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Pharmacokinetics of a Novel Testosterone Matrix Transdermal System in Healthy, Premenopausal Women and Women Infected with the Human Immunodeficiency Virus¹

Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California 90059; Harbor-University of California-Los Angeles Medical Center, Torrance, California 90509; and Watson Laboratories, Inc.-Utah, Salt Lake City, Utah 84108

Address all correspondence and requests for reprints to: Shalender Bhasin, M.D., University of California School of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, California 90059.

	Abstract

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The clinical consequences of androgen deficiency in human immunodeficiency virus (HIV)-infected women remain underappreciated. The pharmacokinetics of transdermally administered testosterone in premenopausal women and HIV-infected women have not been studied. In this study we compared the pharmacokinetics of a novel testosterone matrix transdermal system (TMTDS) in healthy premenopausal women and women infected with HIV. Eight menstruating HIV-infected women, 18–50 yr of age, who had been receiving stable antiretroviral therapy, including a protease inhibitor, for at least 12 weeks and nine healthy, menstruating women of comparable age were enrolled. After baseline sampling during a 24-h control period in the early follicular phase (days 1–6), two TMTDS patches were applied with an expected delivery rate of 300 µg testosterone daily over an application period of 3–4 days. After 72 h, the patches were removed, a second set of two patches was applied, and blood samples were drawn over 96 h.

Baseline serum total and free testosterone levels were lower in HIV-infected women than in healthy women. A diurnal rhythm of testosterone secretion, with higher levels in the morning and lower levels in the late afternoon, was apparent in both groups of women. Free testosterone levels were in the midnormal range at baseline in healthy women and increased above the upper limit of normal during TMTDS application. In HIV-infected women, free testosterone levels were in the low normal range at baseline and rose into the upper normal range during patch application. Serum total testosterone levels increased into the midnormal range in HIV-infected women and into the upper normal range in healthy women during patch application. The mean increments in free and total testosterone levels were significantly lower in HIV-infected women than in healthy women. Testosterone bioavailability, expressed as the mean ± SEM baseline-subtracted area under the total testosterone curve, was significantly greater in healthy women than in HIV-infected women [3323 ± 566 ng/dL·h (115 ± 20 nmol/L·h) vs. 1506 ± 316 ng/dL·h (52 ± 11 nmol/L·h); P = 0.016]. Assuming a daily testosterone delivery rate of 300 µg/day, the apparent plasma clearance was significantly higher in HIV-infected women than in healthy women (2531 ± 469 vs. 1127 ± 217 L/dayl P = 0.022), respectively. There was no significant change from baseline in serum LH, sex hormone-binding globulin, and estradiol levels in either group. Serum FSH levels showed a greater decrease from baseline in healthy women.

A regimen of two testosterone patches applied twice a week can maintain serum total and free testosterone levels in the mid- to upper normal range, respectively, in HIV-infected women with low testosterone levels. During TMTDS application, the increments in serum total and free testosterone levels are lower in HIV-infected women than in healthy women, presumably due to increased plasma clearance or decreased absorption. Further studies are needed to assess the effects of physiological androgen replacement in HIV-infected women.

	Introduction

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ANDROGEN DEFICIENCY is a well recognized complication of human immunodeficiency virus (HIV) infection in men (1, 2, 3, 4, 5) and is associated with weight loss (2), decreased muscle mass (4), and disease progression (5). However, there is a paucity of data on the prevalence and clinical consequences of androgen deficiency in HIV-infected women. Fifty to 95% of HIV-infected women have serum total and free testosterone levels below the median for healthy, age-matched controls (6, 7, 8, 9). Free testosterone levels correlate directly with muscle mass (6) and inversely with plasma HIV copy number in HIV-infected women (8). However, we do not know whether physiological testosterone replacement of HIV-infected women with low testosterone levels augments lean body mass and muscle function or alters disease outcomes.

