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Department of Medicine (K.M., M.S.), University of California, San Francisco, Division of Endocrinology, San Francisco General Hospital, San Francisco, California 94110; Statistical and Data Analysis Center (R.Z., T.L., T.U.), Harvard University, Boston, Massachusetts 02115; Northwestern University Medical Center (J.H.V.R.), Chicago, Illinois 60611; National Institutes of Health (M.A.C), Bethesda, Maryland 20892; Departments of Medicine and Pharmacology and Cancer Institute (M.J.E.), University of Pittsburgh, Pittsburgh, Pennsylvania 15213; University of Southern California Keck School of Medicine (F.R.S.), Los Angeles, California 90033; University of California, San Diego (C.A.B.), San Diego, California 92103; Social and Scientific Systems, Inc. (S.S.), Silver Spring, Maryland 20910; and University of Texas Southwestern Medical Center (R.J.A.), Dallas, Texas 75390
Address all correspondence and requests for reprints to: Kathleen Mulligan, Ph.D., Division of Endocrinology, San Francisco General Hospital, Building 30, Room 3501K, 1001 Potrero Avenue, San Francisco, California 94110. E-mail: kmulligan{at}sfghgcrc.ucsf.edu.
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Abstract |
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Objective: The objective of the study was to determine whether coadministration of testosterone with MA could enhance lean body mass (LBM) accrual and evaluate the effects of MA, alone or combined with testosterone, on sexual functioning and the hypothalamic-pituitary-adrenal axis.
Design: This was a randomized, double-blind, placebo-controlled, multicenter trial.
Setting: Fourteen AIDS Clinical Trials Units in the United States participated in the study.
Subjects: Seventy-nine HIV-positive men with 5% or more weight loss or body mass index less than 20 kg/m2 took part in the study.
Intervention: Subjects were randomized to receive MA (800 mg daily) plus testosterone enanthate (200 mg; MA/TE; n = 41) or placebo (MA/PL; n = 38) biweekly for 12 wk.
Main Outcome Measures: Weight, body composition (bioelectric impedance analysis), adrenal and gonadal hormones, and sexual functioning (questionnaire) were measured.
Results: Both groups experienced robust increases in weight (median 5.3 and 7.3 kg in MA/TE and MA/PL, respectively), LBM (3.3 and 3.3 kg), and fat (3.0 and 3.8 kg). There were no significant differences between groups in the magnitude or composition of weight gain (P = 0.44, 0.90, and 0.11 for weight, LBM, and fat, respectively). Trough testosterone concentrations decreased to a greater extent in MA/PL (–12.3 vs. –6.1 nmol/liter in MA/TE; P = 0.04). Cortisol levels became nearly undetectable in subjects with plasma MA levels greater than 150 ng/ml. Sexual functioning was preserved with MA/TE but worsened in MA/PL.
Conclusions: MA produced robust weight gain. Coadministration of testosterone preserved sexual functioning but did not enhance LBM accrual.
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Introduction |
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Although the pathogenesis of wasting in HIV infection is multifactorial, reduced energy intake is considered a primary contributing factor (15, 16). Thus, there has been interest in pharmacological appetite stimulation as a means of increasing food intake and reversing weight loss. Megestrol acetate (MA), a synthetic orally active progestational agent, has stimulated appetite and weight gain in patients with cancer (17, 18, 19), cystic fibrosis (20), or chronic obstructive pulmonary disease (21) and elderly individuals (22, 23) as well as patients with HIV-associated wasting (24, 25, 26, 27). However, the majority of weight gained was fat, rather than LBM (17, 23, 24, 25, 27).
MA suppresses testosterone production and has been used to induce hypogonadism in men with prostate cancer (28). It has been speculated that the apparently preferential gain of fat during MA treatment for wasting may be related to profound suppression of testosterone (29, 30, 31). Hypogonadism in non-HIV-infected men is associated with increases in fat and decreases in LBM that are reversed by replacing testosterone (32, 33). Thus, we hypothesized that correction of MA-induced hypogonadism by testosterone supplementation might promote LBM gain in men with HIV infection. The study described herein was designed to determine whether administration of a conventional replacement dose of testosterone concomitantly with MA could produce greater gain of LBM than treatment with MA alone.
