Reproductive Function in Human Immunodeficiency Virus Infection1

Joan C. Lo and Morris Schambelan

Division of Endocrinology, San Francisco General Hospital, and Department of Medicine University of California–San Francisco, San Francisco, California 94110

Address correspondence to: Joan C. Lo, M.D., Division of Endocrinology, San Francisco General Hospital, Building 30, Room 3501-K, San Francisco, California 94110.

Since the advent of highly active antiretroviral therapy (HAART), the resultant decline in mortality rate associated with human immunodeficiency virus (HIV) infection (1) has allowed patients and clinicians to consider other important health issues beyond short-term survival. Included among these issues is the maintenance of normal gonadal function, as well as ethical and practical considerations for those individuals who wish to conceive and have children. Here, we review the pathophysiology and treatment of abnormalities in gonadal and sexual function and consider some of the challenges surrounding reproductive health among HIV-infected men and women.

Reproductive health in HIV-infected men

Testicular function and sex hormones. Autopsy studies in men with the acquired immune deficiency syndrome (AIDS) reveal a number of histopathologic changes in the testes, including hypospermatogenesis, spermatogenic arrest, and "Sertoli-only" findings, as well as tubular basement membrane thickening and atrophy and peritubular fibrosis (2, 3, 4, 5). On average, approximately 30% of testicular germ cells are HIV infected (4). Within the last decade, a more pronounced loss of germ cells has been evident on histologic examination and is likely due to several factors, such as duration of HIV infection, direct HIV cytopathic effects, the use of gonadotoxic or antiandrogenic drugs, malnutrition, wasting, fever, and other systemic illnesses or chronic infections (5). Direct testicular involvement by opportunistic infections has also been reported in men with AIDS, with cytomegalovirus, Toxoplasma gondii, and Mycobacterium avium intracellulare, the most common pathogens (2, 3, 5). In addition, neoplastic infiltration of the testes by Kaposi’s sarcoma and lymphoma has been noted in patients with evidence of disseminated disease at autopsy (5, 6).

The extent to which specific effects on gonadal endocrine function can be attributed to HIV per se, associated opportunistic infections, or neoplasms is not completely understood, but certain general patterns have been observed. Early in the course of HIV infection, total and free testosterone levels have been reported as normal or, in some cases, elevated (7), accompanied by an exaggerated response of LH to infusion of GnRH (8). Thereafter, testosterone levels tend to fall with progression of HIV disease, as a consequence of both gonadal and extragonadal factors that contribute to testicular dysfunction (7, 9). At that point, measurement of free or bioavailable testosterone may be the most sensitive indicator of hypogonadism, because increased sex hormone-binding globulin levels have been observed in HIV infection (9, 10, 11). Although primary hypogonadism and testicular atrophy have been reported in men with AIDS (12), hypogonadotropic (or secondary) hypogonadism occurs more commonly (6, 13). For the majority of cases, the etiology is multifactorial and may be attributable to systemic illness, opportunistic infections, malnutrition, cachexia and weight loss, and HIV-associated cytokines (6, 13, 14, 15). A significant number of patients with the AIDS wasting syndrome have some degree of androgen deficiency, and it has been hypothesized that the decline in circulating testosterone levels may contribute to the critical loss of lean body tissue and muscle mass in these patients (11, 16). Furthermore, pharmacologic doses of systemic glucocorticoids or megestrol acetate, the latter used as an appetite stimulant in the treatment of AIDS wasting, are known to suppress the hypothalamic-pituitary-gonadal axis (17, 18). Ketoconazole, particularly at higher doses, inhibits testosterone biosynthesis (19). Chronic use of alcohol, opiates, and marijuana has also been associated with diminished testosterone production (20). Direct pituitary or hypothalamic destruction by secondary opportunistic infection (e.g. cytomegalovirus and toxoplasmosis) is rare (21, 22).

Gynecomastia in HIV-infected men is typically associated with low testosterone and/or elevated estrogen levels, liver disease, and the use of alcohol, marijuana, and other recreational drugs. Medications such as ketoconazole, cimetidine, steroid hormones, and hormone antagonists have also been implicated. More recently, there have been reports of gynecomastia occurring in men treated with HAART, including a protease inhibitor, in the absence of any other apparent cause (23, 24, 25). Although HIV protease inhibitors seem to inhibit cytochrome P450 3A4-mediated metabolism of testosterone in human liver microsomes in vitro (26), effects on testosterone metabolism in vivo have not been observed. Typically, gynecomastia does not resolve after cessation of protease inhibitor therapy, and the role of these drugs, as well as other antiretroviral agents (27), in promoting breast enlargement has not been elucidated. Gynecomastia has also been reported in the setting of peripheral fat loss and central fat accumulation and may, indeed, be another facet of the HIV-related fat redistribution syndrome (28).

