most endocrine activity is governed by a series of feedback loops involving the hypothalamus and the pituitary. When receptors in the hypothalamus sense a decreased level of a specific hormone in the blood, the gland secretes a releasing hormone that tells the pituitary to signal the appropriate subsidiary gland to ramp up its activity. Conversely, as blood levels of a hormone increase, the hypothalamus decreases production of the releasing hormone, in effect "turning off" the subsidiary gland.

For example, when the body is under physical or emotional stress, the hypothalamus relays this information by releasing CRH into a bed of capillaries that feeds the pituitary. CRH causes the anterior pituitary to increase its production of ACTH, which in turn stimulates the adrenal cortex to produce more of the stress hormone cortisol. As cortisol levels rise, the hypothalamus senses this change and stops producing CRH. Without CRH, the pituitary stops secreting ACTH, and the lack of ACTH, in turn, shuts down production of cortisol by the adrenal glands. This negative feedback loop is called the hypothalamic-pituitary-adrenal axis. Similar regulatory pathways exist for the thyroid and the gonads.

Endocrine function can go awry in several ways. The hypothalamus and/or pituitary can produce too much or too little of the hormones that stimulate the activity of other glands. Subsidiary glands may also produce too much or too little hormone, a condition known as primary gland failure. In addition, cell receptors may fail to respond appropriately to a hormone.


Hormones and HIV/AIDS

Because hormones are involved in so many different bodily processes, it is no surprise that a systemic disease like HIV can affect endocrine function, and vice versa. The first wave of research on endocrine dysfunction in people with HIV occurred in the late 1980s and early 1990s, before the advent of highly active antiretroviral therapy (HAART). Autopsy studies of people who died from AIDS-related conditions often revealed direct infection of endocrine glands by opportunistic pathogens such as cytomegalovirus (CMV), Pneumocystis carinii, or Mycobacterium avium. In addition, several drugs used to treat opportunistic illnesses (OIs) can contribute to endocrine dysfunction (see table above). Today, it is clear that serious endocrine dysfunction occurs more often in people with AIDS or symptomatic HIV disease than in those with early-stage disease and mild immune suppression.

Some endocrine disorders are associated with serious illness in general. For example, many severe systemic illnesses, including AIDS, are associated with reduced thyroid hormone production, a condition known as euthyroid sick syndrome (meaning the thyroid gland itself is normal, but its function is impaired). In various studies, decreased T3 has been associated with lower CD4 cell counts, active OIs, and severe weight loss.

The endocrine, nervous, and immune systems are interrelated in complex ways that are not yet fully understood. The neuroimmune-endocrine connection is most evident in the hypothalamic-pituitary-adrenal axis, which regulates cortisol production in response to bodily stresses such as infection, inflammation, pain, fear, or emotional distress. Cortisol suppresses many aspects of the immune response, including the proliferation of lymphocytes; the activity of natural killer cells, macrophages, and neutrophils; and the production of certain cytokines. High cortisol levels are seen in individuals with many types of severe acute or chronic illness, and AIDS is no exception.

Not long after HAART came into widespread use, physicians began noticing similarities between certain metabolic manifestations associated with antiretroviral therapy -- such as abdominal obesity and dorsocervical fat pad ("buffalo hump") -- and an uncommon form of excessive cortisol production known as Cushing's syndrome. But researchers determined that most individuals with asymptomatic HIV disease did not have inappropriately high cortisol levels. Indeed, by slowing disease progression, HAART likely restrains the release of cortisol. Nevertheless, some researchers believe cortisol may play an as yet unknown role in lipodystrophy syndrome (metabolic and body fat disturbances).

It can be challenging to diagnose endocrine problems in people with HIV because certain symptoms may be associated with altered levels of more than one hormone. For example, fatigue and depression may be due to low levels of thyroid hormone, cortisol, growth hormone, or testosterone. In addition, multiple endocrine mechanisms may interact in complex syndromes such as wasting, lipodystrophy, and other metabolic abnormalities.

While severe endocrine problems are seen less often since HAART became widely available, some experts believe that subtle endocrine disorders are still common in people with HIV. Such subtle imbalances may have a major impact on quality of life, and many people with HIV may benefit from testing of hormone levels and supplementation, if appropriate.


