HIV and Hormones

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.

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).

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.

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.

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).

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 th