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From the Clinical Research Centers |
Neuroendocrine (S.G., K.M. C.C., C.A.) and Infectious Disease (N.B., D.C.) Departments, and the General Clinical Research Center (E.A., D.S.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; Department of Obstetrics and Gynecology, Brigham and Women’s Hospital (R.T.), Boston, Massachusetts 02115; Dimock Community Health Center (L.H.), Boston, Massachusetts 02119; and TheraTech, Inc. (C.D., K.C., N.M.), Salt Lake City, Utah 84108
Address all correspondence and requests for reprints to: Steven Grinspoon, M.D., Neuroendocrine Unit, Bulfinch 457B, Massachusetts General Hospital, Boston, Massachusetts 02114.
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Abstract |
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Fifty-three ambulatory women with the AIDS wasting syndrome defined as weight less than 90% of ideal body weight or weight loss of more than 10% of the preillness maximum, free of new opportunistic infection within 6 weeks of study initiation, and with screening serum levels of free testosterone less than the mean of the normal reference range (<3 pg/mL) were enrolled in the study. Subjects were age 37 ± 1 yr old (mean ± SEM), weighed 92 ± 2% of ideal body weight, and had lost 17 ± 1% of their maximum weight. CD4 count was 324 ± 36 cells/mm3, and viral burden was 102,382 ± 28,580 copies.
Subjects were randomized into three treatment groups, in which two placebo patches (PP), one active/one placebo patch (AP group), or two active patches (AA group) were applied twice weekly to the abdomen for 12 weeks. The expected nominal delivery rates of testosterone were 150 and 300 µg/day, respectively, for the AP and AA groups. Forty-five subjects completed the study (PP group, n = 13; AP group, n = 14; AA group, n = 18). Two additional subjects from the PP group and two from the AP group were included in the intent to treat analysis. Serum free testosterone levels increased significantly from 1.2 ± 0.2 to 5.9 ± 0.8 pg/mL (AP) and from 1.9 ± 0.4 to 12.4 ± 1.6 pg/mL (AA) in response to testosterone administration (P < 0.0001 for comparison of AA vs. PP and AP vs. PP; normal range, 1.3–6.8 pg/mL). Testosterone administration was generally well tolerated locally and systemically, with no adverse trends in hirsutism scores, lipid profiles, or liver function tests.
Weight increased significantly in the AP group (1.9 ± 0.7 kg) vs. the PP group (0.6 ± 0.8 kg; P = 0.043), but did not increase significantly in the AA group (0.9 ± 0.4 kg; P = 0.263 vs. PP, by mixed effects model assessing the interaction of time and treatment on all available data, one-tailed test). Improved social functioning (P = 0.024, by one-tailed test) and a trend toward improved pain score (P = 0.059) were observed in the AP vs. the PP-treated patients (RAND 36-Item Health Survey questionnaire). Five of six previously amenorrheic patients in the AP group had spontaneous resumption of menses compared to only one of four amenorrheic patients in the AA group (P = 0.045 for comparison of actual number of periods during the study).
This study is the first investigation of testosterone administration in women with AIDS wasting. We demonstrate a novel method to augment testosterone levels in such patients that is safe and well tolerated during short term administration. At the lower of the two doses administered in this study, testosterone therapy was associated with positive trends in weight gain and quality of life. Higher, more supraphysiological, dosing was not associated with positive trends in weight or overall well-being. These data suggest that testosterone administration may improve the status of women with AIDS wasting. Further studies are needed to assess the effects of testosterone on weight in HIV-infected women and to define the optimal therapeutic window for testosterone administration in this population.
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Introduction |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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Experimental Subjects |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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Study design
Screening. Study subjects were recruited through collaborating physicians and by advertising in community newspapers and on the radio. At a screening visit, a complete medical history and physical examination were performed. Serum was drawn for determinations of total and free testosterone levels, complete blood count, creatinine, SGOT, total bilirubin, and alkaline phosphatase to determine eligibility. HIV seropositivity was documented for each patient by enzyme-linked immunosorbent assay and Western blot.