Growth Hormone, Wasting, and Lipodystrophy

While growth hormone (GH) promotes growth and development in children, it helps regulate metabolism and body composition in adults. GH deficiency is characterized by loss of muscle mass, increased fat (especially in the abdomen), fatigue, and depression. GH acts through a cytokine called insulin growth factor 1 (IGF-1), produced by the liver, that promotes muscle building and the breakdown of fat. HIV-positive people with wasting (as well as HIV-negative people suffering from malnutrition) may have GH resistance, a condition in which tissues do not respond normally to the hormone. In contrast to the normal GH/low IGF-1 profile typically seen in individuals with wasting, lipodystrophy appears to be associated with decreased GH secretion.

Recombinant (genetically engineered) human growth hormone has been shown to improve HIV-related wasting. In a controlled study of 178 mostly male HIV-positive subjects by Morris Schambelan, M.D., of San Francisco General Hospital and colleagues (reported in the December 1, 1996 issue of the Annals of Internal Medicine), those taking GH (0.1 mg/kg of body weight) experienced sustained weight gain, increased lean body mass, decreased body fat, and improved exercise performance. GH has also been studied as a therapy for lipodystrophy. In the STARS trial, Donald Kotler, M.D., of St. Luke's-Roosevelt Hospital Center and colleagues found that 4 mg of GH daily or every other day for 36 weeks reduced visceral fat in 142 HIV-positive subjects with abdominal fat accumulation. More recently, Kotler reported at the 11th Conference on Retroviruses and Opportunistic Infections this past February that low maintenance doses of GH (1-2 mg daily) can sustain normalized body fat distribution after higher-dose GH induction therapy.

There are several brands of recombinant GH, but only Serono Laboratories' Serostim is approved for HIV-related wasting. Side effects of GH may include muscle and bone pain, carpal tunnel syndrome, edema (swelling), and reduced insulin sensitivity. While GH remains an option for HIV-positive people with wasting or lipodystrophy, many physicians prefer to first try other therapies such as testosterone. "Given the high cost and reported side effects of growth hormone therapy ... it is best reserved for patients with severe weight loss in whom other therapies are ineffective," wrote Colleen Corcoran, NP, and Steven Grinspoon, M.D., in a review article in the June 3, 1999 issue of the New England Journal of Medicine. (For more information on GH, see "The Many Faces of Human Growth Hormone," BETA, Winter 2003.)


Sex Hormones

In the HAART era, sex hormone imbalances may be the most common endocrine disorders in HIV-positive people. Hypogonadism -- low testosterone in men and decreased levels of estrogen, progesterone, and/or testosterone in women -- can lead to a variety of symptoms including fatigue, anemia, depression, loss of libido, impaired sexual function, and decreased fertility. In women, altered sex hormone levels can cause disturbances in the menstrual cycle. Sex hormones also affect body composition, including the synthesis of muscle tissue and the relative distribution of muscle and fat. Both testosterone and estrogen protect the bones, and the risk of bone loss (osteopenia or osteoporosis) rises as levels of these hormones decrease with age. As people with HIV live longer due to effective antiretroviral therapy, they are subject to the same age-related conditions -- including naturally declining sex hormone levels -- as their HIV-negative counterparts.


Men

Hypogonadism in HIV-Positive Men

Severe hypogonadism is seen most often in men with advanced HIV disease. For example, in an early study of HIV-associated endocrine problems, Adrian Dobs, M.D., of Johns Hopkins University in Baltimore and colleagues reported in the March 1988 issue of the Annals of Internal Medicine that 6% of asymptomatic HIV-positive men, about 40% of men with symptomatic HIV disease, and 50% of men with AIDS were hypogonadal; lower testosterone levels were correlated with weight loss and lower CD4 cell counts. Likewise, Steven Grinspoon, M.D., and colleagues from Massachusetts General Hospital (MGH) reported in the November 1996 issue of the Journal of Clinical Endocrinology and Metabolism (JCEM) that in a study of 75 men with AIDS wasting, about one-half had free (bioavailable) testosterone levels below the normal range for men their age.

In contrast, Julio Collazos, M.D., of Hospital de Galdakao in Vizcaya and colleagues reported in the April 12, 2002 issue of AIDS that in a study of nearly 200 clinically stable HIV-positive men (average CD4 cell count 451 cells/mm3; 64% with undetectable viral load), most subjects had testosterone levels within the normal range. Men receiving no anti-HIV therapy had the lowest testosterone, while those using a regimen combining three classes of antiretroviral drugs had the highest levels. Among the 15 men who had both pre- and post-treatment testosterone measurements, levels increased after starting HAART. But because testosterone levels normally begin to decline around age 40 (a phenomenon known as "andropause"), the beneficial effects of HAART on hypogonadism may be offset as treatment enables HIV-positive men to live to older ages.