Testosterone replacement of oophorectomized and postmenopausal women has been reported to improve sexual function and well-being (10, 11, 12, 13). Addition of an androgen to a regimen of estrogen replacement in postmenopausal women is associated with a greater increase in bone mineral density (10) and markers of bone formation (14) than observed with estrogen replacement alone (12). It has been speculated that androgen deficiency among HIV-infected women may contribute to changes in body composition, diminished functional capacity and mental well-being, as well as health perceptions (6, 7, 15). In a pilot study, Miller et al. (15) evaluated a novel testosterone matrix transdermal system (TMTDS) for the treatment of wasting in androgen-deficient HIV-infected women. At a nominal dose of 150 µg/day, 3-month treatment with the TMTDS increased free testosterone levels into the upper normal range and was associated with positive trends in weight gain and quality of life (15). A similar group of patients treated with a 300 µg/day dose achieved supraphysiological free testosterone levels and did not show significant improvements in body weight or fat-free mass. Interestingly, serum total and free testosterone levels achieved at both doses of the TMTDS in HIV-infected women were substantially greater (15) than those reported previously in surgically menopausal women (16, 17). This finding suggested that compared with the latter group, HIV-infected women had either absorbed more testosterone from the TMTDS or had a diminished clearance rate.

To gain a better understanding of the pharmacokinetics of the TMTDS in HIV-infected women, we therefore conducted the present study in androgen-deficient HIV-infected women and compared the results with those from a control group of healthy, premenopausal women of comparable age. To minimize the confounding influence of endogenous hormonal fluctuations, all participants in the study (HIV-infected and controls) were premenopausal and were studied in the early follicular phase of their menstrual cycles. In addition, because protease inhibitors may alter testosterone metabolism (18, 19, 20, 21, 22, 23, 24, 25, 26), we recruited HIV-infected women who had been on a stable antiretroviral regimen that included at least one protease inhibitor.

	Subjects and Methods

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This protocol was approved by the institutional review boards of Charles R. Drew University (Los Angeles, CA) and Harbor-University of California-Los Angeles Research and Education Institute (Torrance, CA). All women gave informed written consent.

Participant characteristics

Eight HIV-infected women, 18–50 yr of age, with regular menstrual cycles were enrolled in the study. HIV-infected women had baseline, early morning, serum total testosterone levels of less than 33 ng/dL (1.1 nmol/L), the median testosterone level in healthy, premenopausal women in our laboratory (8). The patients were free of acute illness, malignant disease, or fever and had been receiving stable antiretroviral therapy that included at least one protease inhibitor for more than 12 weeks. Patients with diarrhea (more than four stools per day), significant liver function abnormalities, defined as alanine aminotransferase or asparate aminotransferase levels greater than 3 times the upper limit of normal or serum bilirubin levels greater than 2 mg/dL, were excluded from the study. We also excluded women with active substance abuse in the preceding 6 months or skin intolerance to transdermal systems. None of the participants had received anabolic agents, such as human GH and androgenic steroids, or appetite stimulants, such as megesterol acetate and marinol, in the preceding 3 months. Women using oral contraceptives or progestational agents were excluded from the study. Serum hCG was measured to exclude pregnancy, and women were advised to use a nonhormonal method of birth control during the course of the study.

The control group included nine healthy, premenopausal, menstruating women, 18–50 yr of age. We excluded women with body weight in excess of 125% of ideal body weight, polycystic ovary disease, acne, hirsutism, or history of illicit drug use in the previous 6 months. Women taking birth control pills or anabolic agents such as androgenic steroids were excluded from the study.

All subjects were studied in the early follicular phase (day 1–6). The blood sampling started between 0700 –1100 h.

Study design

This was an open label pharmacokinetic study, conducted in the setting of a general clinical research center (GCRC). The study consisted of a screening period, a 24-h control period, and a 7-day treatment period.

Screening. A complete medical history was obtained, and physical examination was performed. Blood was drawn for complete blood counts, chemistries, and serum total testosterone levels to determine eligibility. The participants provided detailed menstrual history, a pregnancy test was performed, and concomitant medications were recorded.

