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Women, Immunity, & Sex Hormones




 

GMHC Treatment Issues 1992 Jun 20; 6(7): 2

For some time, women with HIV illness, health care providers, and activists have been concerned with the effects of HIV infection and treatment on women's hormones and the effects of hormones on HIV infection. Sex hormones are important because they make up the system responsible for regulating reproduction and sexual function. Questions about this matter are often asked by women with HIV and include: "Does HIV lead to menstrual abnormalities such as missed periods, heavier, or irregular bleeding?"; "Are these problems caused by AZT?"; "Will my menstrual cramps and problems worsen because of HIV?"; "Am I going through early menopause?"; "Why have I lost my sex drive?"; and "Can I take birth control pills?" Researchers have scrutinized how pregnancy impacts HIV infection in HIV-positive women, but thus far they have barely begun to address these other important concerns.

IMMUNE SYSTEM The immune system's purpose is to keep the body healthy. Its job is to recognize what belongs to the body and is therefore part of it, and what is foreign or "other." It must attack and remove disease-causing substances and organisms without causing damage to itself. The immune system is a complicated network of cells and chemicals, and can be thought of as consisting in two parts: the humoral system (substances called antibodies) and the cell-mediated system (mainly white blood cells). Both systems activate white blood cells, called lymphocytes--T-cells and B-cells and T- cells (including T4s).

T-cells recognize foreign substances (antigens), attach to their surfaces, and release substances (lymphokines) which communicate with B-cells. B-cells then produce unique substances called antibodies. Each type of antibody formed in this complicated interaction is highly specific and able to identify and destroy only one antigen. Immune system dysfunction can come from an under- or overproduction of any one or a combination of these substances.

ENDOCRINE SYSTEM The function of the endocrine system is to communicate and regulate the body's many complicated activities. This system works by hormones and other substances that are produced in organs called glands.* Hormones are sent to distant locations in the body called "target organs" to communicate specific instructions that regulate important bodily functions. These include energy production, growth, body temperature, certain behaviors, and reproductive and sexual functions.

Menstrual and reproductive functions are only a portion of the entire makeup of the endocrine system. However, this article will be limited to the portion of the endocrine system concerned with reproduction. Menstruation occurs by a communication between the pituitary gland in the brain and the ovaries. The menstrual cycle directs the ovaries to produce a ripe egg approximately once a month during a woman's reproductive years. The process works as follows: 1. The hypothalamus gland stimulates the pituitary gland, the brain center which acts as the master switch for the hormone system.

2. The pituitary gland releases two hormones called follicle stimulating hormone (FSH) and luteinizing hormone (LH). These signal the ovary to produce its own hormones (estrogen and progesterone).

3. Estrogen and progesterone, sometimes referred to as the female hormones, stimulate the release of a ripe egg, the thickening of the lining of the uterus, and changes in the breast. If the egg becomes fertilized it will embed itself in the thick lining, which becomes the placenta. If the egg is not fertilized, the lining will be shed from the body as a menstrual period.

4. Estrogen and progesterone levels lessen, signaling the hypothalamus gland to begin the cycle again.

WHERE ENDOCRINE AND IMMUNE FUNCTION MEET Research has shown that the endocrine system is affected by: 1) differences in male and female immune responses; 2) administering hormones and hormone therapy (as in the case of oral contraception); 3) pregnancy; and 4) immune deficiency and gynecological disease. Much of this research has been conducted in test tubes or animals. Also, many of the reports offer theoretical explanations for their observations. In other words, even research fails to describe the real life hormonal/immunological phenomena in women's bodies.