Treatment considerations. Treatment of hypogonadism associated with HIV infection depends on an understanding of the underlying etiology, the severity of symptoms, and the specific purpose of therapy (29). For patients who are symptomatic due to primary or secondary hypogonadism, treatment with replacement doses of testosterone is warranted, after excluding reversible etiologies. There are three main routes of testosterone delivery. The testosterone esters (e.g. enanthate and cypionate) are administered by im injection every 2–3 weeks and provide a relatively safe, effective, and inexpensive approach to androgen replacement therapy. However, because intermittent injections can lead to large fluctuations in circulating testosterone levels (30), the newer transdermal delivery systems have been developed to provide a more stable, continuous mode of testosterone replacement. Many patients prefer the testosterone patch to im injections, although they are more costly, require daily application, and may be associated with skin irritation. Up to 30% of men develop a local rash with the Androderm patch; in these cases, pretreatment with triamcinolone cream under the patch is generally effective in preventing the rash and does not interfere with drug absorption. A new gel formulation (Androgel) has also been shown to maintain serum testosterone levels within the normal range without significant adverse effects (31, 32), but patients should be aware that vigorous skin contact (e.g. with a female partner) may lead to significant drug transfer, as a large percentage of the dose remains on the skin after drying (31). In addition, the testosterone gel and patch may not deliver an adequate testosterone level at the recommended doses in every patient, so that measurement to determine whether therapeutic testosterone concentrations have been achieved should be considered.

Testosterone replacement in hypogonadal men without HIV infection has been associated with improvement in body composition, bone density, sexual functioning, quality of life, cognitive function, and mood—potential benefits that are likely to be evident in the setting of HIV infection as well (29). In hypogonadal men with HIV-associated weight loss, physiologic testosterone administration alone or in combination with resistance training has been shown to increase lean body mass, muscle strength, and quality of life (33, 34, 35). Despite an increase in muscle mass, the role of higher dose testosterone therapy in eugonadal men with HIV-associated weight loss is less clear, given the potential adverse effects on high-density lipoprotein cholesterol and lack of long-term safety data (36). Substantial increases in lean tissue accrual and strength gains from resistance exercise training have also been reported with supraphysiologic androgen therapy including an anabolic steroid, but with significant reduction in high-density lipoprotein cholesterol levels (37). The impact of these anabolic therapies on future reproductive function and fertility has not been systematically evaluated.

Whereas diminished libido and impotence in HIV-infected men have generally been associated with low testosterone levels, sexual dysfunction may also be related to other factors, including neurological disorders, systemic disease, medication effects, weakness, fatigue, and psychosexual issues (38, 39, 40, 41). The overall prevalence of erectile and ejaculatory dysfunction has been estimated to be in the range of 60% among men with advanced HIV disease (40). Sexual dysfunction has also been reported in men receiving protease inhibitor therapy, in the absence of any clear identifying cause; these preliminary reports suggest a possible association between protease inhibitors and the development of sexual dysfunction, the mechanism of which remains unclear (42, 43). Many patients have benefited from the use of sildenafil citrate (Viagra) to improve erectile function, although clinicians should be aware that sildenafil is also metabolized by cytochrome P450 3A4, the microsomal enzyme involved in the hepatic metabolism of protease inhibitors such as indinavir, ritonavir, saquinavir, and nelfinavir. Protease inhibitor pharmacokinetics are not significantly altered during sildenafil coadministration, but sildenafil concentrations can be substantially elevated (44, 45), increasing the risk of sildenafil-related adverse events. Hence, only the lowest starting dose of sildenafil (25 mg) should be used, and with particular caution, in patients receiving these protease inhibitors concomitantly (45).

Fertility and reproductive issues. In early HIV disease, semen parameters (i.e. sperm count and morphology) are generally normal and consistent with fertility, whereas untreated men with advanced stages of HIV disease have been reported to have both a reduced sperm count and an increased percentage of abnormal sperm forms (46, 47). HIV-infected men tend to produce more viscous semen containing fewer motile sperm and round cells, compared with healthy seronegative controls (48). These early studies also showed that administration of zidovudine had no deleterious effect on sperm production or other semen parameters (46, 47, 48).

The main ethical considerations surrounding reproduction for men with HIV infection have focused on risks to the future child, as well as to the female partner if she is HIV negative. Even in patients with undetectable levels of plasma HIV RNA, the virus remains detectable in semen (49). For those HIV-discordant couples who desire children, semen washing, followed by artificial insemination, has been investigated as a potentially safer method of reproduction, based on evidence that the primary reservoir for HIV in semen is the seminal plasma and nongerminal cells rather than the spermatozoa (50). Preliminary studies suggest that sperm washing can yield undetectable levels of HIV RNA in semen and substantially reduce HIV transmission rates compared with natural conception (51, 52, 53, 54). However, because the procedure is costly and the risk of infection is not completely eliminated, this approach has not been widely accepted. In vitro fertilization using intracytoplasmic sperm injection has been proposed as an alternative method in cases in which semen quantity is insufficient or there is a lack of fallopian tube patency (55); this method might further reduce the risk of HIV transmission, although larger trials are needed.

Reproductive health in HIV-infected women

Ovarian function and sex hormones. Because the ovaries have not been systematically examined during autopsy surveys in women with AIDS, remarkably little is known regarding ovarian pathology in HIV infection. Presumably, the ovaries are susceptible to HIV and secondary opportunistic infections, and, indeed, there is a single case of cytomegalovirus oophoritis reported in the literature, occurring in a woman with disseminated cytomegalovirus infection (56). It has also been shown that HIV can infect cells and tissues from the female reproductive tract, including the fallopian tubes, uterus, and cervix (57). Shedding of HIV-infected cells occurs in both the endocervix and vagina throughout the menstrual cycle (58) and seems to be increased by hormone contraceptive use, vitamin A deficiency, and gonorrheal or candidal infection (59).