Control period. Eligible subjects returned for a baseline visit timed to correspond to the early follicular phase (days 1–6). During the 24-h control period, blood samples were drawn at 0, 2, 4, 6, 8, and 24 h in the GCRC, starting between 0700–1100 h. Complete blood counts and chemistries, CD4 and CD8 T lymphocyte counts, and plasma HIV copy number were measured.

Treatment period. After 24 h of baseline sampling, the participants applied two testosterone patches on the abdomen and left them in place for 72 h. The women returned to the GCRC after 72 h; at this time, the patches were removed, and a second set of two patches was applied and left in place for 96 h. Blood samples were drawn at 0, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, and 96 h after application of the second set of patches. After the last blood sample was drawn at 96 h, the patches were retrieved for analysis of residual testosterone. Any adhesive residue left on the skin was also removed and included in the residual analysis.

TMTDS

The TMTDS, provided by Watson Laboratories, Inc.-Utah (Salt Lake City, UT), is a translucent patch that has a surface area of 18 cm² and contains testosterone, sorbitan monooleate as a permeation enhancer, and a hypoallergenic acrylic adhesive in an alcohol-free matrix patch. The average testosterone content of each patch is 4.1 mg. Each patch is designed to deliver testosterone at a nominal rate of 150 µg/day over an application period of 3–4 days. Therefore, two testosterone patches, applied simultaneously, were expected to deliver testosterone at a nominal rate of 300 µg/day.

Evaluation procedures and outcome measures

The primary outcome measures were serum total and free testosterone levels. In addition, we measured LH and FSH, 17ß-estradiol, and sex hormone-binding globulin (SHBG) levels in serum at selected time points on each of the 7 treatment days.

Hormone measurements

Serum total testosterone levels were measured with a sensitive assay that uses iodinated testosterone as tracer, as we described previously (8, 27). This assay has a sensitivity of 0.44 ng/dL and intra- and interassay coefficients of variation of 13.2% and 8.2%, respectively.

Free testosterone levels were measured by a sensitive equilibrium dialysis method (8), optimized to measure the low concentrations prevalent in women with precision and accuracy. Two hundred microliters of serum in the inner compartment were dialyzed against 2.4 mL dialysis buffer that was designed to approximate the composition of a protein-free ultrafiltrate of human serum (8). Dialysis was performed overnight for 16 h at 37 C. Concentrations of testosterone in the dialysate were measured by RIA (8), using ¹²⁵I-labeled testosterone purchased from ICN Pharmaceuticals, Inc. (Irvine, CA). To enhance assay sensitivity, we used a larger volume of serum, a smaller amount of the antitestosterone antibody (final concentration, 1:4,000,000), and a longer incubation time (16 h at 4 C) than those used in the traditional assay. The sensitivity of the free testosterone assay is 0.6 pg/mL (2.0 pmol/L), and intra- and interassay coefficients of variation were 4.2% and 12.3%, respectively. Serum LH, FSH, and SHBG levels were measured by two-site directed, immunofluorometric assays (Delfia-Wallac, Inc., Gaithersburg, MD), with sensitivities of 0.05 U/L, 0.15 U/L, and 6.25 nmol/L, respectively, as described previously (27). The intra- and interassay coefficients of variation were 10.7% and 13.0% for LH, 3.2% and 11.3% for FSH, and 10.0% and 10.2% for SHBG, respectively. Plasma HIV RNA copy number was measured by RT-PCR (Amplicor, Roche, Indianapolis, IN).

Residual testosterone analysis

For analysis of residual testosterone, testosterone was extracted from the removed patches, wipes, spatula, and adhesive material by high performance liquid chromatography (HPLC) grade methanol and assayed using a sensitive and specific HPLC method, validated for the assay of testosterone in matrix transdermal systems. The HPLC method uses an acetonitrile/water mobile phase, a C₁₈ column, and a detector set at 225 nm. Independent standards with a range of concentrations bracketing the expected sample concentration were injected before the samples and periodically throughout the run, with at least one injection at the end. A standard curve was generated by linear regression of the standard concentrations and their respective peak areas, with the correlation coefficient (r²) required to be greater than 0.995. The performance of the HPLC system was assessed by analyzing five replicates of a standard that had a testosterone concentration close to the expected sample concentration; a coefficient of variation of less than 2.0% was required to demonstrate system suitability.

