Hormone Levels and HIV
- Cortisol/DHEA Connection
- Growth Hormone
Decline in several important hormones is associated with HIV and, in many cases, has also been associated with progression of severity of disease. Some of the hormones known to be related to HIV will be discussed below.DHEA.
According to researchers, low serum levels of DHEA-sulfate are associated with HIV illness markers, including viral load, and tend to indicate a negative prognosis (Yang 1994; Ferrando et al. 1999). DHEA has been found to decline in patients as they progress from only being HIV-positive, to displaying symptoms, to having the full-blown AIDS (Jacobson 1991; Mulder et al. 1992). These declines in DHEA have been associated with the development of opportunistic infections and malignancies. Interestingly, about 6 months after therapy with a protease inhibitor is begun, DHEA begins to rise.
Because levels of DHEA are also age-related, as well as HIV-illness related, testing of DHEA levels is recommended before beginning supplementation. DHEA is a hormone that progressively declines with age so reliably that it can even be used as a biomarker of aging. However, a 20-year-old with AIDS may have a very low DHEA level and benefit from supplementation, while in the healthy adult, DHEA supplementation is very rarely needed under age 35. Oversupplementation with DHEA and other androgenic substances can contribute to liver disease, which is also often associated with AIDS or with the side effects of AIDS therapy. This must be considered before beginning DHEA supplementation. Liver function tests must be followed regularly, as would be expected with the monitoring of the HIV state itself. This "first pass effect" of the DHEA through the liver may be circumvented by opening the capsule and placing it under the tongue, allowing the contents to be absorbed through the mucosal tissue rather than in the GI tract. If some is swallowed, this amount will be metabolized in the liver. If the remainder is not swallowed (e.g., spit out), the levels may be variable or similar to those compared to an oral dose. Thus, it is again essential to monitor DHEA levels with blood tests.
DHEA helps to maintain healthy functioning of the immune system, while HAART helps to reduce viral load but is "less effective in immune constitution" (Clerici et al. 2000). DHEA is contraindicated in both men and women with hormone-related cancers. Please refer to the DHEA Replacement Therapy protocol for more information.The Cortisol/DHEA Connection.
Cortisol is a major hormone produced by the adrenal glands. At normal levels, cortisol assists in the metabolism of glucose, protein, and fats. It also has a strong impact on the immune system. At consistently high levels due to illness or stress, cortisol suppresses immune response and accelerates the aging of major organ systems. Rises in cortisol herald the onset of numerous illnesses. In general, rising levels of cortisol are associated with physical and severe mental stress. Similarly, in HIV, cortisol levels are increased (Clerici et al. 2000). Cortisol induces apoptosis of the CD4 lymphocyte, thereby decreasing CD4 counts.
In several studies, DHEA and cortisol levels have been monitored and expressed as a cortisol/DHEA ratio. With progression of HIV disease, cortisol rises and DHEA decreases; therefore this ratio would increase with disease progression and decrease with improvement in clinical status. A therapeutic goal would be to decrease the ratio. This could be done by decreasing cortisol levels, increasing DHEA, or preferably both. Supplementation with DHEA can be started after blood levels are checked. There are very few measures that decrease cortisol levels. DHEA, vitamin C, and aspirin have been shown to block excess cortisol production. Various techniques in stress reduction do affect cortisol levels favorably. The European procaine drug, Gerovital (or GH3), has been claimed to block the effects of cortisol on the immune system.
Increases in the cortisol/DHEA ratio are seen with the development of malnutrition and lipodystrophy (fat metabolism abnormalities) in AIDS. In regard to the evidence that decreasing the ratio of cortisol/DHEA in the AIDS patient might have clinical significance, Christeff et al. (2000) stated: "These findings have practical clinical implications, since manipulation of this ratio could prevent metabolic (protein and lipid) perturbations." Cortisol should be measured as a fasting level drawn upon waking. There is considerable variability in cortisol levels throughout the day, and variations as well from person to person, making values difficult to interpret. The DHEA level or cortisol/DHEA levels are easier to interpret if fasting blood is consistently drawn.Growth Hormone.
Supplemental growth hormone (GH) is an approved treatment for AIDS wasting. This means the therapy is covered by many health insurance plans. When a person has lost at least 10% of their baseline body weight, a diagnosis of AIDS wasting is considered. In this situation, GH is usually given for a 12-week period. Some studies have also shown that a 2-week course of GH at the time of acute OI is beneficial (Paton et al. 1999). This may be a less expensive option than the longer course of treatment for those who must pay for the therapy themselves.