This study was also designed to evaluate the effect of MA on adrenal function. Transient adrenal insufficiency may occur during or after MA therapy (34, 35, 36, 37), potentially as a result of binding of MA to the glucocorticoid receptor that could result, in turn, in suppression of the hypothalamic-pituitary axis (38). However, the effect of MA on the hypothalamic-pituitary-adrenal axis has never been investigated prospectively in patients with HIV infection. Therefore, we also measured adrenal and gonadal hormones. Other secondary objectives were to compare the effects of MA with testosterone with those of MA alone on weight, energy intake, and quality of life, including sexual functioning, and evaluate the safety of this combination therapy.
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Subjects and Methods |
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Seventy-nine HIV-infected men aged 18 yr or older with documented involuntary weight loss 5% or greater or body mass index (BMI) less than 20 kg/m2 were studied at 14 clinical sites between January 22, 1997 and March 30, 1999. [One male subject was found to be ineligible after enrollment. In addition, although the hypotheses underlying the study pertained to men only, two women were enrolled and given a smaller dose of testosterone enanthate (100 mg biweekly). Both women discontinued due to toxicity before completing the study. Results from these three subjects are not included in this report.] The study was approved by the institutional review boards at each site, and signed informed consent was obtained from all subjects before enrollment. Subjects using antiretroviral therapy were required to be on stable regimens for at least 30 d preceding enrollment and were asked to plan to remain so during the study. Subjects who had received no antiretroviral therapy for the preceding 30 d and had no plans to initiate therapy during the study were allowed to enroll. Other eligibility requirements included serum total testosterone level within normal limits, Karnofsky score 60 or greater and life expectancy 6 months or longer.
Exclusion criteria included an active opportunistic infection or other major systemic illness in the preceding 30 d; platelets 50,000/µl or less; aspartate aminotransferase alanine, aminotransferase, and alkaline phosphatase 5 times or greater the upper limit of normal (ULN); direct bilirubin 1.5 or greater times ULN; serum creatinine 3.0 times or greater ULN; prothrombin and partial thromboplastin times 1.5 times or greater ULN; receipt of cytokines, MA, anabolic steroids, systemic glucocorticoids, GH, dehydroepiandrosterone (DHEA), ketoconazole, anticoagulants, or hypoglycemic agents within 30 d of entry; weight gain 3% or greater during the preceding 4 wk; diabetes mellitus; current or past history of cardiomyopathy or congestive heart failure; impaired oral intake; grade 2 or greater intractable nausea or vomiting; persistent diarrhea (4 or more stools/d while using antidiarrheal medication); history of thromboemboli; parenteral nutrition or tube feeding; and systemic chemotherapy or radiation therapy. Subjects using oral nutritional supplements were not excluded.
Treatment
All subjects received 800 mg MA oral suspension (Megace 40 mg/ml; Bristol-Myers Squibb, Plainsboro, NJ), taken 1 h before or 2 h after breakfast. In addition to receiving MA, subjects were randomized, in a 1:1 fashion, to receive either 200 mg testosterone enanthate (MA/TE) or a matching placebo (MA/PL) by im injection, every 2 wk. Testosterone and placebo were provided by Biotechnology General Corp. (Iselin, NJ). All injections of study medication were administered by study personnel who were blinded to treatment assignment.
Outcome assessments
At baseline and wk 6 and 12, subjects underwent measurements of weight, body composition, hormones, quality of life, and dietary intake. Subjects were asked to fast for 8 h or more before each of these study visits. Height was measured before randomization, following standardized AIDS Clinical Trials Group procedures. Weight was measured on the same calibrated scale at each visit with subjects wearing a hospital gown. Body composition was measured by single-frequency bioelectrical impedance analysis (BIA; RJL Quantum, Clinton Township, MI). Electrode placement for BIA was standardized during central training of study coordinators. Fat, LBM, and body cell mass (BCM) were calculated using published equations (39). Fasting blood samples were collected for chemistries, liver function tests, and hematology, including CD4 counts. Serum was stored for subsequent batch analysis of total testosterone, LH, cortisol, DHEA, androstenedione, and MA levels. These samples were collected before subjects received their injection of TE or placebo. Three-day written food intake diaries prepared before each of these study visits were reviewed with a dietitian before calculation of energy and macronutrient intake. Subjects also completed a written quality-of-life questionnaire that was specifically designed for this study and included detailed questions about sexual functioning. Clinical signs and symptoms were evaluated biweekly.