Altered testosterone levels have been linked to wasting and other changes in body composition, but the cause and effect relationship is unclear. Severe weight loss can lead to decreased production of the gonadotropins that direct the production of testosterone; in turn, low testosterone, which stimulates the buildup of muscle, contributes to wasting. (Wasting and body composition changes are also associated with growth hormone abnormalities; see table.)

Other symptoms associated with low testosterone include fatigue, depression, loss of libido, and impaired sexual function (e.g., erectile dysfunction, or impotence). For example, in the January 2000 issue of JCEM, Grinspoon and colleagues reported that in a study of 52 hypogonadal and ten eugonadal (normal testosterone level) men with HIV-related wasting, those with lower testosterone levels had higher scores on the Beck Depression Inventory (that is, they were more depressed).

To help diagnose hypogonadism, researchers from St. Louis University devised a questionnaire called Androgen Deficiency in Aging Men, or ADAM; though it was developed to assess normal decreases in androgen levels as men age, the symptoms of testosterone deficiency are the same regardless of cause (see table below).


St. Louis University Androgen Deficiency in Aging Men (ADAM) Screening Questionnaire

  • Do you have a decrease in libido (sex drive)?

  • Do you have a lack of energy?

  • Do you have a decrease in strength and/or endurance?

  • Have you lost height?

  • Have you noticed a decreased "enjoyment of life"?

  • Are you sad and/or grumpy?

  • Are your erections less strong?

  • Have you noticed a recent deterioration in your ability to play sports?

  • Are you falling asleep after dinner?

  • Has there been a recent deterioration in your work performance?


Androgen Supplementation in Men

Diagnosing hypogonadism can be difficult because normal levels vary greatly from person to person. To get a complete picture, different forms of testosterone may be measured. Normally, most testosterone is bound to carrier proteins in the blood; only about 2% is unbound. A total testosterone test measures both bound and unbound hormone. A free testosterone test measures only unbound, or bioavailable, testosterone. A typical normal range for total testosterone is 250-1,200 nanograms/deciliter (ng/dL), while a normal free testosterone range is about 100-200 ng/dL. Total testosterone levels of 250-400 ng/dL are considered borderline low, and may have functional consequences. However, testosterone levels depend on age; older men have lower normal levels than younger men.

When diagnosing endocrine problems it is important to look not just at absolute levels of specific hormones, but also at the balance between them. For example, if a man begins to convert more testosterone to estrogen, his androgen/estrogen ratio will shift and he may begin to experience "feminizing" symptoms such as breast growth, even if his testosterone remains within the statistically normal range. Also, a testosterone level within the normal range may be inadequate for a given individual if his usual level is higher. Some experts recommend getting a baseline testosterone measurement soon after HIV is diagnosed, against which later measurements may be compared.

Hypogonadal men can be treated with supplemental testosterone or synthetic androgens. Testosterone may be administered in several forms. Testosterone cypionate or enanthate are injected intramuscularly, usually every 2-4 weeks. While this is the least expensive method, cyclical injections provide fluctuating blood levels of the hormone, peaking soon after administration and decreasing over time. Transdermal testosterone patches provide a more steady level. The Testoderm patch is applied daily to the scrotum, while the newer Androderm patch is applied daily to the back, abdomen, upper arm, or thigh. Testosterone gel (AndroGel) and creams are also available. Oral testosterone pills are not commonly used since they can cause liver toxicity.

Injected testosterone may increase overall body weight and especially lean body mass. In the July 1, 1998 issue of the Annals of Internal Medicine, Grinspoon and colleagues reported that hypogonadal men with HIV-associated wasting gained muscle mass and reported improved appearance and quality of life after six months of testosterone therapy (one injection every three weeks). Grinspoon's team also found that Beck Depression Inventory scores decreased (indicating improvement) in men treated with testosterone. Judith Rabkin, Ph.D., M.P.H., and colleagues from the New York State Psychiatric Institute reported in the February 2000 issue of the Archives of General Psychiatry that 74% of HIV-positive men receiving biweekly testosterone injections reported increased libido, 59% had improved energy levels, and 58% of men with depression reported improved mood.

Testosterone skin patches are also effective. Shalender Bhasin, M.D., of the University of California at Los Angeles and colleagues reported in the September 1998 issue of JCEM that men using Androderm patches experienced greater increases in lean body mass, larger decreases in fat, and more improvement in quality of life compared with men using placebo patches.