The dose of GH in AIDS therapy is much higher than the dose used for replacement therapy in the aging adult who does not have HIV. Lipodystrophy (disturbances in fat metabolism) is common in AIDS and also is associated with AIDS drug treatments. The lipodystrophy syndrome includes abnormalities in lipids (cholesterol, LDL cholesterol) and also redistribution of body fat stores to the abdomen and redistribution of body mass from muscle to fat. GH therapy helps counteract these fat abnormalities. GH and its messenger hormone IGF-1 have been shown to enhance immune function (Koo et al. 2001). According to Roubenoff (2000), "randomized, double-blind trials have shown that GH therapy increases total body weight, lean body mass, exercise capacity, and quality of life."
As noted earlier, many insurance companies will underwrite the cost of GH therapy if the treatment is concurrent with the use of antiretroviral drugs. If you do not have insurance or the resources to pay for GH therapy, call the National Organization of Rare Disorders (NORD) at (888) 628-6673. NORD can provide you with the names of compassionate care programs available from several drug manufacturers. NORD also has its own compassionate care program.Melatonin.
Melatonin is a hormone secreted by the pineal gland during sleep. It is considered to be a master hormone because it is a neuroendocrine modulator and can exert a regulatory effect over many different areas in the body. Evidence suggests HIV immune suppression may be slowed by nightly intake of melatonin. Melatonin enhances the production of T-helper cells. It also stimulates the production of other immune system components, including NK cells; interleukin-2, -4, and -10; gamma-interferon; eosinophils; and red blood cells (Lissoni et al. 1995). In addition to enhancing different modalities of the immune system, melatonin is a formidable antioxidant in its own right and can prevent immune system cell loss directly through this mechanism.
Dr. George Maestroni, a pioneer in melatonin immunotherapy, conducted a pilot AIDS study in Italy, wherein 11 people with HIV were given 20 mg of melatonin every night. After a month of treatment, the patients had a 35% increase in T-helper cells, a 57% increase in NK cells, and a 76% increase in lymphocyte production.
In spite of these remarkable findings, this line of research has not been pursued because melatonin cannot be patented and consequently will never generate enormous profits for the pharmaceutical giants. However, melatonin appears to benefit persons with AIDS in many other ways, including providing protection against AZT toxicity and wasting syndrome.Testosterone.
In both men and women, testosterone declines with HIV progression. In a study of men with HIV, the scrotal testosterone patch raised blood levels of testosterone but did not improve the participant's symptoms (Dobs et al. 1999), implying perhaps that the drug should be given by injection. There are also nonscrotal patches that make testosterone replacement therapy easier and enhance patient compliance. Because low testosterone levels are very common in males with HIV, they may also be especially associated with the AIDS wasting syndrome. Furthermore, treatment with HAART at this stage does not reverse the testosterone deficiency, and replacement of testosterone itself is required (Rietschel et al. 2000). Testosterone is one of the rare therapies in HIV that helps depression, as well as improving decreased energy and libido (Rabkin et al. 2000). Testosterone replacement also improves morbidity, such as development of opportunistic infections, dementia, and quality of life (Kopicko et al. 1999).
In women with HIV, between 50-95% have testosterone levels below normal for their age group. A testosterone patch (or some other dermal preparation, such as micronized gel) can maintain normal blood levels (for additional information, see http://womenshealth.medscape.com/24784.rhtml).
In addition to total testosterone in the blood, free testosterone levels should also be monitored. The amount of testosterone bound to protein is also frequently measured, although free testosterone is a more important value because it relates to the biologic effects of testosterone.Other Pharmaceuticals to Consider
- Naltrexone Hydrochloride
- Isoprinosine and Diethyldithiocarboliate
- Thymosin Alpha-1
In 1984, naltrexone (ReVia) was approved as a "narcotic antagonist." It was used in the treatment of heroin and other opiate addictions. In 1995, it was approved for the treatment of alcoholism. Naltrexone works by temporarily blocking opiate receptors in the brain. It also has another interesting effect--it increases the amount of endorphins in the brain. Endorphins are hormonal neurotransmitters and immune modulators. Naltrexone increases the natural brain endorphin, metenkephalin, which in turn enhances NK cell function and stimulates cytotoxic lymphocytes. Endorphins also serve as natural "up-regulators" of the immune system. High endorphins are believed to reduce the abnormally high level of alpha-interferon found in AIDS patients, which seems to interfere with the normal functioning of the immune system.
Naltrexone for HIV infection is taken in a very low dose (about 3 mg in the evening), enough to sustain the up-regulation of the endorphin system. It appears to have no negative side effects when taken at these low doses. At higher doses, such as those used in the treatment of alcoholism and in obesity trials, there were side effects, such as insomnia, nausea, anxiety, nervousness, abdominal pain and cramps, vomiting, low energy, and joint and muscle pain. Naltrexone is currently available in the United States with a prescription. Call the Life Extension Foundation for a list of physicians who offer this therapy.Isoprinosine and Diethyldithiocarboliate.