Unlike the direct or associated pathologic effects of HIV infection on ovaries, the abnormalities in menstrual cycle and reproductive function have been better characterized in the last decade. Increased rates of oligoamenorrhea and amenorrhea have been reported in HIV-infected women without AIDS-defining illnesses (60), as well as in women with the AIDS wasting syndrome compared with those women with AIDS who have stable weight or manifest only mild weight loss (61). These latter findings are not unexpected for women with a severe catabolic illness complicating their HIV infection. In some women, changes in menstrual pattern have been associated with a past history of substance abuse, suggesting that socioeconomic factors may be involved (60). In addition, narcotics, marijuana, and chronic alcohol consumption are known to affect menstrual function and ovulation (20). Other surveys indicate that infection with HIV does not seem to have clinically significant effects on menstruation or vaginal bleeding rates (62, 63). Recent prospective data from two large cohorts demonstrate that HIV serostatus has little overall effect on amenorrhea, menstrual cycle length, or variability; however, among HIV-infected women, higher viral loads and lower CD4 cell counts were associated with increased cycle variability and polymenorrhea (64). In women with self-reported regular menstrual cycles, normal levels of estradiol and progesterone have been observed during the follicular and luteal phases (65).

Since the advent of HAART, specific body composition changes have been reported in women, primarily, but not exclusively, in the presence of protease inhibitor therapy. These include breast enlargement, abdominal obesity, and wasting of fat in the lower extremities and gluteal region, but without overt endocrine perturbations (66, 67, 68). Interestingly, in one patient, this redistribution of body fat was also associated with coexisting evidence of the polycystic ovary syndrome, including hirsutism, polycystic ovaries, and an increased LH to FSH ratio (69). However, the majority of women experiencing HIV-associated fat redistribution do not have typical features of hyperandrogenism. A recent pilot study in nine HIV-infected women with the fat redistribution syndrome, five of whom were eumenorrheic, found that androgen levels were increased compared with HIV-infected women without fat redistribution and healthy seronegative controls (70). These findings were accompanied by higher fasting insulin levels, dyslipidemia, and an increased LH to FSH ratio. Although the biochemical features in this small cohort are reminiscent of the polycystic ovary syndrome in seronegative women, additional studies are needed in a larger population to confirm these results and to explore potential pathophysiologic mechanisms.

Treatment with protease inhibitors has also been associated with the development of hypermenorrhea and anemia in four women, which was severe enough in two cases to require blood transfusions (71). No abnormalities were found on pelvic examination, platelet counts were normal, and the women did not report intermenstrual bleeding. One patient also experienced hemoptysis, and the possibility of decreased hemostatic function was raised. In a separate series of four patients, initiation of protease inhibitors (for HAART or post-HIV exposure prophylaxis) was associated with galactorrhea (72). In three of these cases, marked hyperprolactinemia was reported; of these, two patients had received metoclopramide and a third patient, fluoxetine, both of which may increase serum PRL levels. However, symptom resolution was only evident after the protease inhibitors were discontinued. These cases may reflect a direct effect of protease inhibitors, or rather, an indirect effect through potentiation of the dopamine antagonist effect of other drugs (72).

Treatment considerations. Because there have been few studies specific to women with HIV infection, the treatment considerations for affected women with ovarian dysfunction or failure are generally similar to that for immunocompetent individuals. Remarkably, little is known about therapies to restore hormonal balance in HIV-infected women for the purpose of improving reproductive potential. Recommendations for contraception include a combination of a barrier method and another form of contraception suitable to the woman, for maximum safety (73). Treatment with the combined oral contraceptive pill may increase the risk of HIV shedding in the lower genital tract (59), and there remains the possibility that contraceptive efficacy is affected by antiretroviral drugs and other medications (73). For postmenopausal women with symptoms of estrogen deficiency, hormone replacement therapy should be considered (74). It may also protect against the bone mineral loss associated with estrogen deficiency. The cardioprotective effects of hormone replacement are more controversial, based on current data showing no benefit of estrogen plus progestin in seronegative postmenopausal women with established coronary heart disease (75).

Given recent observations that circulating testosterone levels are lower in HIV-infected women compared with healthy seronegative women (76), increasing attention has been directed toward the role of androgen replacement therapy in these individuals, including androgenic anabolic steroids. Estratest provides combined estrogen-androgen replacement but contains methyl testosterone, which may contribute to hepatic dysfunction; it should also be noted that concomitant treatment with a progestin is necessary for women with an intact uterus to prevent endometrial hyperplasia. Preliminary studies indicate that low-dose twice-weekly transdermal testosterone administration in HIV-infected women is well tolerated (77, 78); furthermore, in those with the AIDS wasting syndrome, physiologic testosterone treatment was associated with positive trends in weight gain and quality of life (77). Additional studies are needed to determine the long-term consequences of physiologic androgen replacement on ovarian physiology, sexual function, body composition, functional status, quality of life, and other health-related outcomes.

