AIDS TREATMENT NEWS #140, December 6, 1991
Denny Smith

The endocrine system is a complex of glands and their hormone messengers which regulate the body's metabolism. This system interacts closely with the nervous system; both serve as information pathways, and they share some common mechanisms. The endocrine system maintains everyday internal functions, and is primed as well to deal with external stresses, whether they be traumatic or gradual. Consequently, endocrine activities are involved in any chronic disease process, like HIV infection, as well as episodes of acute illness, such as AIDS-related opportunistic infections.

Several recent reports describe how HIV might affect, or be affected by, the endocrine system. Endocrine problems can also be consequences of opportunistic diseases like CMV, PCP, or Kaposi's sarcoma, and of some drugs used in AIDS care, like pentamidine or ketoconazole.

The signs of endocrine disorders, depending on which gland is affected, can include fevers, low blood pressure and blood sugar, decreased libido, electrolyte imbalances and prolonged recovery from acute illnesses. Unfortunately, these symptoms are not very specific, and are commonly attributed to a variety of causes. An experienced HIV clinician will be able to identify drug and disease-specific symptoms; then follow questions of whether an endocrine dysfunction can be diagnosed, or corrected.

If endocrine imbalances are contributing to symptoms, the results could be significant. For example, one report from Albert Einstein College of Medicine in New York suggested that "failure to thrive" in children with HIV may be due to problems with thyroid regulation. Thyroid problems are commonly treated in non-HIV infected people with thyroid hormone supplements.

Example: DHEA

At the Sixth International Conference on AIDS in 1990, a phase I study of dehydroepiandrosterone (DHEA) in 13 patients showed some dose-dependent immune function improvement and no toxicities (abstract S. B. 488). A modest increase in T4 cells was seen in the five patients who were given more than 750 mg daily.

A more recent report, from the San Francisco Men's Health Study, describes an association between HIV progression and decreased levels of DHEA. This steroidal hormone is derived from cholesterol and contributes to the synthesis of testosterone. We asked the primary author of the new report, Mark Jacobson, M. D., if supplements of DHEA could correct the deficiency or even be directly useful against HIV progression.

Dr. Jacobson said this study showed only that low DHEA levels preceded progression to AIDS in HIV-infected men with T4 helper cell counts below 500. He feels that further interpretation is speculative: perhaps low DHEA levels reflect HIV-induced damage to the adrenal glands, and so only represent a marker for HIV progression; or perhaps, before its levels are depleted, DHEA actually does inhibit HIV.

Dr. Jacobson is currently looking for more conclusions from another clinical study he conducted in which participants were given DHEA; he does not think there is now a solid basis for people with HIV to spend money and risk side effects trying it on their own. He does think that more intensive studies are warranted, including studies of how DHEA, which is an androgenic hormone, affects women with HIV. DHEA levels are naturally higher in men than in women.

Some protective effect on the part of DHEA in HIV infection would not be inconsistent with other activity already connected to this hormone.

As Dr. Jacobson's report noted, DHEA has been associated with in vitro inhibition of viral expression, including that of HIV; it is also associated with a decreased risk of cancer and heart disease. His report concludes by noting that DHEA and its sulfate derivative, DHEA-S, have been administered orally in other clinical situations for months or years at doses up to 1600 mg a day, with no serious side effects -- leading to the suggestion that DHEA be investigated as a potential therapy in HIV infection.

[Some readers may remember that DHEA provoked a flurry of community excitement almost four years ago as an underground treatment, after AIDS TREATMENT NEWS reported positive news of a DHEA trial in Paris (issue #48, January 15, 1988). Its popularity faded, but DHEA has remained occasionally available through AIDS community buyers' clubs. The work of Dr. Jacobson and his colleagues has resurrected some good questions about DHEA. We hope that the search for answers this time takes less than four years, and does not fail to account for the role of DHEA in women with HIV.]