Baseline testing, randomization, and follow-up visits. Eligible subjects returned for a baseline visit. In subjects with regular menstrual function, the visit was timed to correspond to the early follicular phase (days 1–7) of the menstrual cycle. After the completion of baseline testing, subjects were randomized into three treatment groups in which either two placebo skin patches (PP group), one active and one placebo patch (AP group), or two active patches (AA group) were applied twice weekly to the abdomen at 0800 h for 12 weeks. Randomization was blinded to investigators and subjects.
Each patient returned for interim study visits at 4 and 8 weeks and again to complete the study at 12 weeks. A pregnancy test was performed at each visit. Weight, medical history, medication history, physical examination, fasting morning hormone samples, and skin tolerability were assessed at each visit. Body composition analysis, including bioimpedance analysis and dual energy x-ray absorptiometry (DEXA); nutritional analysis; exercise functional capacity; and quality of life were assessed at the initial and final study visits. Compliance was determined by a count of the used patches at each visit.
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Materials and Methods |
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Investigational active and placebo patches were supplied by TheraTech (Salt Lake City, UT). TMTDS is a proprietary alcohol-free matrix patch (18 cm2) containing testosterone, sorbitan monooleate as a permeation enhancer, and a hypoallergenic acrylic adhesive. Each active patch contains 4.1 mg testosterone and was expected to deliver testosterone at a nominal delivery rate of 150 µg/day over a 3- to 4-day application period (TheraTech, unpublished data). The simultaneous application of two active patches (AA group) was expected to deliver testosterone at a nominal rate of 300 µg/day.
Body composition analysis
Fat and lean body mass were determined by DEXA using a Hologic-2000 densitometer (Hologic, Waltham, MA). The DEXA technique has a precision error of 3% for fat and 1.5% for lean body mass (6). Bioimpedance analysis was also performed to assess total body water.
Hormonal assessment
Serum levels of total and free testosterone and sex hormone-binding globulin (SHBG) were measured at each visit. In addition, serum levels of estradiol (E2), P, dehydroepiandrostenedione sulfate (DHEAS), and gonadotropins (LH and FSH) were measured at the baseline and week 12 visits. Hirsutism scores were assessed at the baseline and 12 week visits using the Lorenzo rating scale (7), a modification of the Ferriman-Gallwey hirsutism score.
Menstrual status
Menstrual status was assessed by self-report (recall over 3 months before initiation of study) and by menstrual diary during the study. Subjects who had not had a period within the last 3 months before study initiation were categorized as amenorrheic, subjects with one period in the last 3 months were characterized as oligoamenorrheic, and subjects with two or more periods in the 3 months before the initiation of the study were categorized as eumenorrheic. The number of menstrual periods occurring during the 12 weeks of treatment were tabulated from the menstrual diary.
Nutritional assessment
Before study entry and again immediately before study completion, subjects were instructed on completion of a 4-day food record, which was analyzed for total calorie, protein, fat and carbohydrate content (Minnesota Nutrition Data Systems, version 8A/2.6, Minneapolis, MN). Resting energy expenditure was also determined at the beginning and end of the study by indirect calorimetry with a metabolic cart (EMS/50 Enhanced Metabolic System, Life Energy Systems, Murray, UT).
Quality of life
Quality of life indexes were compared before and after treatment by a RAND 36-Item Health Survey questionnaire (8). Scoring was divided into 8 domains, emotional well-being, role functioning emotional, role functioning physical, energy/fatigue, general health, pain, physical functioning, and social functioning. Perceived well-being was also assessed at the end of the study using nine linear analog scale questions adapted from Oster et al. on the overall treatment effect, change in quality of life, personal appearance, weight, and appetite (9). A global well-being score was computed for each patient by adding up the scores on each individual question.