Fertility and reproductive issues. Retrospective studies demonstrate that pregnancy and birth rates among women with HIV infection are lower than the general population and the rates of therapeutic abortion are higher, outcomes which, in part, are related to knowledge of HIV antibody status (79, 80, 81). A history of iv drug use and other sociodemographic factors may contribute to increased rates of pregnancy termination (80). Large cohort studies indicate that sexual risk behavior and unplanned pregnancies remain prevalent among HIV-infected women, emphasizing the need for further implementation of safer sex practices and contraceptive counseling (79, 81, 82). Because discovery of HIV diagnosis is generally followed by a decrease in sexual activity (81), it is difficult to predict the direct biologic impact of HIV infection on fertility in women. Certainly, other mechanisms might also impact reproductive potential, including weight loss, systemic illness, drug abuse, and sexually transmitted diseases of the reproductive tract (20, 83). It has been suggested that rates of spontaneous fetal loss are increased in HIV-infected women and related to HIV transmission and fetal thymic dysfunction (84, 85), but these observations were made in women who did not receive antiretroviral therapy during pregnancy and may not reflect trends in the current era. Overall, among HIV-infected women with a low prevalence of AIDS, maternal seropositivity seems to have little demonstrable impact on the health status at birth of live newborns (86).

Increased routine screening of all pregnant women has identified a substantial number of HIV-infected women early in pregnancy, enabling them to make timely reproductive decisions and seek appropriate health care. The use of zidovudine during pregnancy reduces the risk of vertical transmission of HIV from mother to infant by nearly 70% (87). In addition, effective maternal viral load suppression with aggressive antiretroviral therapy seems to further minimize this risk, as may other adjunctive measures such as elective cesarean section and avoidance of breast feeding (88, 89, 90, 91, 92). While the issues concerning conception in women with HIV infection are becoming increasingly relevant in the current era of effective antiretroviral therapy, they remain complex and involve a range of ethical and sociocultural issues (93, 94, 95). For example, in a recent survey of selected fertility centers in the United Kingdom, only a few centers offered intrauterine insemination or in vitro fertilization in cases in which the female partner was found to be seropositive (96).

For women with HIV infection who do become pregnant, several large cohort studies conducted in industrialized countries have shown that there are no apparent deleterious effects of pregnancy on HIV disease progression or associated immunologic parameters (97, 98, 99). In general, antiretroviral treatment recommendations for pregnant women have been based on the premise that therapies of known benefit to women should not be withheld during pregnancy unless there are known risks that outweigh the benefit (91). Important drug considerations unique to pregnancy include the pharmacokinetic changes that occur during gestation, the effectiveness in reducing perinatal HIV transmission risk, and the potential for adverse effects on the fetus and newborn (91, 100). Careful evaluation of patients during gestation and close coordination of care between the HIV clinician and obstetrician are recommended. Currently, experience with combination antiretroviral drug treatment in pregnancy remains limited and further observational studies are needed to determine overall safety (101). Very preliminary data suggest that adverse effects related to protease inhibitors are relatively uncommon during gestation (102), although women may be at higher risk for glucose intolerance. In addition, recent cases of fatal lactic acidosis in pregnant women receiving didanosine and stavudine in combination have led to heightened concern regarding the risk for lactic acidosis in patients treated with this drug combination, as well as nucleoside reverse transcriptase inhibitors in general. Additional studies are necessary to determine whether there are long-term adverse effects of perinatal antiretroviral drug exposure on the offspring, particularly in light of the possible association between perinatal nucleoside analog therapy and mitochondrial dysfunction in children exposed in utero and after birth (103, 104).

Summary

HIV infection is associated with unique and varied abnormalities in gonadal function in affected men and women. There remains a need for greater insight into the direct and indirect effects of HIV infection and its therapies on reproductive health. Future research should identify effective therapeutic strategies to prevent and treat gonadal dysfunction, as well as to minimize the risk of HIV transmission associated with reproduction. Finally, the existing socioethical challenges surrounding reproductive considerations in patients with HIV infection have yet to be resolved.

Footnotes

1 Supported in part by the NIH (Grants DK45833 and RR-00083). J.C.L. is a recipient of a Clinical Associate Physician Award from the National Center for Research Resources. Back

Received February 6, 2001.

Accepted March 18, 2001.