Data analysis

Baseline and pharmacokinetic parameters were averaged across subjects within each group to obtain means, SDs, and SEMs. The time-average free and total testosterone concentrations during the 24-h control period (baseline levels) were computed from the areas under the respective curves, divided by 24 h. We evaluated the following pharmacokinetic parameters from the 96-h profiles of free and total testosterone measured during the second TMTDS application: time-average, steady state concentration (Css); baseline-subtracted, time-average, steady state concentration (C’ss); maximum concentration (Cmax); time of maximum concentration (Tmax); minimum concentration (Cmin); area under the curve (AUC); and baseline-subtracted area under the curve (AUC’). The Css and C’ss parameters were computed from AUC and AUC’, respectively, by dividing by 96 h. The baseline-subtracted profiles during the 96-h TMTDS application were computed as follows: baseline concentrations measured at 2, 4, 6, and 8 h were subtracted from the corresponding time points of the TMTDS application; the average of the 0 and 24 h baseline concentrations was subtracted from the 0, 24, 48, 72, and 96 h values during the TMTDS application; the 12 h baseline concentration was interpolated from the 8 and 24 h baseline levels and subtracted from the 12, 36, 60, and 84 h points of the TMTDS application. The apparent amount of testosterone released from each worn patch was determined by subtracting the residual testosterone content of that patch from the average testosterone content of 17 unworn control patches. The daily testosterone release from each patch was calculated by dividing the apparent amount of testosterone released from each patch by the number of days (n = 4) the system was worn. The total daily testosterone release was the sum of the release rates from the 2 patches. The apparent plasma testosterone clearance was calculated assuming a nominal testosterone delivery rate of 300 µug/day, using the standard pharmacokinetic formula (28): apparent clearance (L/day) = testosterone delivery rate (µg/day) ÷ C’ss (ng/dL), with appropriate correction for units.

The hormone concentrations, testosterone release rates, and clearance estimates in HIV-infected and healthy women were compared using two-tailed, unpaired t tests. P < 0.05 was considered statistically significant.

	Results

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Baseline characteristics of participants (Table 1)

The mean ± SD age of healthy women was 29 ± 7 yr, body weight was 61.2 ± 12.2 kg, and body mass index was 24.4 ± 4.3 kg/m². The mean ± SD age of HIV-infected women was 40.3 ± 3.1 yr, weight was 68.9 ± 10.8 kg, and body mass index was 25.8 ± 4.3 kg/m². Their CD4 and CD8 T lymphocyte cell counts were 272 ± 188 and 850 ± 692 x 10⁹/L, respectively, consistent with HIV disease of moderate severity. The baseline plasma HIV copy number was 629 ± 724/mL. All HIV-infected women were receiving antiretroviral therapy that included at least one protease inhibitor (Table 2). Three HIV-infected women had lost between 5 and 12 lb in the preceding 6 months; the others had not lost weight.

The patches were well tolerated, and there were no significant skin reactions recorded in either group of women. One healthy woman reported exacerbation of acne 1 week after completion of the patch application period. One HIV-infected woman experienced irregular vaginal bleeding during testosterone treatment; on later evaluation this patient was found to have uterine fibroids. There was no significant change in hemoglobin, aspartate aminotransferase, and alanine aminotransferase levels during treatment.

Hormone levels

Free testosterone levels. Baseline serum free testosterone levels, measured by equilibrium dialysis, were significantly lower in HIV-infected women than in healthy women (Fig. 1 and Table 3). In both groups of women, serum free testosterone levels displayed a diurnal rhythm, with higher levels between 0700–1100 h than in the late afternoon (Fig. 1). In healthy women, serum free testosterone levels were in the midnormal range at baseline and exceeded the upper limit of the normal range during patch application (Fig. 1A). In HIV-infected women, free testosterone levels were in the low normal range at baseline and increased into the upper end of the normal female range during TMTDS application (Fig. 1B).