Exercise functional capacity
Exercise functional capacity was assessed by a 6-min walk test, a sit to stand test, and a timed get up and go test at the baseline and end of study visits (10, 11, 12). Previous exercise history was assessed by a standardized questionnaire (13).
Virological and immunological parameters
Viral burden and CD4 count were determined twice for each patient at baseline. Comparison of the end of study level and the average baseline level was made to determine change over time within the treatment groups.
Laboratory methods
Hematocrit, white blood count, platelet count, albumin, total
bilirubin, alkaline phosphatase, SGOT, and creatinine were measured
using previously described methods (14). All hormone analyses were
performed in duplicate on frozen serum by Endocrine Sciences. Total
testosterone, E2, and P were measured by specific
RIAs after extraction in hexane-ethyl acetate and column chromatography
(T and E2). The sensitivity of the total
testosterone assay is 3 ng/dL, with an intraassay coefficient of
variation (CV) less than 8.1%. The sensitivity of the E2
assay is 0.5 ng/dL, with an intraassay CV less than 8%. The
sensitivity of the P assay is 10 ng/dL, with an intraassay CV less than
12%. The intraassay CVs were developed using pooled sera covering the
range of the assay. The free testosterone concentration was determined
as the product of the percent free T, measured by equilibrium dialysis,
and the total T concentration. The sensitivity of the determination of
percent free T by this method is 0.1%, determined by reasonable
counting error equivalent to the square root of the counts over the
total counts. The assay has an intraassay CV of 6.9%. DHEAS was
measured by RIA after enzymolysis of the sulfate moiety (sensitivity,
10 µg/dL; intraassay CV, <7%). SHBG was measured by
immunoradiometric assay (sensitivity, 0.2 nmol/L; intraassay CV,
<4%). LH (sensitivity, 0.1 IU/L; intraassay CV, <4.7%) and FSH
(sensitivity, 0.5 IU/L; intraassay CV, <7%) were measured by
immunochemiluminometric assays. The normal ranges for all of the
hormone assays are shown in Table 1
and
are based on a 95% confidence interval from an Endocrine Sciences
database on normal cycling women between the ages of 16–46 yr.
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Statistical analysis
The study was powered to detect changes in hormone levels and to determine safety and tolerability of testosterone administration. The primary end points for efficacy analysis were the changes in total and free testosterone levels. Secondary end points for efficacy analysis included weight, fat-free mass, fat mass, quality of life indexes, and exercise functional capacity. Safety parameters included CD4 count, viral burden, hirsutism score, lipid levels, liver function tests, and menstrual function. Baseline parameters were compared between the groups by ANOVA for continuous variables and Fisher’s exact test for noncontinuous variables. For variables for which ANOVA assumptions were not met, the Kruskal-Wallis test was used for baseline comparisons. The changes in total and free testosterone levels were determined by subtracting the baseline level from the average of each patient’s data at weeks 4, 8, and 12 and were compared between the groups using the Wilcoxon rank sum test. The assumption of no time association with either total or free testosterone levels during treatment was tested and verified by analysis of covariance. Secondary efficacy variables of weight and related parameters (percent ideal body weight and body mass index) were compared by a one-tailed mixed effects model analysis of covariance to assess the difference in slopes (linear time trend) between the groups. Analysis was performed by intent to treat, using all available data on patients. Analysis of secondary end points, such as body composition, for which only beginning and end of study assessments were made was based on the population of patients that completed the study and was determined by t test or, if distributions were markedly skewed, by the Wilcoxon rank sum test.