More recently, testosterone has been studied as a treatment for lipodystrophy and other metabolic manifestations associated with HAART. In individuals with mixed lipodystrophy (loss of fat from the limbs and face accompanied by abdominal fat gain), the hormone may both decrease fat and increase lean tissue mass. In the January 2000 issue of JCEM, Colleen Hadigan, M.D., and colleagues (part of the MGH team) reported that in a study of 52 HIV-positive hypogonadal men with wasting, those who received supplemental testosterone experienced improved insulin sensitivity as their lean body mass increased. Further, Wesley Fairfield, M.D., from MGH and colleagues reported that testosterone therapy led to increased bone density in eugonadal HIV-positive men with osteopenia.

In addition to testosterone, synthetic androgenic steroids may also be used. Some have a more androgenic (masculinizing) effect, while others have a more anabolic (muscle-building) effect. The latter may provide some of the benefits of testosterone without unwanted virilization, which is especially important for women, as discussed below. Steroids with more anabolic effects include nandrolone decanoate (Deca-Durabolin), which is injected every 1-2 weeks, and oxandrolone (Oxandrin), which is taken orally every day. Julian Gold, M.D., and colleagues from Prince of Wales Hospital in Sydney reported in the June 1996 issue of AIDS that nandrolone increased lean body mass, enhanced exercise performance, and improved quality of life in HIV-infected hypogonadal men. Oxandrolone, too, has been shown to improve wasting in HIV-positive men, and the drug is FDA-approved for this indication. For example, Joseph Berger, M.D., and colleagues reported in the December 1996 issue of the same journal that daily treatment with either 5 mg or 15 mg of oxandrolone had a positive impact on the weight and well-being of men with HIV.

The potential side effects of testosterone and its synthetic analogs include acne, elevated liver enzymes, altered blood lipids (especially decreased HDL, or "good" cholesterol), mood changes, painful erections, gynecomastia (breast enlargement in men), sleep apnea, edema, excess red blood cell production, high blood pressure, and virilizing effects such as male pattern baldness. In addition, supplemental androgens influence the hypothalamic-pituitary-gonadal axis and shut down natural production of testosterone, which can lead to testicular atrophy (shrinkage). Side effects are less likely when using physiological doses to approximate natural levels, as opposed to supraphysiological doses that exceed the normal range (e.g., for bodybuilding). When using patches, gels, or creams, which deliver a steady dose of testosterone, blood levels should be measured soon after supplementation begins and regularly (every 6-12 months) during the course of therapy.

The long-term effects of androgen therapy in HIV-positive men are unknown. Because androgens can lower the level of cardioprotective HDL cholesterol, there is concern that they may increase the risk of heart disease, especially when combined with antiretroviral drugs that also cause dyslipidemia (altered blood fats). But in the September 1, 2003 Clinical Infectious Diseases supplement, Bhasin suggested that by reducing visceral fat and improving glucose metabolism, androgen therapy may actually decrease the risk of cardiovascular disease in HAART-treated men. Increased cancer risk is another concern, and men taking supplemental androgens should receive regular prostate cancer screening.

Grinspoon recommends that all men with HIV-related wasting should be screened for testosterone deficiency and given supplements if their levels are low. Douglas Dieterich, M.D., of Mt. Sinai School of Medicine in New York City suggests that men with symptoms of hypogonadism should be tested and treated even if they have not experienced severe weight loss.

While testosterone replacement therapy is beneficial for HIV-positive men with hypogonadism, it is unclear whether extra testosterone offers additional benefit for men who already have normal levels. While some studies have shown that supplemental androgens can increase lean body mass, reduce fat, and improve well-being even in eugonadal men, such use remains controversial since the long-term effects of supraphysiological testosterone are unknown.


Women

Sex Hormones in HIV-Positive Women

Since the beginning of the epidemic, women with HIV have reported missed periods, unusually light or heavy periods, severe premenstrual syndrome (PMS), and early menopause. These can be caused by altered sex hormone levels, but other factors -- such as opiate use, certain psychiatric medications, or stress -- may also be responsible for such changes. (For a discussion of fertility in women with HIV, see "Fertility, Conception and HIV" in this issue.)