View larger version (21K): [in this window] [in a new window]   Figure 1. Serum free testosterone levels in healthy, menstruating women (A) and HIV-infected women (B). The normal range in healthy, menstruating women is shown by heavy dotted lines, the baseline circadian free testosterone levels by light dotted lines, and serum levels during the second TMTDS application period by solid lines. The data are the mean ± SEM. To convert free testosterone levels from picograms per mL to picomoles per L, multiply by 3.467.

Total testosterone. Baseline serum total testosterone levels were lower in HIV-infected women than in healthy women (Fig. 2 and Table 3). In both groups of women, a diurnal rhythm was apparent, with higher testosterone levels in the morning and lower levels in the afternoon. After application of two patches, serum testosterone levels increased from baseline in both groups of women (Fig. 2) and remained relatively stable during the 96-h patch application period. During TMTDS application, serum total testosterone concentrations were at the upper end of the normal female range in healthy, premenopausal women and in the midnormal range in HIV-infected women. The maximal testosterone concentrations (Cmax) and the average testosterone concentrations (Css) during the 96-h patch application period were significantly lower in HIV-infected women than in healthy women (Table 3). The mean time-average, baseline-subtracted testosterone increment was significantly greater in healthy women than in HIV-infected women (Table 3). Testosterone bioavailability, calculated as baseline-subtracted, area under the testosterone curve, was significantly greater in healthy women than in HIV-infected women (Table 3).

View larger version (22K): [in this window] [in a new window]   Figure 2. Serum total testosterone levels in healthy, menstruating women (A) and HIV-infected women (B). The normal range in healthy, menstruating women is shown by heavy dotted lines, the baseline circadian free testosterone levels by light dotted lines, and serum levels during the second TMTDS application period by solid lines. The data are the mean ± SEM. To convert total testosterone levels from nanograms per dL to nanomoles per L, multiply by 0.03467.

Serum LH, FSH, SHBG, and estradiol levels (Table 4). Serum baseline LH and FSH levels were not significantly different between healthy and HIV-infected women. There was no significant change in LH levels during the 7-day testosterone treatment period in either group (Table 4). Serum FSH levels did not significantly change during treatment in HIV-infected women, but decreased significantly from baseline in healthy women (Table 4). The change in serum FSH levels during treatment was greater in healthy women than in HIV-infected women (Table 4).

Serum baseline estradiol levels were not significantly different between the two groups of women (Table 4). Serum estradiol levels increased in healthy women, but did not change significantly in HIV-infected women. The change in serum estradiol concentrations from baseline in healthy women was consistent with the expected rise in serum estradiol concentrations during the follicular phase of the normal menstrual cycle.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our data demonstrate that treatment with two TMTDS increases and maintains serum free testosterone levels into the high normal range in HIV-infected women and slightly above the upper limit of the normal range in healthy, premenopausal women during the 96-h patch application period. The flatness of the total and free testosterone concentration profiles is consistent with relatively uniform testosterone delivery during TMTDS application.