The analysis plan was to first test the AA compared to the PP groups and, if significant, to then test the AP compared to the PP group. However, a typical dose-response curve was not observed for secondary efficacy variables, and therefore, the AA and AP regimens were each tested separately against PP. Comparisons among treatment groups in the quality of life surveys were made using the Wilcoxon rank sum test. For analysis of safety variables, mean differences were compared among treatment groups using ANOVA. If ANOVA assumptions were not met, Kruskal-Wallis tests were used. The change in CD4 count between the groups was also analyzed by analysis of covariance, controlling for baseline CD4 count. Because the study was exploratory with respect to anthropometric and quality of life indexes, it was decided a priori in the study design to use P < 0.1 (by one-tailed test) to indicate a positive trend for secondary end points of weight, body composition, and quality of life. For analysis of the primary end points (change in testosterone levels), safety parameters, and baseline clinical characteristics, P < 0.05 (by two-tailed test) indicates significance.
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Results |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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No significant differences were observed at baseline between the
groups in age, weight parameters, E2, gonadotropin levels,
or viral burden (Table 1
). Menstrual status was not significantly
different among the groups at baseline; 53%, 44%, and 50% of the
patients in the PP, AP, and AA groups, respectively, reported regular
menstrual cycles at the start of the study. In addition, no significant
differences in medication history or antiviral usage were demonstrated
(data not shown). The CD4 count was higher in the AA group, and the
total and free testosterone levels were higher in the PP group at
baseline.
Fat and fat-free mass determined by DEXA were indexed for height and compared to values previously obtained in healthy, age-matched, HIV-negative controls (n = 12) (4). No differences in height-adjusted fat and fat-free mass were observed among the treatment groups (data not shown). On the average, study subjects demonstrated 91% of fat-free mass (14.2 ± 0.2 vs. 15.5 ± 0.4 kg/m2), but only 65% of fat mass (5.5 ± 0.3 vs. 8.5 ± 0.7 kg/m2), compared to healthy control subjects.
Treatment responses
Hormonal function. Serum total and free testosterone levels
increased significantly in a dose-dependent fashion (Fig. 1). Free testosterone increased from
1.2 ± 0.2 to 5.9 ± 0.8 pg/mL (AP) and from 1.9 ± 0.4
to 12.4 ± 1.6 pg/mL (AA; P < 0.0001 for AA
vs. PP and AP vs. PP; normal range, 1.3–6.8
pg/mL). Total testosterone increased from 24.8 ± 2.7 to
166.8 ± 15.5 ng/dL (AA) and from 17.8 ± 2.5 to 93.0 ±
13.9 ng/dL (AP; P < 0.0001 for AA vs. PP
and AP vs. PP; normal range, 14.0–54.3 ng/dL). The mean
serum free testosterone level was within the low normal range for the
PP-treated patients, the upper normal range for the AP-treated
patients, and the supraphysiological range for the AA-treated patients
during the study. For the AP-treated group, 33% of free testosterone
levels measured during treatment were above the normal range. Total
testosterone levels increased into the supraphysiological range for
both the AP- and the AA-treated groups. No significant differences in
SHBG, E2, P, or FSH levels were found between the
groups (Table 2). LH levels increased in
the AA-treated compared to the PP-treated patients, and DHEAS increased
in AP-treated compared to the PP-treated patients (Table 2).
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Weight, body composition, and nutritional status. Weight
change, expressed in absolute terms, as body mass index, or a
percentage of ideal weight, increased most within the AP-treated group
[0.6 ± 0.8 (PP), 1.9 ± 0.7 (AP), 0.9 ± 0.4 kg
(AA)]. A time-trend analysis by mixed model ANCOVA yielded
P = 0.043 for comparison of the slope of the change of
AP vs. PP and P = 0.276 for AA
vs. PP (by one-tailed test; Fig. 2). Repeat analyses with baseline
testosterone levels, CD4 count, viral burden, and the number of
antiviral medications used as individual covariates yielded very
similar results (P = 0.027, 0.047, 0.047, and 0.055,
respectively, for the comparison of AP vs. PP). For the
AP-treated patients, the weight gain amounted to 4% of the initial
body weight over 12 weeks. Of the 1.9 kg in weight gained by the
AP-treated patients, 1.6 kg were fat (Table 3). In contrast, fat-free mass increased
to the greatest extent by 0.5 ± 0.3 kg in the AA-treated group.