Differences in male and female immune responses are well documented. It has been determined that female sex hormones, especially estrogen and progesterone, have a distinct effect on immune function.[1] Women seem to be more resistant to a variety of viral, bacterial, and fungal infections than men. Women also bear the burden of greater susceptibility to autoimmune disorders.[2] These occur when the immune system ends up attacking the body.[3] Examples of autoimmune disorders include lupus, rheumatoid arthritis, idiopathic thrombocytopenic purpura (ITP), and thyroiditis. Females are also more likely to reject transplant organs or grafts than males. Some researchers speculate that a woman's better ability to fend off illness may be the reason why women live longer than men. The exact mechanism for this difference between men and women, however, is not clearly understood. Apparently, both humoral and cellular immune activities are more aggressive in women than men.[4] While sex hormones seem to directly affect the activity of the immune system, HIV-related implications remain unexamined at this time.

CLINICAL CONCERNS Hormone problems are often faced by women whose treatment may be complicated by immune suppression. The use of hormone therapy, like estrogen replacement for menopause or oral contraception, has neither been approved nor forbidden for women with AIDS by current standards of care. Too often, in an effort to "do no harm," hormones are withheld from patients. This policy may be reinforced by the mistaken idea that immune-suppressed patients will all progress to AIDS in the very near future. There may also be a belief that women with HIV infection are "asexual," or should not have sex, and therefore do not have the same concerns that others do about menstruation, menopause, and sexuality. These attitudes, unfortunately, only deny women the life-enhancing, considerate health care which is their right.

MENSTRUAL PROBLEMS HIV-positive women frequently complain of changes in their menstrual cycles, such as irregular periods, heavier or scantier periods, or an increase in noted premenstrual symptoms such as breast pain, swelling, anxiety, depression, and cramps. It is unknown whether these changes are due to HIV itself or to specific medications, particularly AZT. Some other variables that need to be considered include use of other medications, street drugs like cocaine and crack, and weight loss.

Certain noted menstrual irregularities can adversely affect a woman's health during HIV illness. For instance, an increase in the amount of period blood (hypermenorrhea) may predispose a woman to anemia. Anemia may already be a chronic problem, especially in women with HIV. Skipped periods (amenorrhea) requires prompt investigation into possible underlying causes such as pregnancy, ovarian cyst or failure, and early menopause.

Amenorrhea should be investigated in all women, regardless of a woman's intention to become pregnant in the future. An endocrine specialist should be consulted if easy diagnosis is not possible. All heterosexually active women should have a pregnancy test. All women who have not completed menopause and who miss two periods should receive a pelvic examination, and tests to determine if the problem lies outside the reproductive track (i.e., a thyroid or pituitary tumor). Blood tests include the thyroid stimulating hormone (TSH) and prolactin levels. If these values are normal and pregnancy can be ruled out, the woman is often given progesterone challenge (Provera 10 mg daily for five days) to induce bleeding. If bleeding occurs, this establishes that she is producing estrogen, but is not ovulating. These women are at risk for developing endometrial or breast cancer due to constant estrogen administration.

If menstruation does not start after a progesterone challenge, it means that the woman is not producing estrogen and has either an ovarian failure to produce estrogen, or hypothalamic failure to stimulate production of FSH or LH. This indicates a need to run a serum FSH and LH level test to distinguish between the two causes. Hypothalamic failure will demonstrate low levels of FSH and LH. Such a failure is usually stress-related, perhaps due to weight loss, and often will resolve without treatment. High levels of FSH prove that the ovaries are not producing estrogen. Ovarian failure can be due to premature menopause, autoimmune disease, or a destructive disease of the ovaries. The cause should be diagnosed and treated.

MENOPAUSE Menopause, the natural ending of the menstrual cycle, is a normal feature of a woman's life cycle and does not generally require treatment. However, premature menopause seems to be more common in immune-suppressed women. Hormone replacement is indicated for severe symptoms of menopause, such as hot flashes, irritation of the vagina (vaginitis), and irritation of the tube through which urine exits the body (urethritis), vaginal dryness, itch, and discomfort during urination. Replacement hormones may also prevent osteoporosis and damage the cardiac system. The main concern about hormone replacement is that it increases the risk of cancer, due to the use of estrogen alone. Hormone replacement regimens now include estrogen and progesterone to reduce the risk of cancer.