Treatment with TMTDS was associated with significantly lower circulating concentrations of total and free testosterone in HIV-infected women than in healthy, menstruating women. The testosterone release rates, measured by analysis of residual testosterone in the used patches, did not differ between the two groups of women, suggesting that similar amounts of testosterone were absorbed into the skin and presumably into the bloodstream in the two groups of women. If we assume a uniform testosterone delivery rate of 300 µg/day into the bloodstream, the apparent plasma clearance rates of testosterone are higher in HIV-infected women than in healthy, premenopausal women. Changes in testosterone clearance in HIV-infected women could occur due to alterations in drug metabolism induced by the antiretroviral therapy or other chemotherapeutic agents. Protease inhibitors affect the activity of cytochrome P450 isoforms (18, 19, 20, 21, 22, 23, 24, 25, 26), although there is heterogeneity in the ability of different protease inhibitors to alter drug metabolism (18, 20, 22). These therapeutic agents may increase the clearance of some drugs (22, 23, 24, 25) and inhibit the metabolism of others (18, 19). For instance, Ritonavir administration reduces the area under the curve for drugs such as alprazolam, mepridine, and methadone (25). Similarly, nelfinavir can induce cytochrome P450-mediated drug metabolism and is known to increase the degradation of ethinyl estradiol (23). The nonnucleoside HIV reverse transcriptase inhibitor, nevirapine, decreases circulating methadone levels and may precipitate withdrawal symptoms in patients on methadone maintenance (24). Other medications frequently used in HIV-infected patients, such as macrolide antibiotics, trimethoprim-sulfamethoxazole, and azole-antifungal drugs, can also alter drug metabolism (22, 26). Six HIV-infected women in our study were taking nelfinavir, two were taking Ritonavir, one was taking nevirapine, five were taking a combination of lamivudine and Zidovudine, three were taking stavudine, four were taking didanosine, five were taking trimethoprim-sulfamethxazole, and one was taking acyclovir. Therefore, in these patients, there was potential for significant alterations in testosterone metabolism because of the known effects of one or more of these drugs. We do not know whether circulating cytokines and other mediators of the systemic inflammatory response, the HIV itself, or the host response to the infection affect testosterone metabolism. It is also possible that the metabolism of testosterone in the skin at the patch application site might be different in healthy and HIV-infected women. Further studies are needed to more directly measure testosterone clearance rates in healthy and HIV-infected women.

Miller et al. (15) reported that HIV-infected women treated with the testosterone matrix transdermal testosterone system had higher serum testosterone levels than surgically menopausal women (16, 17). We do not know why our results differ from those of the previous study; several explanations are possible based on differences in patient populations and study design. The patients recruited for the previous study (15) were selected based on significant weight loss; weight loss was not an enrollment criterion in our study. We only included premenopausal, HIV-infected women with normal menstrual cycles to minimize heterogeneity in estrogen levels due to menopause. We recruited HIV-infected patients who had been on a stable antiretroviral regimen that included at least one protease inhibitor; only some of the women in the previous study were taking protease inhibitors. Also, the patients in our study were on significantly different antiretroviral regimens than those in the previous study because of the different time periods and differences in the prevalent practices in the two cities. Any or all of these factors could account for the differences in the results of the two studies.

This is the first study that has comprehensively evaluated the pharmacokinetics of testosterone in HIV-infected women and healthy premenopausal women. The increments in serum testosterone levels in healthy, premenopausal women treated with two testosterone patches in our study were consistent with pharmacokinetic results reported previously in surgically postmenopausal women (16, 17).

Many postmenopausal women with low testosterone levels experience decreased libido, fatigue, and impaired sense of well-being (10, 11, 12, 13, 14); testosterone replacement in these women has been associated with improvements in these symptoms (10, 11, 29, 30, 31). The doses of testosterone employed in many studies were relatively high and increased serum testosterone levels into a range that is supraphysiological for healthy women (10, 11). Testosterone replacement increases lean body mass (32, 33, 34) and maximal voluntary muscle strength (33) in androgen-deficient, HIV-infected men. In the pilot study by Miller et al. (15), testosterone supplementation of HIV-infected women with the acquired immunodeficiency syndrome wasting syndrome at a nominal delivery rate of 150 µg/day by TMTDS patch was associated with significant gains in body mass, mostly due to increments in the fat mass. It is possible that the effects of physiological testosterone replacement on body composition may differ in HIV-infected men and women due in part to gender differences in premorbid body composition, hormonal milieu, and composition of weight loss. We do not know, however, whether physiological testosterone replacement can produce clinically significant improvements in muscle function and disease outcomes in HIV-infected women with weight loss and whether such benefits can be achieved without the virilizing side-effects. Clinical trials to assess the therapeutic effectiveness of physiological testosterone replacement in HIV-infected women are in progress.