Despite the frequency of anecdotal reports, controlled studies of menstrual irregularities in HIV-positive women have yielded inconsistent results. Some research suggests that HIV has little or no impact on menstrual function. Based on interviews with 197 HIV-positive and 189 HIV-negative women, Tedd Ellerbrock, M.D., of the Centers for Disease Control and Prevention (CDC) and colleagues reported in the June 1996 issue of Obstetrics and Gynecology that the number and duration of menstrual cycles did not differ significantly between the two groups. In the March 1994 issue of the same journal, P. Shah and colleagues reported no significant differences in rates of amenorrhea (lack of periods), sparse or heavy menstruation, or menstrual cramps between HIV-positive and HIV-negative women. In addition, no association was seen between CD4 cell count and menstrual irregularities, nor were there differences between symptomatic and asymptomatic HIV-positive women. In another study Susan Cu-Uvin, M.D., of Brown University and colleagues found no significant differences in progesterone and estradiol (a form of estrogen) levels based on CD4 cell count, baseline viral load, or type of antiretroviral therapy.

In contrast, Keith Chirgwin, M.D., of the State University of New York Health Science Center and colleagues reported in the August 1996 issue of the Journal of AIDS (JAIDS) that HIV-positive women without AIDS were more likely than HIV-negative women to go longer than six weeks between periods and were more likely to have amenorrhea for more than three months. And based on a large study of 802 HIV-positive and 273 HIV-negative women, Sioban Harlow, Ph.D., of the University of Michigan in Ann Arbor and colleagues reported in the May 2000 issue of JAIDS that women with HIV were slightly more likely to have unusually short (less than 18 days) or very long (more than 90 days) menstrual cycles, and that higher viral load and lower CD4 cell count were associated with increased cycle variability and unusually frequent periods.

According to Kathleen Squires, M.D., of the University of Southern California in Los Angeles, menstrual irregularities, intensified premenstrual symptoms, and early menopause likely have more to do with advanced illness and wasting than with HIV per se. (Among HIV-negative women, it is well known that young women with anorexia nervosa and women athletes with low body fat percentages may stop menstruating.) Indeed, in a study of 43 HIV-positive women with a range of CD4 cell counts published in the May 1997 issue of JCEM, Grinspoon and colleagues found that women with wasting were more likely to have sparse or absent periods compared with those who had stable weight or only mild weight loss; among women with serious wasting, 38% were amenorrheic compared with 17% of women without weight loss. In addition, the euthyroid sick syndrome (described above) is associated with irregular menstruation.

Menstrual problems in HIV-positive women are seen less often since the advent of HAART, but anti-HIV treatment itself may sometimes contribute to such irregularities. For example, Henrik Nielsen, M.D., of Aalborg Hospital in Denmark reported in the March 6, 1999 issue of The Lancet on four cases of hypermenorrhea (unusually heavy periods) in women taking ritonavir (Norvir); hypermenorrhea is a concern because it can lead to anemia due to excessive blood loss.

Much remains to be learned about how female sex hormones and the immune system interact. For example, hormonal factors appear to influence women's vulnerability to HIV infection (see table below). Studies have shown that HIV-positive women have higher CD4 cell counts than men who have been infected for a similar length of time, and show greater disease progression than men with the same CD4 cell counts. Hormonal factors may also help explain differences in how women and men metabolize antiretroviral drugs.


Sex Hormones and HIV Transmission

Research suggests that female sex hormones play a role in HIV transmission and acquisition. Some studies indicate that levels of HIV in women's genital fluids fluctuate over the course of the menstrual cycle as hormone levels change, which could have implications for sexual and mother-to-child transmission. In addition, Chia Wang, M.D., of the University of Washington and colleagues reported in the January 23, 2004 issue of AIDS that use of hormonal contraceptives was associated with increased cervical shedding of HIV.

Hormone levels also appear to affect women's vulnerability to infection. In research on female macaque monkeys, administration of estrogen appeared to protect the animals from infection with SIV (a simian virus similar to HIV), while monkeys who received high-dose progesterone were about seven times more susceptible, likely due to thinning of the linings of the vagina and uterus. Other research suggests that the use of oral or injected hormonal contraceptives without additional barrier methods increases the likelihood that women will contract HIV. In the March 5, 2004 issue of AIDS, Ludo Lavreys, M.D., and colleagues from the University of Washington in Seattle reported that in a study of nearly 1,500 female sex workers in Mombasa, Kenya, women using hormonal contraceptives were at increased risk for HIV infection (1.5 times higher with oral contraceptives; 1.8 times higher with injected Depo-Provera). Looking at a subset of more than 150 women who seroconverted, the same team found that women using hormonal contraceptives at the time of infection were more likely to have a higher viral load set-point and multiple viral variants, which are associated with more rapid disease progression.


