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Neuroendocrine Unit (K.K.M., B.M.K.B., C.B., J.G.L., J.J., A.K.) and Departments of Neurosurgery (B.S.) and Radiation Oncology (J.L.), Massachusetts General Hospital Biostatistics Center (D.S.), and Psychology Assessment Center (J.C.S.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Karen K. Miller, Neuroendocrine Unit, Bulfinch 457B, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: kkmiller{at}partners.org.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Objective: The objective of the study was to determine whether physiologic testosterone replacement improves bone density, body composition, and/or neurobehavioral function in women with severe androgen deficiency secondary to hypopituitarism.
Design: This was a 12-month randomized, placebo-controlled study.
Setting: The study was conducted at a general clinical research center.
Study Participants: Fifty-one women of reproductive age with androgen deficiency due to hypopituitarism participated.
Intervention: Physiologic testosterone administration using a patch that delivers 300 µg daily or placebo was administered.
Main Outcome Measures: Bone density, fat-free mass, and fat mass were measured by dual x-ray absorptiometry. Thigh muscle and abdominal cross-sectional area were measured by computed tomography scan. Mood, sexual function, quality of life, and cognitive function were assessed using self-administered questionnaires.
Results: Mean free testosterone increased into the normal range during testosterone administration. Mean hip (P = 0.023) and radius (P = 0.007), but not posteroanterior spine, bone mineral density increased in the group receiving testosterone, compared with placebo, as did mean fat-free mass (P = 0.040) and thigh muscle area (P = 0.038), but there was no change in fat mass. Mood (P = 0.029) and sexual function (P = 0.044) improved, as did some aspects of quality of life, but not cognitive function. Testosterone at physiologic replacement levels was well tolerated, with few side effects.
Conclusions: This is the first randomized, double-blind, placebo-controlled study to show a positive effect of testosterone on bone density, body composition, and neurobehavioral function in women with severe androgen deficiency due to hypopituitarism.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Data regarding the effects of testosterone administration in women are primarily derived from a menopausal population and focus on neurobehavioral effects, particularly libido and sexual function. This includes a report by Shifren et al. (5), who administered low-dose testosterone by patch to a group of surgically menopausal women and demonstrated an improvement in libido, sexual function, and mood in those who received testosterone, compared with placebo. The data with regard to libido and sexual function in surgically menopausal women were recently confirmed by three larger additional studies (6, 7, 8). There are few published data on the effects of low-dose testosterone replacement on bone density and body composition in women and none in women with hypopituitarism.
We report the results of a randomized, placebo-controlled study of the effects of testosterone replacement on bone density, body composition, and neurobehavioral function in a group of women with profound androgen deficiency due to hypopituitarism.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Fifty-three women, aged 19–50 yr, with hypopituitarism leading to adrenal insufficiency and/or hypogonadism, participated in the study, and 51 were included in the analysis. A serum free testosterone level less than the median of the reference range for premenopausal women, 3.1 pg/ml, as determined by Esoterix Endocrinology (Calabasas Hills, CA), was required at the time of screening. All patients were estrogen replete, whether with regular menstrual periods (n = 7) or receiving exogenous hormone administration in the form of oral contraceptives or hormone replacement therapy (n = 41), for at least 1 yr before study participation. Subjects were offered Ortho-Cyclen 28 (Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ); 15 women therefore received this preparation, whereas the remainder of the subjects continued to take the preparation prescribed by their physicians before study participation. Patients were excluded from participation if receiving androgens, dehydroepiandrosterone (DHEA), supraphysiologic glucocorticoid therapy, anabolic agents, bisphosphonates, or any other medications known to affect bone density within the year before study enrollment. In addition, smokers older than 35 yr who were receiving oral contraceptives were not allowed to participate. Because of the known effects of GH on bone density, body composition, and quality of life, potential subjects were required to be GH naïve or to have been on a stable dose of GH for at least 2 yr to participate in the study. Study participants fell into four groups regarding GH status: 1) not evaluated for GH deficiency (n = 10), 2) diagnosed with GH deficiency and receiving stable replacement doses for at least 2 yr (n = 19), 3) diagnosed with GH deficiency and not receiving GH replacement (n = 18), and 4) not GH deficient (n = 4). Serum creatinine or alanine aminotransferase (ALT) more than three times the upper limit of normal were additional exclusion criteria. The study was approved by the Massachusetts General Hospital Institutional Review Board, and all subjects gave informed, written consent before study participation.