	Footnotes

 
¹ This work was supported primarily by a research grant from the FDA, Orphan Drug Program Grant OPD 1397, NIH Grant 1RO1-DK-49296, General Clinical Research Center Grant MO-00543, and Research Centers for Minority Institutions (RCMI) Grants P20-RR-11145-01 (RCMI) Clinical Research Initiative) and G12-RR-03026.

Received November 17, 1999.

Revised February 25, 2000.

Accepted March 22, 2000.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Arver SA, Sinha-Hikim I, Shen R, Beall G, Guerrero M, Bhasin S. 1999 Serum testosterone and dihydrotestosterone concentrations in HIV-infected men. J Androl. 20:611–617.[Abstract/Free Full Text]
2. Coodley GO, Loveless MO, Nelson HD, Coodley MK. 1994 Endocrine function in HIV wasting syndrome. J Acquired Immune Defic Retrovirol. 7:46051.
3. Dobs AS, Few WL, Blackman MR, Harman SM, Hoover DR, Graham NMH. 1996 Serum hormones in men with human immunodeficiency virus-associated wasting. J Clin Endocrinol Metab. 81:4108–4112.[Abstract/Free Full Text]
4. 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/Free Full Text]
5. Salehian B, Jacobson, Swerdloff RS, Grafe MR, Sinha-Hikim I, McCutcham JA. 1999 Testicular pathologic changes and the pituiitary-testicular axis during human immunodeficiency virus infection. Endocr Pract. 5:1–9.[Medline]
6. Grinspoon S, Corcoran C, Miller K, et al. 1997 Body composition and endocrine function in women with acquired immunodeficiency syndrome wasting. J Clin Endocrinol Metab. 82:1332–1337.[Abstract/Free Full Text]
7. Javanbakht M, Bhasin S. 1999 Can physiologic testosterone replacement produce clinically meaningful changes in body composition and muscle strength in HIV-infected patients? J Parenter Enteral Nutr. 23:S195–S201.
8. Sinha-Hikim I, Arver S, Beall G, et al. 1998 Measurement of free testosterone levels by a sensitive equilibrium dialysis method during the normal menstrual cycle in healthy women and in HIV-infected women. J Clin Enodcrinol Metab. 83:1312–1318.[Abstract/Free Full Text]
9. Engelson ES, Goggin KJH, Rabkin JG, Kotler DP. Nutrition and testosterone status of HIV⁺ women [Abstract Tu.B. 2382]. Proc of the 11th Int Conf on AIDS. 1996.
10. Davis SR, McCloud P, Strauss BJ, Burger H. 1995 Testosterone enhances estradiol’s effects on postmenopausal bone density and sexuality. Maturitas. 21:227–236.[CrossRef][Medline]
11. Sherwin BB, Gelfand MM. 1987 The role of androgen in the maintenance of sexual functioning in oophorectomized women. Psychosom Med. 49:397–409.[Abstract/Free Full Text]
12. Raisz LG, Wiita B, Artis A, et al. 1996 Comparison of the effects of estrogen alone and estrogen plus androgen on biochemical markers of bone formation and resorption in postmenopausal women. J Clin Endocrinol Metab. 81:37–43.[Abstract]
13. Davis S. 1999 Androgen replacement in women. J Clin Endocrinol Metab. 84:1886–1891.[Abstract/Free Full Text]
14. Sarrel PM. 1999 Psychosexual effects of menopause: role of androgens. Am J Obstet Gynecol. 180:319–324.[CrossRef]
15. Miller K, Corcoran C, Armstrong C, et al. 1998 Transdermal testosterone administration with acquired immunodeficiency syndrome: a pilot study. J Clin Endocrinol Metab. 83:2717–2725.[Abstract/Free Full Text]
16. Bowen AJ, Caramelli KE, Mazer NA. Physiological testosterone replacement for women: pharmacokinetics of experimental transdermal testosterone matrix patches in surgically menopausal subjects [Abstract P3–59]. Proceeding of the 80th Annual Meeting of The Endocrine Society, 1998.