Isoprinosine is a drug that has been shown to be capable of slowing down the progression of AIDS. Since 1986, the Foundation has recommended that persons with HIV add this antiviral to their treatment program. Isoprinosine therapy can beneficially boost thymus gland activity. Isoprinosine has been approved by every regulatory agency in the world except the Food and Drug Administration in the United States. A study published in the New England Journal of Medicine in 1990 is one of many reporting that isoprinosine can boost immune function in persons with HIV (Pedersen et al. 1990). Isoprinosine has also been shown to boost immune function in cancer patients and even in healthy people (Tsang et al. 1985; Richner 1991).
In 1985, the Foundation recommended that persons with HIV take isoprinosine to slow down the progression of immune suppression, which can lead to full immune system collapse. Isoprinosine and some other immune-boosting drugs work best when taken on an alternating dosing schedule (e.g., 2 months on and 2 months off).
As early as 1985, researchers demonstrated that a reducing agent, diethyldithiocarboliate (Imuthiol), which has been used as an immunomodulator--and has also inhibited tumor production--could be useful to improve the immune response in persons with HIV by preventing and treating AIDS (Pompidou et al. 1985a; Pompidou et al. 1985b; Lang et al. 1988; Brewton et al. 1989; Reisinger et al. 1990; Hadden 1991).Biostim.
A French drug called Biostim was studied with regard to its effect on modulating various immune responses. In response to Staphylococcus infection, Biostim therapy significantly increased the critical phagocytic component of immune attack (Scheffer et al. 1991). Biostim also modulated synthesis of human polymorphonuclear granulocytes (Roch-Arveiller et al. 1991).
The immunological effect in aged humans was studied to understand which specific immune components were affected by oral administration of Biostim. The results showed significant restoration of cell-mediated immunity; an increased percentage of CD3+, CD2+, CD4+, and HNKI+ immune cells; and increased phagocytic activity.
Preincubation of immune cells with Biostim resulted in augmentation of natural microbicidal activity. Nonspecific activation of host defenses may have a significant impact on the outcome of infections in the immunocompromised patient. Biostim was shown to be effective in increasing resistance to experimental infections in animals. It also exhibited anti-Candida effects.
Alveolar macrophages are issued from circulating monocytes and are the front line defense of the lungs. The effectiveness of Biostim in respiratory infections is due to its action in cells deep in the lungs, in particular, alveolar macrophages. This drug has been shown to stimulate phagocytosis, increase enzymatic activities, and promote interleukin-1 secretion and TNF-alpha (Sozzani et al. 1988). These activities have been demonstrated in vitro, as well as in animal and human subjects. In one study, Biostim (RU 41740) was found to have a nonspecific enhancing effect on cellular and humoral immune responses and to stimulate phagocytosis in patients with chronic bronchitis (Boissier 1988). In another study on chronic bronchitis, Biostim increased the anti-Candida activity of monocytes and enhanced the phagocytosis indexes of both polymorphonuclear and mononuclear phagocytes (Fietta et al. 1988).
Biostim is an immunomodulator of organic origin, acting on cells of the immune system (B-cells, T-cells, phagocytic cells) and on mediators (IL1-CSG). Its mode of action has been explored by means of experimental infections. The types of defenses involved differed according to whether the experimental infection was caused by an extracellular or intracellular microorganism. Candida albicans and Saccharomyces cerevisiae were used to produce fungal infections, although bacterial infections were produced with Staphylococcus, Escherichia coli, Streptococcus, and other organisms. The influenza virus was used to produce a viral infection. In these experimental models in animals, Biostim increased the survival time of the infected animals and reduced bacterial, fungal, and viral proliferation. These effects were also observed in immunocompromised mice. These studies have demonstrated Biostim as an effective immune adjunct in vitro and in vivo (el Abbouyi et al. 1988; Joly 1988).
Persons with HIV should consider using Biostim in 3-month dosing schedules as follows: 2 tablets daily for 8 days, then discontinue for 3 weeks; 1 tablet daily for 8 days, then discontinue for 3 weeks; 1 tablet daily for 8 days, then discontinue for 9 months.Thymosin Alpha-1.
Thymosin alpha-1 is a peptide that has been extensively studied for its beneficial effects on immune response and therapeutic value. In more than 70 studies, thymosin alpha-1 exhibited immunomodulatory activity and demonstrated benefits, whether used alone or in conjunction with a conventional therapy. Many effects of thymosin alpha-1 appear to be synergistic with those of other cytokines (alpha interferon and interleukin-2), and thymosin alpha-1 may work best in combination with other immunomodulators.
Originally isolated from the thymus gland, thymosin alpha-1 is an amino-terminal acylated peptide of 28 amino acids. It is found in highest concentrations in the thymus but has also been detected in spleen, lung, kidney, brain, blood, and a number of other tissues.