Additionally, a trend toward increased total body water was
demonstrated in the AA-treated patients (Table 3). No significant
differences in caloric intake were noted between the groups, but a
trend toward increased caloric intake was seen in the AP-
vs. PP-treated patients (482 ± 386 vs.
-107 ± 174 Cal; P = 0.113).
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). A significantly greater
score in the social functioning category (P = 0.024)
and a trend toward improved scores in pain (P = 0.059)
were observed in the AP- vs. PP-treated patients. A decrease
in role functioning due to emotional limitations was noted among the
AA-treated patients (P = 0.006). The global quality of
life score at the end of the study was also highest among the
AP-treated group and was highly correlated with the change in weight
among the study subjects (r = 0.65; P <
0.001).
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Adverse events and safety parameters. Forty-five women
completed the study. Six patients were discontinued for protocol
violations, including one women who became pregnant and five patients
who began a new antiretroviral therapy immediately before the baseline
visit. Two additional women were discontinued for adverse events, one
patient developed worsening of a generalized erythematous skin
condition, which antedated entry into the protocol and a second
experienced worsening congestive heart failure thought to be related to
discontinuation of diuretic usage. Both patients were in the AP group,
but in neither case was the study drug believed likely to have
contributed to the adverse event. No adverse effects on liver function
tests, hematological parameters, lipid parameters, or viral burden were
seen (Table 4). A trend toward increased
hematocrit (2.1 ± 1.1%; P = 0.071, by one-tailed
test) was seen in the comparison of the AP- to the PP-treated patients.
CD4 count decreased more in the AA than the PP group (-123 ± 45
vs. 5 ± 13 cells/mm3; P =
0.012, by two-tailed test), but the baseline CD4 count was higher in
this group. No significant changes in CD4 count between groups were
demonstrated after controlling for baseline CD4 count by analysis of
covariance, and no significant differences in the number of
opportunistic infections or antiretroviral medications were noted
between the groups. No statistically significant differences in
hirsutism scores were observed between the groups, although two
patients in the AA-treated group reported increased hair growth on the
upper lip. The patches were generally well tolerated, and no patient
had to discontinue usage related to local skin irritation. Moderate
erythema was noted in association with 15.8%, 6.7%, and 6.9% of skin
evaluations in the PP, AP, and AA groups, respectively.
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Discussion |
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Previous studies of androgen administration in women have investigated pharmacological androgen administration, most often synthetic oral androgen derivatives (18). Pharmacological androgen administration in women may be associated with virilization, hirsutism, acne, and menstrual dysfunction. Furthermore, oral androgen administration is associated with liver toxicity, including cholestatic jaundice (19). In contrast, we used a newly developed transdermal matrix patch system to increase serum testosterone levels (TMTDS) (20). Because the testosterone production rate in women is roughly equivalent to 300 µg/day (21, 22), we used a parallel dose design and tested both a single active and a dual active patch system designed to deliver approximately 150 and 300 µg/day, respectively. Our subjects were selected based on the screening entrance criterion of a free testosterone level below the mean of the normal, age-appropriate, reference range (<3.0 pg/mL). Of note, 55% of the enrolled subjects demonstrated free testosterone levels below the lower limit of the normal range and were therefore androgen deficient. This study design was chosen to minimize potential adverse events associated with androgen administration and to ensure relatively homogeneous baseline androgen levels with respect to the pharmacokinetic analysis.
Mean serum free testosterone levels increased significantly in both treatment groups. Dosing with the single active patch regimen (AP) resulted in free testosterone levels that were at or slightly beyond the upper end of the normal reference range in 33% of measurements. However, the mean serum free testosterone level remained within the normal reference range in the AP-treated group. In contrast, dosing with the double active patch regimen (AA group) resulted in supraphysiological levels. Testosterone levels remained relatively constant within each group over the course of treatment. Serum total testosterone levels paralleled the free testosterone levels, but were above the normal range even in the AP-treated group. Altered testosterone binding and/or clearance may occur among HIV-infected women. Furthermore, it is possible that relatively increased SHBG concentrations (73% above the normal reference mean) may be one factor contributing to the differences in total and free testosterone levels.