Protocol
Study subjects were recruited through referrals from physicians and through advertisements. At the screening visit, a complete medical history and physical examination were performed. Blood was drawn for measurement of free testosterone, total testosterone, ALT, and creatinine.
Each eligible subject returned for a baseline visit during which the following tests were performed. Blood was drawn for determination of free testosterone, total testosterone, SHBG, ALT, and a lipid profile [total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides], which were all measured in real time. Serum was frozen at –80 C for measurement of other hormones, including estradiol and IGF-I, which were assayed at the end of the study. Urine pregnancy tests were performed on all patients. Bone mineral density and body composition were measured by dual x-ray absorptiometry (DXA), using a Hologic QDR-4500 (Hologic Inc., Waltham, MA), with an accuracy error for bone of less than 1% (9), body fat mass of 1.7%, and fat-free mass of 2.4% (10). Cross-sectional muscle area was determined using single-slice quantitative computed tomography (CT) scans of the midthigh using 10-mm-thick images (General Electric RP High Speed Helical CT scanner, Milwaukee, WI) and graphical analysis software (General Electric Advantage Windows Workstation version 2.0; General Electric). All measurements were made in duplicate. Technical factors for the scan were as follows: 80 kVp, 70 mA, 2-sec scan time. Abdominal adipose deposition, including cross-sectional areas of total fat, sc fat, and intraabdominal fat were determined in duplicate using single-slice quantitative CT scans at the level of L4 using 10-mm-thick axial images with the same scanner and software as described above. The Beck Depression Inventory (BDI) was administered to measure mood (11). Sexual function was measured using the Derogatis Interview for Sexual Function-Female Version (12). Quality of life was measured using the RAND 36-Item Health Survey 1.0 (13, 14), the Nottingham Health Profile (NHP) (15) and the Psychologic General Well-Being (PGWB) Index questionnaire (16). Cognitive function was measured using the Wechsler Abbreviated Scale of Intelligence (WASI) (17), the Vanderberg and Kuse Mental Rotations Test (18), the Hopkins Verbal Learning Test-Revised (19), the Woodcock Johnson Cross-Out Test (20), and the Grooved Pegboard Test (21).
After completion of all baseline testing, participants were randomly assigned to receive transdermal testosterone (300 µg, Intrinsa; Procter & Gamble Pharmaceuticals, Cincinnati, OH), in the form of two 150-µg patches, placed on the abdomen and changed twice weekly, or two placebo patches, also changed twice weekly. The 150-µg patch delivers a mean 150 µg of testosterone daily, resulting in a mean time-averaged increment in serum-free testosterone concentration of 2.7 ± 0.9 pg/ml, and the free testosterone level remains relatively constant for 96 h after patch application (22). The 300-µg dose used in this study is approximately 6% of a typical 5-mg male dose. A health care professional not involved with the study monitored free testosterone levels and implemented dose reductions in subjects with serum-free testosterone levels above the upper limit of normal for women of reproductive age. Dose reductions were from 300 µg (two patches) to 150 µg (one patch). A study subject receiving placebo patches was sham dose reduced concurrently with each such subject receiving testosterone to maintain blinding of study subjects and investigators. Dose increases were not made. This resulted in nine participants being dose reduced from 300 to 150 µg testosterone and another nine, who were receiving placebo, being sham dose reduced. Randomization was stratified based on whether subjects were receiving GH, and assignments were blinded to the investigators and subjects.