References

  1. Palella Jr FJ, Delaney KM, Moorman AC, et al. 1998 Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 338:853–860.[Abstract/Free Full Text]
  2. Chabon AB, Stenger RJ, Grabstald H. 1987 Histopathology of testis in acquired immune deficiency syndrome. Urology. 29:658–663.[Medline]
  3. De Paepe ME, Waxman M. 1989 Testicular atrophy in AIDS: a study of 57 autopsy cases. Hum Pathol. 20:210–214.[Medline]
  4. Shevchuk MM, Nuovo GJ, Khalife G. 1998 HIV in testis: quantitative histology and HIV localization in germ cells. J Reprod Immunol. 41:69–79.[CrossRef][Medline]
  5. Shevchuk MM, Pigato JB, Khalife G, Armenakas NA, Fracchia JA. 1999 Changing testicular histology in AIDS: its implication for sexual transmission of HIV. Urology. 53:203–208.[CrossRef][Medline]
  6. Dobs AS, Dempsey MA, Ladenson PW, Polk BF. 1988 Endocrine disorders in men infected with human immunodeficiency virus. Am J Med. 84:611–616.[Medline]
  7. Christeff N, Gharakhanian S, Thobie N, Rozenbaum W, Nunez EA. 1992 Evidence for changes in adrenal and testicular steroids during HIV infection. J Acquir Immune Defic Syndr. 5:841–846.[Medline]
  8. Merenich JA, McDermott MT, Asp AA, Harrison SM, Kidd GS. 1990 Evidence of endocrine involvement early in the course of human immunodeficiency virus infection. J Clin Endocrinol Metab. 70:566–571.[Abstract]
  9. Laudat A, Blum L, Guechot J, et al. 1995 Changes in systemic gonadal and adrenal steroids in asymptomatic human immunodeficiency virus-infected men: relationship with the CD4 cell counts. Eur J Endocrinol. 133:418–424.[Medline]
  10. Martin ME, Benassayag C, Amiel C, Canton P, Nunez EA. 1992 Alterations in the concentrations and binding properties of sex steroid binding protein and corticosteroid-binding globulin in HIV+ patients. J Endocrinol Invest. 15:597–603.[Medline]
  11. Grinspoon S, Corcoran C, Lee K, et al. 1996 Loss of lean body and muscle mass correlates with androgen levels in hypogonadal men with acquired immunodeficiency syndrome and wasting. J Clin Endocrinol Metab. 81:4051–4058.[Abstract]
  12. Croxson TS, Chapman WE, Miller LK, Levit CD, Senie R, Zumoff B. 1989 Changes in the hypothalamic-pituitary-gonadal axis in human immunodeficiency virus-infected homosexual men. J Clin Endocrinol Metab. 68:317–321.[Abstract]
  13. Poretsky L, Can S, Zumoff B. 1995 Testicular dysfunction in human immunodeficiency virus-infected men. Metabolism. 44:946–953.[Medline]
  14. Baker HW. 1998 Reproductive effects of nontesticular illness. Endocrinol Metab Clin North Am. 27:831–850.[Medline]
  15. Sellmeyer DE, Grunfeld C. 1996 Endocrine and metabolic disturbances in human immunodeficiency virus infection and the acquired immune deficiency syndrome. Endocr Rev. 17:518–532.[Abstract]
  16. Dobs AS, Few III WL, Blackman MR, Harman SM, Hoover DR, Graham NM. 1996 Serum hormones in men with human immunodeficiency virus-associated wasting. J Clin Endocrinol Metab. 81:4108–4112.[Abstract]
  17. Engelson ES, Pi-Sunyer FX, Kotler DP. 1995 Effects of megestrol acetate therapy on body composition and circulating testosterone concentrations in patients with AIDS. AIDS. 9:1107–1108 (Letter).[Medline]
  18. Wagner GJ, Rabkin JG. 1998 Testosterone, illness progression, and megestrol use in HIV-positive men. J Acquir Immune Defic Syndr Hum Retrovirol. 17:179–180 (Letter).[Medline]
  19. Sonino N. 1987 The use of ketoconazole as an inhibitor of steroid production. N Engl J Med. 317:812–818.[Medline]
  20. Smith CG, Asch RH. 1987 Drug abuse and reproduction. Fertil Steril. 48:355–373.[Medline]
  21. Milligan SA, Katz MS, Craven PC, Strandberg DA, Russell IJ, Becker RA. 1984 Toxoplasmosis presenting as panhypopituitarism in a patient with the acquired immune deficiency syndrome. Am J Med. 77:760–764.[Medline]
  22. Sullivan WM, Kelley GG, O’Connor PG, et al. 1992 Hypopituitarism associated with a hypothalamic CMV infection in a patient with AIDS. Am J Med. 92:221–223 (Letter).[Medline]
  23. Peyriere H, Mauboussin JM, Rouanet I, et al. 1999 Report of gynecomastia in five male patients during antiretroviral therapy for HIV infection. AIDS. 13:2167–2169 (Letter).[CrossRef][Medline]
  24. Schurmann D, Bergmann F, Ehrenstein T, Padberg J. 1998 Gynaecomastia in a male patient during protease inhibitor treatment for acute HIV disease. AIDS. 12:2232–2233 (Letter).[Medline]
  25. Toma E, Therrien R. 1998 Gynecomastia during indinavir antiretroviral therapy in HIV infection. AIDS. 12:681–682 (Letter).[Medline]
  26. Inaba T, Fischer NE, Riddick DS, Stewart DJ, Hidaka T. 1997 HIV protease inhibitors, saquinavir, indinavir and ritonavir: inhibition of CYP3A4-mediated metabolism of testosterone and benzoxazinorifamycin, KRM-1648, in human liver microsomes. Toxicol Lett. 93:215–219.[CrossRef][Medline]
  27. Melbourne KM, Brown SL, Silverblatt FJ. 1998 Gynecomastia with stavudine treatment in an HIV-positive patient. Ann Pharmacother. 32:1108 (Letter).[Free Full Text]