The increase in free testosterone seen in response to TMTDS administration in HIV-positive women was approximately 2-fold greater than previously seen in a pharmacokinetic study conducted in surgically menopausal women (TheraTech, data on file). The greater increase in free testosterone compared to that seen in surgically menopausal women may relate to increased skin absorption, altered metabolism, or decreased testosterone clearance in HIV-infected women compared to that in other androgen-deficient populations. In addition, use of protease inhibitors in HIV-infected subjects may contribute to decreased testosterone clearance by inhibiting P450-mediated testosterone metabolism (23).
No obvious deleterious effect of testosterone administration could be discerned in this study. In fact, compliance to patch use (>90%) and tolerability were excellent. Hirsutism scores did not change significantly between the groups, and liver function and lipid tests were not adversely affected over the 12 weeks of the study. However, further studies are needed to investigate the long term consequences of testosterone administration in this population. Hematological parameters were not adversely affected, and hematocrit tended to increase in the AP group. The significant decrease in CD4 count in the AA group is difficult to interpret because CD4 counts were higher at baseline in this group, and no significant differences in CD4 count between the treatment groups were observed after adjusting for baseline CD4 levels. Furthermore, there is no evidence by clinical or medication history or viral burden level that the AA group did any worse in terms of disease status than the other groups in this short term study.
Although both the AP and the AA groups tolerated testosterone administration very well, significant positive trends in weight and quality of life parameters were observed in the AP-treated, but not the AA-treated, patients. The 1.9-kg average weight gain among the AP-treated subjects is similar in magnitude to that reported in studies of GH and megestrol acetate administration in HIV-positive men with AIDS wasting (9, 16, 24). The observation of a relatively larger weight gain in response to low compared to high dose testosterone administration was not expected. Higher baseline testosterone levels were observed in the placebo-treated patients despite the randomized, double blind, placebo-controlled design of the study. Nonetheless, we measured change over time, and therefore, our analysis controlled for differences in baseline testosterone levels. Furthermore, we cannot attribute these results to differences in either treatment or disease status in the AP-treated patients, as covariate analysis with CD4 and viral burden yielded similar results. Due to the relatively small number of patients in each treatment group, we cannot definitively rule out the possibility that the positive trend of increased weight in the AP group and the lack of a typical dose-response curve were simply the result of random variation in this population. Further studies are needed to assess the effects of testosterone on weight in HIV-infected women and to define the optimal therapeutic window for testosterone administration in this population.
The mechanism of potential weight gain among the AP-treated patients is not clear. Caloric intake tended to increase in the AP-treated, but not the AA-treated, patients, and this may account in part for the weight gain. No changes in resting energy expenditure were observed. Of the weight gained among the AP-treated patients, the majority was fat mass. We have previously shown that women with AIDS wasting lose fat disproportionately to fat-free mass (4), and that fat mass correlates with serum androgen levels in this population (unpublished data). A disproportionate reduction in fat mass vs. fat-free mass was also observed among the patients in this study (35% reduction in fat mass vs. 9% reduction in fat-free mass at baseline before therapy). The observation of a gain in fat mass in response to physiological testosterone administration is consistent with our initial observation of disproportionately reduced fat mass in this population and is supported by prior studies of human starvation that demonstrate that the amount of fat repletion during weight gain is a function of the baseline fat depletion (25, 26). In addition, animal studies suggest that low dose testosterone administration may be less inhibitory to lipoprotein lipase than high dose testosterone administration (27, 28), but this phenomenon has not been well studied in humans and was not assessed in this study.