Hormone Replacement Therapy for Women

As HIV-positive women live longer, they are subject to the same age-related hormonal changes as their HIV-negative counterparts. The use of hormone replacement therapy (HRT) in women with or without HIV is currently controversial. Once routinely recommended both for ameliorating acute menopausal symptoms and for preventing problems such as osteoporosis, heart disease, and cognitive decline, long-term HRT has fallen out of favor in the wake of studies showing that estrogen, with or without progesterone, appears to confer more risks than benefits.

Menopause typically ensues between the late thirties and late fifties. During menopause and the preceding period known as peri-menopause, declining estrogen levels can cause symptoms such as hot flashes, night sweats, insomnia, fatigue, depression, irritability, forgetfulness, and vaginal thinning and dryness. The more intense symptoms typically improve over two to three years as hormone fluctuations even out. A careful differential diagnosis is necessary to avoid confusing symptoms of menopause with those related to HIV itself, OIs, or antiretroviral therapy.

For young women who experience premature amenorrhea before the normal age of menopause, oral contraceptives may be used to restore levels of estrogen and progesterone and re-establish normal menstrual cycles. For older women undergoing menopause, physicians have traditionally offered HRT using either oral estrogen (e.g., Premarin) or estrogen plus progesterone (e.g., Prempro).

In July 2002 the estrogen/progesterone arm of the Women's Health Initiative (WHI) HRT study, which included more than 160,000 post-menopausal women, was discontinued after data showed that combination HRT increased the risk of breast cancer, heart attacks, and strokes (although the absolute risk was small). HRT did lower the risk of hip fractures and colon cancer, but the researchers concluded that the overall risks outweighed the benefits. This past March the estrogen-only arm of the study was also halted after seven-year data revealed that estrogen not only failed to provide the hoped-for cardiovascular benefits, but also appeared to slightly raise the risk of strokes. (Because estrogen without progesterone increases the risk for uterine cancer, this arm included nearly 11,000 women who had undergone hysterectomies.)

The WHI results were "earth-shaking," according to Lori Kamemoto, M.D., of the University of Hawaii in Honolulu. In the wake of the WHI news, Kamemoto's planned ACTG study of HRT in postmenopausal HIV-positive women was put on hold. As it stands, the risks and benefits of HRT in women with HIV remain unknown. HIV-positive women could conceivably benefit from the bone-preserving effects of estrogen, especially since some studies suggest that HAART or HIV itself are associated with a higher risk of osteoporosis. At the same time, women on HAART may be at higher risk for HRT-related heart attacks or strokes due to dyslipidemia and other side effects associated with antiretroviral therapy, and may be at greater risk for cancer due to immune suppression.

Despite this uncertainty, many physicians believe that HRT remains a viable short-term strategy for relieving disabling menopausal symptoms. "I give the same recommendations to women with HIV as I do to HIV-negative women," says Kamemoto. "If you have severe, intractable post-menopausal symptoms, and you've tried waiting it out, perhaps you're one of those who need HRT."

But most experts now agree that routine, long-term use of HRT solely to prevent heart disease or osteoporosis is inappropriate. Medications such as alendronate (Fosamax) and risendronate (Actonel) may help prevent bone loss without the risks of HRT.

For women with low levels of estrogen and/or progesterone, there are other options beside oral hormone supplements. Estrogen and progesterone are also available in creams, patches, and vaginal rings that deliver lower doses and thus may not carry the same risks. Several natural remedies are sometimes recommended as alternatives to HRT, but these generally have not been studied in controlled trials. Soy, which contains plant-derived estrogens, and black cohosh both appeared to relieve menopausal symptoms in clinical studies. Vitamin E, vitamin B complex, magnesium, and evening primrose oil may help ameliorate symptoms such as hot flashes, cramps, bloating, and mood swings.


Androgen Therapy for Women

HIV-positive women may also experience some of the same problems as their male counterparts: muscle wasting, fat gain, fatigue, depression, loss of libido, and impaired sexual function. And, as in men, these symptoms may be due to low testosterone. Normal testosterone levels vary widely from woman to woman; a typical normal range is 20-100 ng/dL for total testosterone or 1-2 ng/dL for free testosterone.