Laboratory methods
Routine laboratory chemistries, hematology, and CD4 counts were measured in clinical laboratories at each site. The following gonadal and adrenal hormones were measured in batched frozen serum samples in the Core Hormone Assay Laboratory of the General Clinical Research Center at San Francisco General Hospital: total testosterone by RIA and LH by immunoradiometric assay (Coat-a-Count; Diagnostic Products, Inc., Los Angeles, CA); cortisol and DHEA by enzyme immunoassay (Diagnostic Systems Laboratories, Inc., Webster, TX); and androstenedione by enzyme immunoassay (American Laboratory Products Co., Windham, NH). Megestrol acetate levels were measured by HPLC (37) at the University of Pittsburgh Cancer Institute.
Statistical methods
The primary analysis compared changes in LBM from baseline to wk 12 in the two groups in an intent-to-treat fashion. Wilcoxon rank-sum tests were used to assess between-group differences in continuous variables; for within-group changes Wilcoxon signed-rank tests were used. Because treatment groups appeared to be unbalanced with respect to body composition at baseline, multiple regression was performed to assess the sensitivity of the unadjusted results to differences in weight, LBM, and fat. Differences between groups in categorical variables were assessed with exact testing procedures. Two-tailed P < 0.05 was considered to be statistically significant. Data reported are median values with interquartile ranges unless indicated otherwise.
Sample size calculations were performed a priori using 85% power and two-sided 5% significance level and were based on detecting a 1.5 kg difference in LBM between treatment groups. A SD of 2.0 kg for change in LBM was used in the sample size calculations (40), yielding a sample size of 32 per group. This number was further adjusted to allow for a 20% dropout rate so that the target total sample size was 80.
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Results |
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Forty-one and 38 eligible men were randomized to receive MA/TE and MA/PL, respectively (Fig. 1
and Table 1). There were no significant differences in age, CD4 counts, energy or macronutrient intake, or adrenal or gonadal hormone levels at baseline. Baseline weight, BMI, and fat were significantly higher in the MA/TE group. Karnofsky scores of 80 (normal activity with effort) or less were reported in 73 and 69% of subjects in MA/TE and MA/PL, respectively, indicating some limitation in physical functioning in the majority of subjects. Overall, there were no differences between groups in antiretroviral treatment regimens at baseline (P = 0.81). More than half of the subjects in each group were on protease inhibitor (PI)-containing regimens. The most frequently reported PIs were indinavir (38%) and nelfinavir (21%). The most frequently reported nucleoside analog reverse transcriptase inhibitors were lamivudine (72%), zidovudine (43%), and stavudine (34%). Use of nonnucleoside reverse transcriptase inhibitors was reported by 18% of subjects, including 11% on nevirapine. Three subjects (all MA/TE) were on no antiretroviral therapy at baseline. Although the protocol asked subjects to avoid changes in antiretroviral regimens, 11 subjects (six MA/TE and five MA/PL) reported a change in their regimens during the study, including one subject on MA/TE who initiated therapy between baseline and wk 6.
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). Three subjects (all MA/PL) died before completing the study (one each from progressive multifocal leukoencephalopathy, extreme wasting, and homicide). Other reported reasons for premature discontinuation were incarceration (two MA/PL), loss of adrenal function (one MA/PL), development of hypertension (one MA/PL), concern about side effects of MA (one MA/PL), grade 4 hyperbilirubinemia (one MA/TE), and nonadherence (one MA/TE). One subject (MA/TE) moved and another two (one MA/TE, one MA/PL) were lost to follow-up. Weight and body composition
Both groups experienced robust increases in weight [median (Q1, Q3) 5.3 (3.4, 8.9) and 7.3 (3.5, 9.2) kg in MA/TE and MA/PL, respectively], LBM [3.3 (0.9, 4.5) and 3.3 (0.9, 4.1) kg, respectively], and fat mass [3.0 (2.1, 4.2) and 3.8 (2.6, 5.1) kg, respectively; Fig. 2]. BCM increased modestly in both groups [1.1 (0.6, 2.8) and 1.0 (0.0, 1.9) kg, respectively]. There were no differences between groups in either the magnitude or composition of weight gain (P = 0.44, 0.90, 0.11, and 0.28 for weight, LBM, fat, and BCM, respectively), even after adjustment for differences in baseline weight, fat, and LBM. A weight gain of 2 kg or more was seen in 80 and 86% of subjects in MA/TE and MA/PL, respectively (P = 0.73). Among subjects who gained 2 kg or more, LBM accounted for 49 and 45% of the weight gain in MA/TE and MA/PL, respectively (P = 0.07).