The anabolic effects of androgen administration on muscle and lean mass are well documented in men, but relatively little is known with respect to androgen effects on body composition in women (29, 30, 31, 32, 33). In postmenopausal women, oral androgen administration is associated with a gain in lean body mass, but comparison with the current study is difficult with respect to the patient populations and androgen preparation (18). In a recent study of younger female patients receiving much larger doses of natural testosterone esters as part of a sex reversal program, weight did not change, muscle area increased, and fat mass decreased significantly over 1 yr of therapy (34). Similarly, our data suggest that fat-free mass tended to increase more in women receiving supraphysiological androgen treatment, whereas weight and fat mass increased to a greater extent in the AP-treated subjects receiving physiological testosterone administration. Further studies with larger numbers of patients will be necessary to confirm these preliminary findings.
HIV-infected women are known to have decreased quality of life, which is associated with disease status and symptomaticity (35, 36). Improvement of quality of life is, therefore, a critical issue for such patients. In this study, a significantly greater score in the social functioning category (P = 0.024) and a trend toward improved scores in pain (P = 0.059) were observed in the AP vs. the PP-treated patients. Scores in five of six of the remaining domains, including emotional well-being, general health, and physical function, were also highest in the AP-treated patients, but these differences did not reach statistical significance. In contrast, a decrease in role functioning due to emotional limitations was noted among the AA-treated patients. Taken together, these data suggest that the patients receiving physiological androgen treatment felt better than either the placebo- or AA-treated patients. The mechanisms of the improved quality of life in the AP-treated patients is unclear. One mechanism may be a simple reflection of weight gain in this population. Weight gain correlated significantly with improved quality of life score among the study subjects, suggesting that weight gain in and of itself may make such patients feel better. Alternatively, increased testosterone levels within the physiological range may have a salutary biological effect on behavior and health perceptions. Again, additional studies with a larger number of patients are needed to investigate the important question of physiological testosterone effects on quality of life in this androgen-deficient population.
A final and potentially interesting result of treatment in the AP group was resumption of spontaneous menses in five of six previously amenorrheic patients. The mechanism of this effect is not clear, but it may be related to a gain in weight or fat mass, secondary conversion of testosterone to estrogen, or a more specific effect of physiological testosterone on GnRH pulsatility in HIV-infected women with hypothalamic amenorrhea. According to the earlier hypotheses of Frisch et al., a critical level of body fat is necessary for normal female reproductive function (37). Indeed, comparison of the weight gain between amenorrheic subjects in the AP- and AA-treated groups suggests a more significant increase in weight in the AP-treated group. Accordingly, the increase in weight, composed primarily of fat mass, may have triggered spontaneous resumption of menses. However, the numbers of patients who were amenorrheic at the start of the study was small, and our data do not permit any definitive conclusion as to the mechanisms of this effect in this study.
This study represents the first investigation of testosterone administration in HIV-infected women with AWS. These data demonstrate that short term testosterone administration is safe and very well tolerated in women with AWS. Furthermore, these data suggest that testosterone administration at relatively low doses may increase weight and critical indexes of quality of life in this population. Higher doses, resulting in more supraphysiological testosterone levels, do not appear to increase weight or quality of life. These data suggest the important need for further studies to investigate the effects of androgen administration on weight, body composition, and quality of life in women with AWS.
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Acknowledgments |
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Footnotes |
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Received January 21, 1998.
Revised March 24, 1998.
Revised May 7, 1998.
Accepted May 12, 1998.
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,
P < 0.100, AP vs. PP; *,
P < 0.050, AP vs. PP; **,
P < 0.010, AA vs. PP (by Wilcoxon
rank sum test). PF, Physical functioning; RLP, role limitations due to
physical health; P, pain; GH, general health; EW, emotional well-being;
RLE, role limitations due to emotional problems; SF, social
functioning; EF, energy/fatigue. PP, n = 13; AP, n = 14; AA,
n = 18.