In women with HIV, symptoms of ovarian failure such as hot flashes may be worse at night. They may be commonly mistaken for night sweats which occur due to TB or MAC. Vaginitis and urethritis may be mistakenly treated as thrush, or may lead to openings and sores on the genitals. These symptoms may interfere with normal sleep, appetite, and sexual activities.

PREGNANCY Unlike other hormonal states, pregnancy has been studied with greater emphasis in humans. It has been observed that the high levels of sex hormones (particularly progesterone) which exist during pregnancy induce a state of immunesuppression. This is logically assumed to be required in order that the pregnant woman not reject the fetus, which, after all, is a "foreign object" potentially presenting danger to the immune system. Several authors note that the combination of hormonal, immune, and vascular (relating to blood vessel) changes during pregnancy contribute to an increased incidence of herpes and outbreaks of anal and genital warts (HPV), which occur with frequency in pregnant women. Influenza infections also occur more severely in pregnant women. In general, they tend to be more susceptible to various viral, bacterial, and fungal infections than non-pregnant women.[5] The majority of medical articles published on pregnancy report a decrease in T4 counts during pregnancy, which is most apparent in the last months of pregnancy. However, most researchers feel the decrease in cell immunity is best described as a decrease in the ratio of the number of T4 cells to T8 cells. In other words, there are more T8 than T4 cells during pregnancy, a phenomenon which also occurs in people with HIV.[6] Other factors observed in pregnancy include an increase in steroids in the body.

Despite the temporary state of immune suppression, it is generally felt that pregnancy will not adversely affect asymptomatic HIV-positive pregnant women. Of course, these women must receive high-quality prenatal and obstetrical care. Treatment for gynecological problems in HIV-positive women is in desperate need of immediate research. In particular need of attention is the role of human papilloma virus (HPV) which is thought to complicate cervical cancer.[7] Additionally, ample documentation exists showing that a depressed immune system makes women susceptible to severe and hard-to-treat vaginal and pelvic infections.[8] CONTRACEPTIVES The use of oral contraception in HIV-positive women should not be confused with concerns regarding transmission of HIV or STDs. The pill has never offered protection from HIV transmission to women or their sexual partners. Use of the pill cannot replace safer sex and the use of latex barriers (condoms and dams). Women may request the pill because they have more control over reproduction and may feel more confident of protection from pregnancy, when this is an important concern. Further, the pill is associated with regular, reasonably short and light periods, a benefit that many women enjoy. HIV-positive women who may be anemic may also benefit from shorter, lighter periods. However, the negative aspects should be considered as well.

In research regarding the pill's effect on the female immune system, a study conducted in 1988 concluded that there are no significant differences in blood levels of immunoglobulins (which are substances related to antibodies) in women who take low-dose oral contraceptive as compared to women who do not.9 However, the ability to produce tetanus antibodies after receiving a tetanus shot, and the ability to respond appropriately to the PPD test which injects TB protein under the skin of the arm to test for active infection, may be impaired in women taking the pill.l� This gives rise to some concern that the pill may have an immune-suppressing effect and may also complicate accurate TB testing in these women.

It is unknown whether the pill has adverse interactions with other commonly used HIV/AIDS drugs, like AZT. However, some drug interactions have been documented, and must be considered (e.g. antibiotics, barbiturates, anticonvulsants, valium, oral anti-diabetics, prednisone, anti-hypertensives, and tylenol). The usual precautions against the pill apply to women with HIV as well. For instance, women with liver dysfunction should not use the pill, since hormones are metabolized in the liver. In summary, oral contraceptions have medical and psychological benefits, as well as risks when used in HIV-positive women. Therefore, it makes sense that the decision should derive from a dialogue with a well-informed health care provider.