  28. Donovan B, Bodsworth NJ, Mulhall BP, Allen D. 1999 Gynaecomastia associated with saquinavir therapy. Int J STD AIDS. 10:49–50.[CrossRef][Medline]
  29. Cofrancesco Jr J, Whalen III JJ, Dobs AS. 1997 Testosterone replacement treatment options for HIV-infected men. J Acquir Immune Defic Syndr Hum Retrovirol. 16:254–265.[Medline]
  30. Dobs AS, Meikle AW, Arver S, Sanders SW, Caramelli KE, Mazer NA. 1999 Pharmacokinetics, efficacy, and safety of a permeation-enhanced testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men. J Clin Endocrinol Metab. 84:3469–3478.[Abstract/Free Full Text]
  31. The Medical Letter, Inc. 2000 Androgel. Med Lett. 42:49–51.
  32. Wang C, Berman N, Longstreth JA, et al. 2000 Pharmacokinetics of transdermal testosterone gel in hypogonadal men: application of gel at one site versus four sites: a General Clinical Research Center study. J Clin Endocrinol Metab. 85:964–969.[Abstract/Free Full Text]
  33. Grinspoon S, Corcoran C, Askari H, et al. 1998 Effects of androgen administration in men with the AIDS wasting syndrome. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 129:18–26.[Abstract/Free Full Text]
  34. Bhasin S, Javanbakht M. 1999 Can androgen therapy replete lean body mass and improve muscle function in wasting associated with human immunodeficiency virus infection? J Parenter Enteral Nutr. 23:S195–S201.
  35. Bhasin S, Storer TW, Javanbakht M, et al. 2000 Testosterone replacement and resistance exercise in HIV-infected men with weight loss and low testosterone levels. JAMA. 283:763–770.[Abstract/Free Full Text]
  36. Grinspoon S, Corcoran C, Parlman K, et al. 2000 Effects of testosterone and progressive resistance training in eugonadal men with AIDS wasting. A randomized, controlled trial. Ann Intern Med. 133:348–355.[Abstract/Free Full Text]
  37. Strawford A, Barbieri T, Van Loan M, et al. 1999 Resistance exercise and supraphysiologic androgen therapy in eugonadal men with HIV-related weight loss: a randomized controlled trial. JAMA. 281:1282–1290.[Abstract/Free Full Text]
  38. Meyer-Bahlburg HF, Exner TM, Lorenz G, Gruen RS, Gorman JM, Ehrhardt AA. 1991 Sexual risk behavior, sexual functioning, and HIV-disease progression in gay men. J Sex Res. 28:3–27.
  39. Jones M, Klimes I, Catalan J. 1994 Psychosexual problems in people with HIV infection: controlled study of gay men and men with haemophilia. AIDS Care. 6:587–593.[Medline]
  40. Tindall B, Forde S, Goldstein D, Ross MW, Cooper DA. 1994 Sexual dysfunction in advanced HIV disease. AIDS Care. 6:105–107.[Medline]
  41. Newshan G, Taylor B, Gold R. 1998 Sexual functioning in ambulatory men with HIV/AIDS. Int J STD AIDS. 9:672–676.[CrossRef][Medline]
  42. Martinez E, Collazos J, Mayo J, Blanco MS. 1999 Sexual dysfunction with protease inhibitors. Lancet. 353:810–811 (Letter).[Medline]
  43. Colebunders R, Smets E, Verdonck K, Dreezen C. 1999 Sexual dysfunction with protease inhibitors. Lancet. 353:1802 (Letter; comment).
  44. Merry C, Barry MG, Ryan M, et al. 1999 Interaction of sildenafil and indinavir when co-administered to HIV-positive patients. AIDS. 13:F101–F107.
  45. Pfizer, Inc. 2000 Viagra (Sildenafil citrate). Prescribing information. New York: Pfizer, Inc.
  46. Krieger JN, Coombs RW, Collier AC, et al. 1991 Fertility parameters in men infected with human immunodeficiency virus. J Infect Dis. 164:464–469.[Medline]
  47. Politch JA, Mayer KH, Abbott AF, Anderson DJ. 1994 The effects of disease progression and zidovudine therapy on semen quality in human immunodeficiency virus type 1 seropositive men. Fertil Steril. 61:922–928.[Medline]
  48. Crittenden JA, Handelsman DJ, Stewart GJ. 1992 Semen analysis in human immunodeficiency virus infection. Fertil Steril. 57:1294–1299.[Medline]
  49. Zhang H, Dornadula G, Beumont M, et al. 1998 Human immunodeficiency virus type 1 in the semen of men receiving highly active antiretroviral therapy. N Engl J Med. 339:1803–1809.[Abstract/Free Full Text]
  50. Alexander NJ. 1998 HIV and germinal cells: how close an association? J Reprod Immunol. 41:17–26.[CrossRef][Medline]
  51. Semprini AE, Levi-Setti P, Bozzo M, et al. 1992 Insemination of HIV-negative women with processed semen of HIV-positive partners. Lancet. 340:1317–1319.[CrossRef][Medline]
  52. Semprini AE, Fiore S, Pardi G. 1997 Reproductive counselling for HIV-discordant couples. Lancet. 349:1401–1402 (Letter; comment).[Medline]
  53. Marina S, Marina F, Alcolea R, et al. 1998 Human immunodeficiency virus type 1–serodiscordant couples can bear healthy children after undergoing intrauterine insemination. Fertil Steril. 70:35–39.[CrossRef][Medline]
  54. Kim LU, Johnson MR, Barton S, et al. 1999 Evaluation of sperm washing as a potential method of reducing HIV transmission in HIV-discordant couples wishing to have children. AIDS. 13:645–651.[CrossRef][Medline]