Example: Cortisol

Probably the most common endocrine dysfunction documented in HIV infection is insufficient adrenal production of the hormone cortisol. Ordinarily cortisol is one of the most important of the many endocrine secretions, and a number of studies have documented a blunted response to cortisol stimulation in people with HIV. During episodes of acute illness, such as moderate to severe bouts of Pneumocystis pneumonia, corticosteroids are often administered to help the body cope with the extreme stress.

As with DHEA, the implications of adrenal insufficiency might seem to extend to all people with HIV, symptomatic or not. Some published reports (see references) lend weight to that idea, others appear to downplay it. Most conclude that while a number of hormones are slightly imbalanced even in early HIV infection, they don't ordinarily present clinical symptoms that warrant replacement therapy. Every researcher or clinician we spoke to said that the whole issue requires more attention, and that it would be premature to begin hormone replacement therapy in HIV infection, except when an opportunistic infection like CMV is causing identifiable symptoms.

Interview With Edward Biglieri, M. D.

For additional information we interviewed Edward Biglieri, M. D., a Professor of Medicine at San Francisco General Hospital who has long studied adrenal insufficiency. It may help the reader to know that cortisol production, while associated with the adrenal glands, is actually generated by a series of messages which are passed along a circuit from the hypothalamus through the pituitary to the adrenals.

DS: So many of the body's systems are well-known to be affected by HIV, now the endocrine system as well?

EB: The endocrine system is clearly involved with AIDS, but there is no clear and uniform disturbance that we've identified. Pituitary problems and thyroid abnormalities are common in the general population anyway, so it can be hard to link these conclusively to an HIV infection. The literature gives the impression that it's sporadic at most. We have focused on the adrenal gland because it seems to be implicated in HIV more than the others. We followed adrenal function in over one hundred patients.

DS: How would the adrenal glands be expected to function in regard to AIDS?

EB: The adrenals release stress hormones during an illness or injury, to help regulate blood pressure, blood sugar, etc. We were first intrigued when we saw certain features in patients on PCP therapy that resembled adrenal insufficiency, such as low blood pressure and elevated potassium levels. Of course, they were also on a drug, pentamidine, that can produce those effects through the kidneys. So we had to ask ourselves, is it the disease, or the therapy, or something else? We monitored people right after an acute illness episode by giving them an ACTH test. ACTH is the normal regulator of cortisol production. We found that 25% of these patients didn't respond normally when given ACTH. Their pituitary was not sending sufficient impulses to the adrenal gland to sustain a normal response. Also, the hypothalamus sends an ACTH releasing factor to tell the pituitary, in turn, to stimulate ACTH and the adrenals. A defect in the pituitary was demonstrated when the releasing factor failed to increase ACTH or the adrenal.

DS: Is this a direct result of HIV infection, or something secondary?

EB: It seems as though one of manifestations of HIV generally can be this insufficient hormonal production. Perhaps one out of four people with AIDS will experience this insufficiency. When these people are diagnosed with something serious like PCP, we can give them what we call "stress doses" of steroids, to facilitate their response to the primary treatment.

DS: Is the pituitary implicated in other endocrine problems in AIDS?

EB: I'm not sure there's convincing evidence of that. Sometimes other hormones are low, including testosterone. But I haven't seen studies of these situations involving 100 or more patients like ours. The pituitary obviously could be involved; I haven't seen compelling evidence of it.

DS: But it would make physiological sense?

EB: Yes; in any event, it appears that 25% of those experiencing AIDS-related illnesses exhibit an adrenal insufficiency. But you don't have the luxury of testing someone for adrenal insufficiency when they are in respiratory distress. So we can presumptively give stress doses of steroids for three or four days. This has helped correct some of the metabolic abnormalities seen at that time.

DS: How do the endocrine system and immune system communicate with each other?

EB: Actually, they tend to contradict each other. High doses of cortisol can suppress the immune system. So of course we avoid massive, extended doses. We just want to help people over the critical days of an acute illness, even if the immune system is insulted briefly. Also, there is some speculation that HIV-infected cells secrete something like ACTH; perhaps to circumvent any inadequate production by the pituitary.