Low testosterone levels appear to be common in HIV-positive women, especially those with wasting syndrome. In Grinspoon's 1997 study of women with HIV, 66% with severe wasting, 50% with early wasting, and 33% with no wasting had free testosterone levels below the normal range for healthy women of the same age. Likewise, in the February 15, 2003 issue of Clinical Infectious Diseases, Jeannie Huang, M.D., and colleagues from MGH reported that about one-half of HIV-positive women in another study had low free testosterone levels, compared with 8% of uninfected women; among the HIV-positive women, 58% of those with severe wasting had low free testosterone, compared with 24% of those with less significant weight loss.

Testosterone supplements may be used in women, but require caution to avoid unwanted, and possibly irreversible, virilizing side effects such as excessive facial or body hair growth (hirsutism), hoarseness or deepening of the voice, and clitoral enlargement. For this reason, testosterone patches, creams, or gels are preferred over higher-dose testosterone injections. Compounding pharmacies can prepare creams that contain the desired dose. If virilizing side effects or menstrual changes occur, doses should be lowered or therapy discontinued. Testosterone is contraindicated in women who are pregnant or trying to become pregnant.

In a study published in the August 1998 issue of JCEM, Karen Miller, M.D., and colleagues, also part of the MGH research group, reported that in a study of 53 HIV-positive women with wasting and low testosterone levels, administration of physiological doses of testosterone (one patch twice weekly) was associated with weight gain and improved quality of life without virilizing side effects. In the April 26, 2004 issue of the Archives of Internal Medicine, Sara Dolan, NP, and colleagues from the MGH team reported that twice-weekly testosterone patches improved muscle function in this population. Importantly, however, more testosterone is not necessarily better. In Miller's study, the same benefits were not seen in women who received supraphysiological doses of testosterone (two patches twice weekly).

Some researchers think anabolic steroids with less androgenic effects, such as nandrolone and oxandrolone, may be a better option for women, although these agents may not provide the same benefits in terms of improving libido or relieving depression. At the 8th Retrovirus conference in February 2001, Kathleen Mulligan, M.D., from San Francisco General Hospital presented results of a study of 38 HIV-positive women with wasting randomly assigned to receive nandrolone or placebo. The women in the nandrolone arm experienced increased total weight and lean body mass, while virilizing side effects were rare. To date, however, neither nandrolone nor oxandrolone has been adequately studied in women with HIV. Grinspoon recommends only natural testosterone, since synthetic anabolic steroids may adversely affect the liver. Another option is combined testosterone/estrogen therapy (e.g., Estratest). For some women, supplementing both androgens and estrogens appears to improve menopausal symptoms, energy, and libido more than either alone.


Hormones and Transgender Individuals With HIV

HIV-positive transgender individuals who are using hormone therapy for gender transition face some special concerns. Individuals transitioning from male to female usually take oral estrogen (with or without androgen-blocking drugs), while individuals transitioning from female to male typically use injected testosterone and sometimes aromatase inhibitors to block the conversion of testosterone to estrogen.

Hormone doses used for sex reassignment are higher than those used for contraception or hormone replacement therapy. The risk of adverse short-term side effects and long-term consequences (such as liver problems, cancer, and heart disease) is therefore greater. The effects of large hormone doses on HIV-positive transgender individuals have not been well studied, nor has the interaction between hormones and antiretroviral medications.

Concurrent use of hormone therapy, especially oral estrogens, and certain NNRTIs and PIs may lead to either increased or decreased hormone levels. This has been seen with the ethinyl estradiol and norethindrone in oral contraceptives. If drug interactions lead to lower blood estrogen levels, this may cause the return of male features such as facial and body hair growth. Levels of anti-HIV medications could potentially also be affected, leading to either subtherapeutic antiretroviral drug levels or intensified side effects. Transgender men usually take large testosterone doses by injection, thus bypassing the drug-metabolizing cytochrome P450 enzyme system in the liver. Interactions have not been documented between antiretroviral drugs and testosterone, although the possibility cannot be excluded.

Transgender individuals with HIV who are taking hormones should receive care from a physician or medical team that has experience with both HIV treatment and hormone therapy for sex reassignment. While taking hormones, it is important to have levels checked regularly, along with monitoring tests for side effects such as liver toxicity and abnormal blood fat levels.


Conclusion

Even in the HAART era, endocrine disorders and hormone imbalances are common in men and women with HIV. Several symptoms frequently seen in HIV-positive individuals -- such as wasting, metabolic abnormalities, fatigue, and depression -- may be associated with multiple endocrine abnormalities.