TRANSSEXUALS Finally, clinicians and researchers must address the use of hormones in pre- and post-operative transsexuals. These clients are often at risk for HIV infection, or may already be aware of their HIV-positive status. Additionally, many such patients have already taken hormones from medical and/or non-medical sources. Often the hormones are needed to support the desired secondary sexual characteristics such as absent facial hair, enlarged breasts, and change in voice quality. Clients may have had surgical castration (surgical removal of sexual organs) with vaginal reconstruction, and/or breast augmentation with implants. The estrogen doses that are commonly taken far exceed the estrogen doses found in oral contraceptives and estrogen-replacing drugs.

It is a questionable practice to refuse to provide a prescription for hormones or medical advice. Perhaps a constructive approach is to supply hormone replacement and work to reach the minimal dose needed to achieve desired effects. Consideration for the client's overall health and relative contraindication, as well as potential for drug interactions, must become part of the discussion.

CONCLUSION In HIV disease, as in all areas of women's health and illness, menstruation must be placed at the top of the research agenda so that women's questions can be adequately addressed. More data and understanding of women's bodies are desperately needed. Neither the immune system nor the endocrine system in humans has been fully understood or described. Attempting to understand and synthesize the subtle interaction between these two networks in women is not easy. A roundtable discussion among immunologists, endocrinologists, obstetrician-gynecologists, neurologists, and women with HIV infection and their advocates would be especially useful.

FOOTNOTES --------- *It should be noted that lymph nodes are often mistakenly called glands. Lymph nodes are not glands, but are actually small bean-shaped organs widely distributed throughout the body.

1. Erbach GT and Bahr JM. Enhancement of in vivo humoral immunity by estrogen: permissive effect of a thymic factor. Endocrinol 128(3):1352-8, 1991.

2. Grossman C. Regulation of the immune system by sex steroids. Endocrine Review 5(3): 435-455, 1984; and Hazzard WR. Why do women live longer than men? Biologic differences that influence longevity. Postgraduate Medicine 85(5):271-8, 1989.

3. Ahmed SA et al . Sex hormones, immune responses and autoimmune diseases. AJP December 1987 (pp.531-551).

4. Racheve C et al. Sex differences information of anti-T-cell antibodies. Nature 263:415418, 1976.

5. Gurka G and Rocklin RE. Reproductive immunology. JAMA 258(20):2983-7,1987; and Minkoff HL. Immune effects in Current Problems in Obstetrics and Gynecology and Infertility: AIDS in Pregnancy. 12(6):214-217, 1989.

6. Castilla IA et al. Decreased levels of circulating CD4 during normal human pregnancy I Repro Immunol 15:103-111, 1985.

7. Schafer A et al. The increased frequency of cervical dysplasia-neoplasia in women infected with HIV is related to degree of immunosuppression. Am J Obstet Gynecol 164 (2):593-99 1991, and Roche JK and Crum CP. Local immunity and the uterine cervix: implications for cancer.

8. Forrest BD. Women, HIV and mucosal immunity. Lancet 337:835-836,1991, Mendling W and Kildovsky U. Immunological findings in patients with chronically recurrent vaginal candidiasis and new therapeutic approaches. Mycoses 32(8):386-90,1989; and Kalo-Klein A and Witkin S. Regulation of the immune response to candida albicans by monocytes and progesterone. Am J OB Gyn 264 (5):1351-1354,1991.

9. Bisset LR and Griffith JFT. Humoral immunity in oral contraceptive users: Plasma immunoglobin levels and in vitro immunoglobin production. Contraception 38(5):567-9,1988.

10. Allen MH. Primary care of women infected with HIV. Obstet Gynecol Clinics of N Amer 17(3):557-69, 1990.

11. Rhoads JL et al. Oral contraceptives and PID. Am J Obstet Gynecol 144: 630-35,1982.

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Copyright © 1992 -Gay Men's Health Crisis, Publisher. All rights reserved to Gay Men's Health Crisis (GMHC) Treatment Issues. Reproduced with permission. Treatment Issues is published twelve times yearly by GMHC, INC. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. GMHC Treatment Issues, The Tisch Building, 119 West 24th Street, New York, NY 10011 Email GMHC. Visit GMHC

Information in this article was accurate in June 20, 1992. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.