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Hormones
MA levels were undetectable in all subjects at baseline and increased in both groups during treatment [+751 (12, 1306) and +1243 (386, 1825) ng/ml in MA/TE and MA/PL, respectively, at wk 12; P < 0.001 vs. baseline in each group; Fig. 3A]. The difference between groups in the increase in MA levels approached, but did not achieve, a level of statistical significance (P = 0.07).
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). These trough levels of testosterone were below the lower limit of the range of values in 95% of adult men with the assay used (9.1 nmol/liter) in both MA/TE [6.1 (3.1, 14.1) and 7.9 (4.6, 11.0) nmol/liter at wk 6 and 12, respectively] and MA/PL [1.9 (0.6, 3.7) and 4.4 (1.7, 7.0) nmol/liter, respectively]. At wk 12, the decrease in testosterone in MA/PL was significantly greater than that in MA/TE [–12.3 (–15.3, – 7.8) vs. –6.1 (–11.9, – 3.0) nmol/liter, P = 0.04]. LH decreased partially and significantly only in MA/PL [–0.8 (–1.7, 0.1) IU/liter; P < 0.01; Fig. 3C], although the number of subjects in MA/TE for whom data were available was small (n = 10 at wk 12).
Cortisol levels decreased significantly in both groups [MA/TE, –200 (–263, –48); MA/PL, –287 (–334, –72) nmol/liter at wk 12; P < 0.01 in both groups; P = 0.15 between groups; Fig. 3D]. At both wk 6 and 12, cortisol levels were nearly undetectable in all subjects with plasma MA greater than 150 ng/ml. Both groups also experienced significant decreases in androstenedione [MA/TE, –0.7 (–1.4, 0.2); MA/PL, –1.2 (–2.4, 0.4) nmol/liter; P < 0.01 for both] and DHEA [MA/TE, –3.8 (–6.9, –1.4); MA/PL, –3.1 (–7.3, –1.7) nmol/liter; P < 0.001 for both; Fig. 3, E and F], but the magnitude of the decreases did not differ significantly between groups. The proportional decline in androstenedione levels tended to be greater in MA/PL than MA/TE (71 vs. 50%, respectively; P = 0.17).
Sexual functioning
There were no differences between groups in sexual functioning at baseline (P > 0.1; Table 2). At wk 12, sexual functioning had worsened significantly in MA/PL but was unchanged or improved with MA/TE. Self-assessment of overall health status did not differ between groups at either baseline or wk 12 (P = 0.26 and 0.67, respectively).
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There were no significant differences between groups in overall toxicity rates, based on a tabulation of grade 3 or 4 toxicities (Table 3). The only symptom that was reported in more than one subject was dyspnea (two in MA/TE). Grade 3 or 4 levels of 
-glutamyl transferase were reported in two subjects on MA/PL. Grade 3 hypertriglyceridemia was reported in one subject in each group, and a grade 3 AST level was reported in one subject on MA/TE.
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Discussion |
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(41). Overall, the exact mechanisms by which MA promotes weight gain remain to be identified. Consistent with other studies in patients with HIV infection, more than half of the weight gained during treatment with MA was fat, rather than LBM. However, it is notable that the absolute value of the median increase in LBM in the present study (+3.3 kg in both groups) falls within the range of increases achieved in placebo-controlled studies of protein anabolic agents in patients with HIV-associated wasting (40, 42, 43, 44, 45, 46, 47, 48, 49, 50). For example, pharmacological doses of GH (40, 42, 43, 44) have produced increases in LBM ranging from 2.5 (44) to 5.2 kg (42). Testosterone treatment in men with HIV wasting (45, 46, 47, 48) has increased LBM from 2.0 (45) to 4.4 kg (46). Among placebo-controlled trials of synthetic anabolic steroids, LBM increased by 1.6 kg in men treated with nandrolone decanoate (44) and 3.5 kg with oxymetholone (49); and BCM increased by 0.9–1.8 kg with increasing doses of oxandrolone (50). A variety of techniques for assessing changes in body composition were used in these studies, so the absolute magnitude of the changes may vary, but all are within a similar range.