17. Mazer NA. 2000 New clinical applications of transdermal testosterone delivery in men and women. J Controlled Release. 65:305–315.
18. Eagling VA, Back DJ, Barry MG. 1997 Differential inhibition of cytochrome P450 isoforms by the protease inhibitors ritonavir, saquinavir, and indinavir. Br J Clin Pharmacol. 44:190–194.[CrossRef][Medline]
19. 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.
20. Lillibridge JH, Liang BBH, Kerr BM, et al. 1998 Characterization of the selectivity and mechanism of human cytochrome P450 inhibition by the human immunodeficiency virus-protease inhibitor nelfinavir mesylate. Drug Metab Dispos. 26:609–616.[Abstract/Free Full Text]
21. Nishime JA, Wang RW, Lin JH, Chiba M. 1999 Modulation of cytochrome P-450 by an investigational HIV protease inhibitor. Drug Metab Dispos. 27:972–976.[Abstract/Free Full Text]
22. Harrington RD, Woodward JA, Hooton TM, Horn JR. 1999 Life-threatening interactions between HIV-1 protease inhibitors and the illicit drugs MDMA and -hydroxybutyyrate. Arch Intern Med. 159:2221–2224.[Abstract/Free Full Text]
23. Kerr B, Lee C, Yuen G, et al. Overview of in-vitro and in-vivo drug interaction studies of nelfinavir mesylate, a new HIV-1 protease inhibitor [Abstract]. Proc of the 4th Conf on Retroviruses and Opportunistic Infections, 1997, p. 547.
24. Alice F, Cooney E, Friedland G. Nevirapine induced methadone withdrawal: implications for antiretroviral treatment in opiate dependent HIV-infected patients [Abstract]. Proc of the 6th Conf on Retroviruses and Opportunistic Infections, 1999, p. 425.
25. Piscitelli S, Rock-Kress D, Bertz R, et al. Ritonavir decreases mepiridine exposure in HIV-negative subjects [Abstract]. Proc of the 6th Conf on Retroviruses and Opportunistic Infections. 1999.
26. Sahal J. 1996 Risks and synergies from drug interactions. AIDS. 157:961–969.
27. Bhasin S, Storer T, Berman N, et al. 1996 The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med. 335:1–7.[Abstract/Free Full Text]
28. Gibaldi M, Perrier D. 1982 Pharmacokinetics, 2nd Ed. New York: Marcel Dekker; 321.
29. Sands R, Studd J. 1995 Exogenous androgens in postmenopausal women. Am J Med. 98:76S–79S.[CrossRef]
30. Gruber DM, Sator MO, Kirchengast S, Joura EA, Huber JC. 1998 Effect of percutaneous androgen replacement therapy on body composition and body weight in post-menopausal women. Maturitas. 29:253–259.[CrossRef][Medline]
31. Watts NB, Notelovitz M, Timmons MC, Addision WA, Witta B, Downey LJ. 1995 Comparison of oral estrogen and estrogen plus androgen on bone mineral density, menopausal symptoms, and lipid-lipoprotein profile in surgical menopause. Obstet Gynecol. 85:529–537.[Abstract]
32. Bhasin S, Storer TW, Asbel-Sethi N, et al. 1998 Effects of testosterone replacement with a non-genital, transdermal system, Androderm, in human immunodeficiency virus-infected men with low testosterone levels. J Clin Endocrinol Metab. 83:3155–3162.[Abstract/Free Full Text]
33. Bhasin S, Storer TW, Javanbakht M, et al. 2000 Effects of testosterone replacement on body composition and muscle strength in HIV-infected men with low testosterone levels and weight loss. J Am Med Assoc. 283:763–770.[Abstract/Free Full Text]
34. Grinspoon S, Corcoran C, Askari H, et al. 1998 Effects of androgen administration in men with AIDS wasting syndrome. a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 129:18–26.[Abstract/Free Full Text]

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