DS: Does adrenal insufficiency become more likely as HIV progresses?

EB: You need to watch for the typical clinical signs -- low blood pressure, low blood sugar, high potassium. As with any debility, you have to consider the role of pituitary hormones.

DS: Is there a patient group you would particularly recommend testing for adrenal insufficiency?

EB: Unless there is some concrete suspicion, I wouldn't do it on asymptomatic patients. It may be a marker in asymptomatics, but even then, there are other markers to follow.

DS: So theoretically, if there is HIV involvement of the pituitary or adrenals in someone with no apparent symptoms, then AZT, ddI or ddC could reverse it or stabilize it?

EB: Yes, if HIV is the problem. Otherwise, I would wait until some symptoms develop. It's an interesting situation that's still evolving, but it shows the diffuse nature of this virus, and the many different systems affected. The endocrine involvement certainly is secondary, but by correcting an insufficiency you can make someone feel a lot better and even shorten an acute illness.

Endocrine System and HIV: Technical Articles

Jacobson, MA and others. Decreased Serum Dehydroepiandrosterone Is Associated with an Increased Progression of Human Immunodeficiency Virus Infection in Men with CD4 Cell Counts of 200-499. The Journal of Infectious Diseases, volume 164, pages 864-868, November, 1991.

Mollison LC and others. Hypothyroidism due to destruction of the thyroid by Kaposi's sarcoma. Reviews of Infectious Diseases, pages 826-827, September-October, 1991.

Spitzer RD and others. Case report: hypothyroidism due to Pneumocystis carinii thyroiditis in a patient with acquired immunodeficiency syndrome. American Journal of Medical Science, volume 302, number 2, pages 98-100, August 1991. Marks JB. Endocrine manifestations of human immunodeficiency virus (HIV) infection. American Journal of Medical Science, volume 302, number 2, pages 110-117, August, 1991.

Strauss KW. Endocrine complications of the acquired immunodeficiency syndrome. Archives of Internal Medicine, volume 151, number 7, pages 1441-1444, July, 1991.

Schwartz LJ and others. Endocrine function in children with human immunodeficiency virus infection. American Journal Diseases of Children, volume 145, number 3, pages 330-333, March 1991.

Raffi, F and others. Endocrine function in 98 HIV-infected patients: a prospective study. AIDS, volume 5, number 6, 1991.

Aguilar, X and others. The use of corticosteroids in the control of the adverse effects of cotrimoxazole in AIDS patients suffering from PCP. AIDS correspondence, volume 5, number 6, 1991.

Cobbs, R and others. Adrenocortical insufficiency with normal serum cortisol levels and hyporeninaemia in a patient with acquired immunodeficiency syndrome (AIDS). Journal of Internal Medicine case report, pages 179-181, 1991.

Poretsky L and others. Endocrinologic and metabolic manifestations of the acquired immunodeficiency syndrome. Mt Sinai Journal of Medicine, volume 57, number 4, pages 236- 241, September 1990.

Verges B and others. Anomolies endocriniennes au cours de l'infection par le VIH. Presse Med, 1990 volume 19, number 27 pages 1267-70, July 7-14.

Merenich JA and others. Evidence of endocrine involvement early in the course of human immunodeficiency virus infection. Journal of Clinical Endocrinology and Metabolism, volume 70, number 3, pages 563-565, March 1990.

Murphy TA and Aron DC. How to approach endocrine complications of AIDS. AIDS Medical Report, volume 2, number 11, pages 117-128, November 1989.

Dobs AS and others. Endocrine disorders in men infected with human immunodeficiency virus. American Journal of Medicine, volume 84, number 3, pt 2, pages 611-616, March 1988.

Membreno L and others. Adrenocortical function in acquired immunodeficiency syndrome. Journal of Clinical Endocrinology and Metabolism, volume 65, number 3, pages 482-487, September 1987.

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