  55. Marina S, Marina F, Alcolea R, Nadal J, Exposito R, Huguet J. 1998 Pregnancy following intracytoplasmic sperm injection from an HIV-1-seropositive man. Hum Reprod. 13:3247–3249.[Abstract]
  56. Familiari U, Larocca LM, Tamburrini E, Antinori A, Ortona L, Capelli A. 1991 Premenopausal cytomegalovirus oophoritis in a patient with AIDS. AIDS. 5:458–459 (Letter).[Medline]
  57. Howell AL, Edkins RD, Rier SE, et al. 1997 Human immunodeficiency virus type 1 infection of cells and tissues from the upper and lower human female reproductive tract. J Virol. 71:3498–3506.[Abstract]
  58. Mostad SB, Jackson S, Overbaugh J, et al. 1998 Cervical and vaginal shedding of human immunodeficiency virus type 1-infected cells throughout the menstrual cycle. J Infect Dis. 178:983–991.[Medline]
  59. Mostad SB, Overbaugh J, DeVange DM, et al. 1997 Hormonal contraception, vitamin A deficiency, and other risk factors for shedding of HIV-1 infected cells from the cervix and vagina. Lancet. 350:922–927.[CrossRef][Medline]
  60. Chirgwin KD, Feldman J, Muneyyirci-Delale O, Landesman S, Minkoff H. 1996 Menstrual function in human immunodeficiency virus-infected women without acquired immunodeficiency syndrome. J Acquir Immune Defic Syndr Hum Retrovirol. 12:489–494.[Medline]
  61. Grinspoon S, Corcoran C, Miller K, et al. 1997 Body composition and endocrine function in women with acquired immunodeficiency syndrome wasting [published erratum appears in J Clin Endocrinol Metab, 1997, 82:3360]. J Clin Endocrinol Metab. 82:1332–1337.
  62. Shah PN, Smith JR, Wells C, Barton SE, Kitchen VS, Steer PJ. 1994 Menstrual symptoms in women infected by the human immunodeficiency virus. Obstet Gynecol. 83:397–400.[Abstract]
  63. Ellerbrock TV, Wright TC, Bush TJ, Dole P, Brudney K, Chiasson MA. 1996 Characteristics of menstruation in women infected with human immunodeficiency virus. Obstet Gynecol. 87:1030–1034.[Abstract/Free Full Text]
  64. Harlow SD, Schuman P, Cohen M, et al. 2000 Effect of HIV infection on menstrual cycle length. J Acquir Immune Defic Syndr. 24:68–75.[Medline]
  65. Cu-Uvin S, Wright DJ, Anderson D, et al. 2000 Hormonal levels among HIV-1-seropositive women compared with high-risk HIV-seronegative women during the menstrual cycle. Women’s Health Study (WHS) 001 and WHS 001a Study Team. J Womens Health Gend Based Med. 9:857–863.[CrossRef][Medline]
  66. Herry I, Bernard L, de Truchis P, Perronne C. 1997 Hypertrophy of the breasts in a patient treated with indinavir. Clin Infect Dis. 25:937–938.[Medline]
  67. Gervasoni C, Ridolfo AL, Trifiro G, et al. 1999 Redistribution of body fat in HIV-infected women undergoing combined antiretroviral therapy. AIDS. 13:465–471.[CrossRef][Medline]
  68. Dong KL, Bausserman LL, Flynn MM, et al. 1999 Changes in body habitus and serum lipid abnormalities in HIV-positive women on highly active antiretroviral therapy (HAART). J Acquir Immune Defic Syndr. 21:107–113.[Medline]
  69. Wilson JD, Dunham RJ, Balen AH. 1999 HIV protease inhibitors, the lipodystrophy syndrome and polycystic ovary syndrome—is there a link? Sex Transm Infect. 75:268–269.[Free Full Text]
  70. Hadigan C, Corcoran C, Piecuch S, Rodriguez W, Grinspoon S. 2000 Hyperandrogenemia in human immunodeficiency virus-infected women with the lipodystrophy syndrome. J Clin Endocrinol Metab. 85:3544–3550.[Abstract/Free Full Text]
  71. Nielsen H. 1999 Hypermenorrhea associated with ritonavir. Lancet. 353:811–812 (Letter).[CrossRef][Medline]
  72. Hutchinson J, Murphy M, Harries R, Skinner CJ. 2000 Galactorrhoea and hyperprolactinaemia associated with protease-inhibitors. Lancet. 356:1003–1004 (Letter).[CrossRef][Medline]
  73. Shah R, Bradbeer C. 2000 Women and HIV—revisited ten years on. Int J STD AIDS. 11:277–283.[CrossRef][Medline]
  74. Clark RA, Cohn SE, Jarek C, et al. 2000 Perimenopausal symptomatology among HIV-infected women at least 40 years of age. J Acquir Immune Defic Syndr. 23:99–100 (Letter).[Medline]
  75. Hulley S, Grady D, Bush T, et al. 1998 Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. JAMA. 280:605–613.[Abstract/Free Full Text]
  76. Sinha-Hikim I, Arver S, Beall G, et al. 1998 The use of a sensitive equilibrium dialysis method for the measurement of free testosterone levels in healthy, cycling women and in human immunodeficiency virus-infected women [published erratum appears in J Clin Endocrinol Metab, 1998, 83:2959]. J Clin Endocrinol Metab. 83:1312–1318.
  77. Miller K, Corcoran C, Armstrong C, et al. 1998 Transdermal testosterone administration in women with acquired immunodeficiency syndrome wasting: a pilot study. J Clin Endocrinol Metab. 83:2717–2725.[Abstract/Free Full Text]
  78. Javanbakht M, Singh AB, Mazer NA, et al. 2000 Pharmacokinetics of a novel testosterone matrix transdermal system in healthy, premenopausal women and women infected with the human immunodeficiency virus. J Clin Endocrinol Metab. 85:2395–2401.[Abstract/Free Full Text]