Testosterone levels decreased to below-normal levels at wk 6 and 12 in both groups, albeit to a greater extent in the MA/PL group. The decrease in testosterone in the MA/PL group (from 16.9 nmol/liter at baseline to 4.4 nmol/liter at wk 12) is similar to decreases observed in studies using a comparable dose of MA in HIV-positive men with wasting [15.4 to 6.3 nmol/liter (29)] and healthy elderly men [
15.0 to 2.5 nmol/liter (23)]. Because we have data only on trough levels, we cannot determine the extent to which testosterone supplementation maintained testosterone levels within the normal range between injections. Previous pharmacokinetic studies have shown that testosterone increases to levels that exceed the upper limit of normal in the first several days after im injection of 200 mg of TE before declining gradually (51), and we expect that similar changes occurred in subjects who received testosterone in the current study. Given that testosterone in replacement doses suppresses SHBG (45, 47), it is also possible that free testosterone levels were maintained in the normal range during the entire interval between injections.
Contrary to our hypothesis, use of a conventional replacement dose of testosterone (equivalent of 100 mg/wk) failed to enhance the accrual of LBM in patients receiving MA, regardless of whether the increases in LBM are compared in absolute terms (3.3 kg in both groups) or as a percentage of weight gain in subjects who gained at least 2 kg (49 and 45% in MA/TE and MA/PL, respectively). Because this dose of testosterone was sufficient to promote accrual of LBM in healthy hypogonadal men whose pretreatment testosterone levels averaged 2.5 nmol/liter (32), we had hypothesized that a similar improvement would be seen in men with hypogonadism induced by MA. This apparent failure of testosterone supplementation to enhance LBM accrual in subjects receiving MA is consistent with a study by Lambert et al. (23) in elderly men, in whom muscle mass actually decreased during coadministration of MA and testosterone. It is conceivable that a higher dose of testosterone could have provided an anabolic stimulus sufficient to overcome the depression of testosterone and adrenal suppression induced by MA. Alternatively, because MA can compete with testosterone for binding to androgen receptors (52) and decrease receptor number (53) in prostate tissue, it is possible that interference with testosterone action may also have contributed to the failure of testosterone supplementation to augment LBM accrual.
An additional feature of this study was the inclusion of specific questions regarding sexual functioning. Previous studies had reported subjective complaints of impotence, but to our knowledge the impact of MA on sexual functioning has not previously been studied systematically. This issue was of particular concern in the HIV community, in which anecdotal reports of impaired sexual functioning had limited the acceptability of MA as a treatment for wasting. Treatment with MA alone was associated with a marked decrease in sexual functioning. In contrast, sexual functioning was maintained in patients in the MA/TE group. Thus, although the conventional replacement dose of testosterone failed to enhance LBM accrual, it appears to have been sufficient to prevent MA-induced reductions in sexual functioning. This apparent difference in threshold levels of testosterone for maintenance or accrual of LBM and maintenance of sexual function is consistent with a study in healthy men by Bhasin et al. (54) in which a higher level of serum testosterone was required for accrual of LBM than for maintenance of sexual activity and desire.
MA markedly reduced cortisol levels, presumably by suppressing both CRH and ACTH secretion (37). This well-known glucocorticoid-like effect of MA accounts for the occasional reports of Cushing’s syndrome (55) and impaired glucose tolerance (34) in patients using this agent. Moreover, suppression of endogenous adrenal function can result in clinical adrenal insufficiency during periods of stress (56) or when MA treatment is abruptly discontinued (34). Practitioners should be aware of these endocrine effects, particularly in patients who have been exposed to MA for long periods, and be prepared to treat such individuals with glucocorticoids during episodes of illness or stress.
To evaluate further the effect of MA on the adrenal and gonadal axes, we monitored the 19-carbon steroids DHEA, which is predominantly of adrenal origin, and androstenedione, which is derived both directly from the gonads and via peripheral conversion of adrenal DHEA. Because MA and medroxyprogesterone acetate inhibit human 3ß-hydroxysteroid dehydrogenase/
5–4-isomerase type 2 (Auchus, Richard J., unpublished observation, and Ref. 57), which metabolizes DHEA to androstenedione, we anticipated a greater decrease in androstenedione than DHEA. However, MA treatment decreased DHEA to a greater extent than androstenedione, suggesting that MA exerts a greater suppression on the adrenal axis than the gonadal axis. Testosterone administration may have blunted the MA-induced decline in androstenedione (50 vs. 71% suppression in MA/TE and MA/PL, respectively) because testosterone can be metabolized to androstenedione in peripheral tissues by 17ß-hydroxysteroid dehydrogenase type 2 (58).