Much remains to be learned about the use of hormone therapy in people with HIV, especially in conjunction with HAART. "Using testosterone or anabolics may help with the body habitus changes in lipodystrophy, but it may exacerbate the lipid disorders. Using growth hormone may also counteract the body changes, but it may exacerbate the insulin resistance seen in these patients," Dieterich wrote in a commentary in the December 9, 1998 issue of the Journal of the American Medical Association. "What is the answer?"

The answer awaits further research, including more studies of how the endocrine and immune systems interact in the context of HIV disease.

In the meantime, people with HIV who have symptoms of hormonal problems should seek a provider or medical team that has experience treating both HIV and endocrine disorders. If hormone supplements are used, levels should be checked soon after therapy is started and regularly thereafter. Other tests, including liver enzymes and blood lipids, also should be performed regularly to monitor potential side effects of hormone therapy.

People with HIV and their providers should be alert to the possibility of interactions between hormones and antiretroviral drugs. It has been demonstrated that several protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) interact with the ethinyl estradiol and/or norethindrone in oral contraceptives, either raising or lowering blood levels. However, it is not yet clear how antiretroviral drugs interact with other types of hormone therapy, or how they affect natural hormone levels. Because drug interactions primarily occur in the liver when oral medications are used, administering hormones in the form of patches, creams, or gels may alleviate this concern.

As Squires notes, in the era of HAART, people with HIV and their clinicians now must think about the general health conditions associated with aging in addition to HIV-specific concerns. Although declining hormone levels are part of the natural aging process, supplementation can play an important role in improving functional capacity and quality of life for individuals experiencing clinical symptoms associated with hormone deficiencies.

Liz Highleyman (liz@black-rose.com) is a freelance medical writer and editor based in San Francisco.


Selected Sources

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  3. Corcoran, C. and S. Grinspoon. Treatments for wasting in patients with the acquired immunodeficiency syndrome diagnosis and treatment of endocrine disorders in the HIV-infected patient. New England Journal of Medicine 340(22): 1740-1750. June 3, 1999.

  4. Corcoran, C. and S. Grinspoon. Diagnosis and treatment of endocrine disorders in the HIV-infected patient. Journal of the International Association of Physicians in AIDS Care. February 1998.

  5. Dieterich, D. Testosterone replacement therapy for HIV-related wasting. Journal of the American Medical Association 280 (22): 1959-1960. December 9, 1998.

  6. Dobs, A. and others. Endocrine disorders in men infected with human immunodeficiency virus. American Journal of Medicine 84: 611-616. March 1998.

  7. Dolan, S. and other. Effects of testosterone administration in human immunodeficiency virus-infected women with low weight. Annals of Internal Medicine 164: 897-904. April 26, 2004.

  8. Grinspoon, S. and others. Body composition and endocrine function in women with acquired immunodeficiency syndrome wasting. Journal of Clinical Endocrinology and Metabolism (JCEM) 82(5): 1332-1337. May 1997.

  9. Grinspoon, S. and others. Effects of androgen administration in men with the AIDS wasting syndrome. Annals of Internal Medicine 129: 18-26. July 1, 1998.

  10. Hadigan, C. and others. Fasting hyperinsulinemia in human immunodeficiency virus-infected men: relationship to body composition, gonadal function, and protease inhibitor use. JCEM 85(1): 35-41. January 2000.

  11. Harlow, S. and others. Effect of HIV on menstrual cycle length. Journal of Acquired Immune Deficiency Syndromes 24(1): 68-75. May 1, 2000.

  12. Kotler, D. and others. Low-dose maintenance therapy with recombinant human growth hormone sustains effects of previous r-hGH treatment in HIV+ patients with excess center fat: treatment results at 60 weeks. 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, February 8-11, 2004. Abstract 80.

  13. Miller, K. and others. Transdermal testosterone administration in women with acquired immunodeficiency wasting: a pilot study. JCEM 83(8): 2717-2725. August 1998.

  14. Rabkin, J. and others. A double-blinded, placebo-controlled trial of testosterone therapy for HIV-positive men with hypogonadal symptoms. Archives of General Psychiatry 57: 141-147. February 2000.

  15. Schambelan, M. and others. Recombinant human growth hormone in patients with HIV-associated wasting: a randomized, placebo-controlled trial. Annals of Internal Medicine 125(11): 873-882. December 1, 1996.


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This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.
 
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