The immunomodulatory activities of thymosin alpha-1 are centered primarily on the augmentation of T-cell function. Studies demonstrate that thymosin alpha-1 shows promise in the treatment of a wide variety of diseases. Thymosin alpha-1 has been shown to increase production of interferon, interleukin-2 (IL-2), and interleukin-3 (IL-3) (Svedersky et al. 1982; Sztein et al. 1986; 1989; Serrate et al. 1987; Hsia et al. 1989; Leichtling et al. 1990; Mutchnick et al. 1991). Thymosin alpha-1 has been shown to increase NK cell activity (Serrate et al. 1987; Favalli et al. 1989; Di Francesco et al. 1994) and enhance production of CD3, CD4, and CD8 cells in patients with chronic hepatitis B (Mutchnick et al. 1991) and cancer (Salvati et al. 1996). Treatment with thymosin alpha-1 has also been shown to decrease replication of the HIV-l virus in human peripheral blood cells, and it has been reported to inhibit the in vitro growth of various nonsmall-cell lung-cancer cell lines (Moody et al. 1993; 1998).
Stimulation of the immune system, especially in combination with antiviral agents, has received considerable interest as a potential means to treat AIDS and HIV-infected patients. Studies have shown a high degree of immune restoration from the combined administration of thymosin alpha-1 and alpha interferon (IFNa). Thymosin alpha-1 in combination with AZT and IFNa has been investigated for treatment of HIV-infected patients. At the University of Rome, a group of researchers conducted a study to investigate the combination of thymosin alpha-1, IFNa, and AZT for the treatment of HIV-infected patients with CD4 counts of 500 or lower (Garaci et al. 1992). The study included seven patients in each of four treatment groups: thymosin alpha-1 + IFNa + AZT; thymosin alpha-1 + AZT; IFNa + AZT; and AZT.
Treatment was continued for 12 months for the majority of patients, with up to 18 months for a smaller cohort of patients. After 1 year, the thymosin alpha-1 + IFNa + AZT combination therapy resulted in a statistically significant increase in CD4 cells and stimulation of lymphocyte cytotoxic activity against natural killer-sensitive target cells compared with the other three treatment groups (Garaci et al. 1992).
Thymosin alpha-1 is available in many countries outside the United States. FDA approval is pending multicenter Phase III trials that are currently underway. Thymosin alpha-1 should be available in the United States by 2004.Other Causes of Immune Suppression
The number one cause of immune deficiency in the world is acknowledged to be malnutrition. Those with intestinal diseases often fail to absorb critical nutrients and are at risk from immune-suppressing agents. That is why maintaining intestinal health is such an important aspect of long-term HIV therapy. A second known cause of immune suppression can result from pharmaceutical or recreational drug use, particularly when used in combination.
The immunosuppressive effects of many drugs have been well-documented for many decades. As recorded in the medical literature for more than 50 years, conditions such as pneumonias, mouth sores, fevers, swollen lymph glands, night sweats, and bacterial infections can be indicative of immunosuppression. Antibiotics, steroids, and antiviral drugs (such as AZT, ddI, ddC, 3Tc, and D4T) are also well-known to have damaging effects on the immune and digestive systems. Many HIV/AIDS treatment drugs are immunosuppressive when used on a daily basis. Bactrim and Septra antibiotics (also known as TMP/SMX) are a double chemotherapeutic, folic-acid inhibitor and are very effective at destroying digestive flora. According to the American Medical Association, these drugs may cause a folic-acid deficiency, resulting in anemia, as well as other adverse effects, such as nausea, vomiting, diarrhea, loss of appetite, headache, dizziness, muscle and joint pain, and rash.
Folic acid is a common B vitamin that is present in most normal diets. It is required by several kinds of bacteria that are normally present in a healthy intestinal colony. A perfectly healthy-looking person can actually have a drug-induced, subclinical state of malnutrition as a result of taking antibiotics, thus promoting a potential end result of immune suppression. TMP/SMX is a powerful sulfonamide derivative. When combined with nitrite, such as is found in amyl nitrite and isobutyl nitrite (a recreational drug known as "poppers"), sulfonamide is a very strong electrophilic oxidizing agent. The immunosuppressive effects of recreational drug use have been recorded in the medical literature since the turn of the century. In large urban areas in Western countries, male homosexuals have patterns of behavior that include the use of recreational nitrite drugs along with long-term prophylactic use of antibiotics. Both chemicals--pharmaceutical SMX and recreational nitrites--reduce the oxygen-carrying capacity of red blood cells by oxidizing ferrous iron to ferric iron in the hemoglobin. This results in a condition known as methemoglobulinemia, a progressively life-threatening deficiency of the oxygen supply in the respiration chain of mitochondria (Home 1979; Dixon et al. 1981; Tyler 1992).Continued
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