This study has several limitations, including the use of single-frequency BIA to measure changes in body composition, rather than techniques such as multifrequency BIA or dual-energy x-ray absorptiometry (DEXA) that are considered to be more accurate. However, we took several measures to assure that our data were obtained and analyzed under optimized conditions. Study coordinators underwent supervised central training for measuring height and weight and electrode placement, following standardized procedures. All measurements were made under fasting conditions to minimize the effects of food and fluid intake. We used published equations for lean tissue that had been validated against DEXA in a group that included patients with HIV infection, as described by Kotler et al. (39). In that report, equations using resistance and reactance measured by single-frequency BIA correctly predicted 1, 3, and 5% changes in lean tissue by DEXA 85, 95, and 100% of the time, respectively. Using these same equations, we observed a median increase in lean tissue of 3.3 kg or approximately 6% in each group in a study that was powered to detect a 1.5-kg (or 3%) difference between groups. Given the magnitude of these changes, we are confident that we would have been able to detect a difference between groups had such existed. Another limitation is the possibility that changes in LBM may have been influenced by differences in activity level, which were not controlled for in this study. Finally, this study was performed before there was widespread appreciation of the alterations in fat distribution that are commonly referred to as HIV lipodystrophy, and we did not measure changes in fat distribution. Given the interaction of MA with glucocorticoid receptors and the presence of altered fat distribution and glucose metabolism in patients with glucocorticoid excess (Cushing’s syndrome), future studies of MA should include measurements of regional fat distribution, insulin, and glucose tolerance.
In summary, MA treatment resulted in robust weight gain and accrual of LBM in men with HIV-associated wasting. Addition of a conventional dose of testosterone preserved sexual functioning but did not significantly increase the proportion of weight gained as LBM, suggesting that either MA-induced hypogonadism is not a significant determinant of the partitioning of weight gain or a higher dose of testosterone is required to overcome the suppressive effects of MA on testosterone production or action. Finally, MA-induced hypocortisolemia warrants close monitoring when MA is discontinued.
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Acknowledgments |
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Footnotes |
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Disclosure Statement: R.Z., M.A.C., F.R.S., C.A.B., T.L., T.U., R.J.A., and S.S. have nothing to declare. K.M., J.H.V.R., M.J.E., and M.S. have received consulting fees from Bristol-Myers Squibb; J.H.V.R. has received lecture fees from Bristol-Myers Squibb; and M.J.E. has received grant support from Bristol-Myers Squibb.
First Published Online November 7, 2006
2 See Acknowledgments for members of the ACTG 313 Study Team. 
Abbreviations: BCM, Body cell mass; BIA, bioelectrical impedance analysis; BMI, body mass index; DEXA, dual-energy x-ray absorptiometry; DHEA, dehydroepiandrosterone; HAART, highly active antiretroviral therapy; LBM, lean body mass; MA, megestrol acetate; MA/TE, MA plus testosterone enanthate; MA/PL, MA plus placebo; PI, protease inhibitor; ULN, upper limit of normal.
Received May 4, 2006.
Accepted October 30, 2006.
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References |
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-hydroxysteroid dehydrogenase activity. J Biol Chem 1268:12964–12969This article has been cited by other articles:
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  C M Wilcox and M S Saag Gastrointestinal complications of HIV infection: changing priorities in the HAART era Gut, June 1, 2008; 57(6): 861 - 870. [Abstract] [Full Text] [PDF]
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 W. J. Evans Megestrol Acetate Use for Weight Gain Should Be Carefully Considered J. Clin. Endocrinol. Metab., February 1, 2007; 92(2): 420 - 421. [Full Text] [PDF]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
, P < 0.01. Significance of differences vs. MA/PL in change from baseline: 
, P = 0.008; 
, P = 0.04. To convert testosterone nanomoles per liter to nanograms per milliliter, divide by 3.467; cortisol nanomoles per liter to micrograms per deciliter, divide by 27.59; androstenedione nanomoles per liter to nanograms per milliliter, divide by 3.492; and DHEA nanomoles per liter to nanograms per milliliter, divide by 3.467.