  79. Stephenson JM, Griffioen A. 1996 The effect of HIV diagnosis on reproductive experience. Study Group for the Medical Research Council Collaborative Study of Women with HIV. AIDS. 10:1683–1687.[Medline]
  80. Thackway SV, Furner V, Mijch A, et al. 1997 Fertility and reproductive choice in women with HIV-1 infection. AIDS. 11:663–667.[CrossRef][Medline]
  81. De Vincenzi I, Jadand C, Couturier E, et al. 1997 Pregnancy and contraception in a French cohort of HIV-infected women. SEROCO Study Group. AIDS. 11:333–338.[CrossRef][Medline]
  82. Wilson TE, Massad LS, Riester KA, et al. 1999 Sexual, contraceptive, and drug use behaviors of women with HIV and those at high risk for infection: results from the Women’s Interagency HIV Study. AIDS. 13:591–598.[CrossRef][Medline]
  83. Korn AP, Abercrombie PD. 1997 Gynecology and family planning care for the woman infected with HIV. Obstet Gynecol Clin North Am. 24:855–872.[Medline]
  84. Langston C, Lewis DE, Hammill HA, et al. 1995 Excess intrauterine fetal demise associated with maternal human immunodeficiency virus infection. J Infect Dis. 172:1451–1460.[Medline]
  85. Shearer WT, Langston C, Lewis DE, et al. 1997 Early spontaneous abortions and fetal thymic abnormalities in maternal-to-fetal HIV infection. Acta Paediatr Suppl. 421:60–64.[Medline]
  86. Minkoff HL, Henderson C, Mendez H, et al. 1990 Pregnancy outcomes among mothers infected with human immunodeficiency virus and uninfected control subjects. Am J Obstet Gynecol. 163:1598–1604.[Medline]
  87. Connor EM, Sperling RS, Gelber R, et al. 1994 Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 331:1173–1180.[Abstract/Free Full Text]
  88. Garcia PM, Kalish LA, Pitt J, et al. 1999 Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission. Women and Infants Transmission Study Group. N Engl J Med. 341:394–402.[Abstract/Free Full Text]
  89. Peckham C, Gibb D. 1995 Mother-to-child transmission of the human immunodeficiency virus. N Engl J Med. 333:298–302.[Free Full Text]
  90. Mofenson LM, Lambert JS, Stiehm ER, et al. 1999 Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team. N Engl J Med. 341:385–393.[Abstract/Free Full Text]
  91. Public Health Service Task Force. 2000 Public Health Service Task Force recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States. Perinatal HIV Guidelines Working Group Members. 1–46 (available at http://www.hivatis.org).
  92. de Martino M, Tovo PA, Tozzi AE, et al. 1992 HIV-1 transmission through breast-milk: appraisal of risk according to duration of feeding. AIDS. 6:991–997.[Medline]
  93. Williams HA, Watkins CE, Risby JA. 1996 Reproductive decision-making and determinants of contraceptive use in HIV-infected women. Clin Obstet Gynecol. 39:333–343.[CrossRef][Medline]
  94. Olaitan A, Reid W, Mocroft A, McCarthy K, Madge S, Johnson M. 1996 Infertility among human immunodeficiency virus-positive women: incidence and treatment dilemmas. Hum Reprod. 11:2793–2796.[Abstract]
  95. Hargreave TB, Ghosh C. 1998 The impact of HIV on a fertility problems clinic. J Reprod Immunol. 41:261–270.[CrossRef][Medline]
  96. Balet R, Lower AM, Wilson C, Anderson J, Grudzinskas JG. 1998 Attitudes towards routine human immunodeficiency virus (HIV) screening and fertility treatment in HIV positive patients—a UK survey. Hum Reprod. 13:1085–1087.[Abstract]
  97. Brettle RP, Raab GM, Ross A, Fielding KL, Gore SM, Bird AG. 1995 HIV infection in women: immunological markers and the influence of pregnancy. AIDS. 9:1177–1184.[Medline]
  98. Weisser M, Rudin C, Battegay M, Pfluger D, Kully C, Egger M. 1998 Does pregnancy influence the course of HIV infection? Evidence from two large Swiss cohort studies. J Acquir Immune Defic Syndr Hum Retrovirol. 17:404–410.[Medline]
  99. Saada M, Le Chenadec J, Berrebi A, et al. 2000 Pregnancy and progression to AIDS: results of the French prospective cohorts. SEROGEST and SEROCO Study Groups AIDS. 14:2355–2360.
  100. Minkoff H, Augenbraun M. 1997 Antiretroviral therapy for pregnant women. Am J Obstet Gynecol. 176:478–489.[Medline]
  101. Lorenzi P, Spicher VM, Laubereau B, et al. 1998 Antiretroviral therapies in pregnancy: maternal, fetal and neonatal effects. Swiss HIV Cohort Study, the Swiss Collaborative HIV and Pregnancy Study, and the Swiss Neonatal HIV Study. AIDS. 12:F241–F247.
  102. Morris AB, Cu-Uvin S, Harwell JI, et al. 2000 Multicenter review of protease inhibitors in 89 pregnancies. J Acquir Immune Defic Syndr. 25:306–311.[Medline]
  103. Blanche S, Tardieu M, Rustin P, et al. 1999 Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. Lancet. 354:1084–1089.[CrossRef][Medline]
  104. The Perinatal Safety Review Working Group. 2000 Nucleoside exposure in the children of HIV-infected women receiving antiretroviral drugs: absence of clear evidence for mitochondrial disease in children who died before 5 years of age in five United States cohorts. The Perinatal Safety Review Working Group. J Acquir Immune Defic Syndr. 25:261–268.[Medline]