Each subject returned for study visits at 1, 3, 6, 9, and 12 months after the baseline visit. Safety evaluation, including pregnancy testing, blood testing for free testosterone, ALT and lipid profile, hirsutism evaluation using the Lorenzo scale (23), and patch site evaluation, was performed at each visit, as was testing for mood, quality of life, and cognitive function end points, except for the WASI, which was administered at baseline and 12 months only. Total testosterone and SHBG were also measured at all study time points. In addition, blood was collected, and serum frozen at –80 C for measurement of estradiol and IGF-I after study completion. Bone density and body composition were measured at baseline and 6- and 12-month visits only.
Laboratory methods
Total testosterone was measured by column chromatography (Esoterix Endocrinology). The sensitivity of this assay is 3 ng/dl (to convert total testosterone to nanomoles per liter, multiply nanograms per deciliter by 0.0347) and the intraassay coefficient of variation (CV) less than 8.1%. The normal range for women of reproductive age is 10–55 ng/dl, as determined by Esoterix Endocrinology. Free testosterone concentration was calculated as the product of percent free testosterone, measured by equilibrium dialysis (Esoterix Endocrinology), and total testosterone concentration. The sensitivity of the determination of percent free testosterone by this method is 0.1%, with an intraassay CV of 6.9%. The normal range of free testosterone for women of reproductive age is 1.1–6.3 pg/ml (to convert free testosterone to picomoles per liter, multiply picograms per milliliter by 3.467), as determined by Esoterix Endocrinology. SHBG was measured by an in-house immunoradiometric assay (Esoterix Endocrinology), with a lower limit of detection of 10 nM, intraassay CV of 2.4–3.9% and a normal female range of 40–120 nM. Estradiol was determined using a RIA kit (Diagnostic Systems Laboratories, Webster, TX), with a sensitivity of 2.2 pg/ml (to convert estradiol to picomoles per liter, multiply picograms per milliliter by 3.671), an intraassay CV of 6.5–8.9%, and a normal range in women of reproductive age of 35–375 pg/ml. IGF-I was measured using a RIA kit (Nichols Institute Diagnostics, San Clemente, CA), with an intraassay CV of 2.4–3.0%, a sensitivity of 14 ng/ml (to convert IGF-I to nanomoles per liter, multiply nanograms per milliliter by 0.131), and a normal range of 182–780 ng/ml (ages 16–24 yr), 114–492 ng/ml (ages 25–39 yr), and 90–360 ng/ml (ages 40–54 yr). Total cholesterol, HDL, triglycerides, ALT, and creatinine were measured using previously described methods (24).
Statistical analysis
JMP Statistical Discoveries (version 4.0.2; SAS Institute, Inc., Cary, NC) was used for statistical analysis of bone density and body composition data and baseline clinical variables. Clinical characteristics were compared by ANOVA. All variables were tested for normality by the Shapiro-Wilk test. For all variables not normally distributed, the Wilcoxon rank-sums test was used to determine significance. For bone density and body composition, analysis of covariance (ANCOVA) was used to determine whether there was an effect of testosterone vs. placebo on 12-month values, controlling for baseline values. Undetectable hormone levels were assigned values just below the lower limit of detection.
Effects of testosterone on all variables measured at more than three time points, including hormone levels, safety end points, mood, sexual function, quality of life, and cognitive function were determined using a mixed model. We examined graphs of a representative variable (BDI) without regard to treatment group to determine the best transformation to normality, independence from baseline, and homoscedasticity. We considered the following transformations: untransformed, square root, and log (y+1). Because the log (y+1) transformation was superior, we then used this transformation on all positive variables. Variables involving T or Z scores were left untransformed. Then the change from baseline was analyzed using a random intercepts model, with a fixed treatment effect and a random intercept with baseline value as a single covariate. This analysis averages the difference between the on-study value and the baseline and uses this as a measure of response to therapy. Side effect frequencies were compared using 
2.
Statistical significance was defined as a two-tailed P < 0.05. Baseline clinical characteristics are mean ± SD. All other results are reported as mean ± SEM.
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Results |
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Clinical characteristics of the study subjects are shown in Table 1
, including the etiology of pituitary dysfunction. Table 1 also compares baseline clinical characteristics in those patients randomized to testosterone with those randomized to placebo patches. There were no significant differences between the two groups in the parameters tested. Fifty-nine percent of participants were depressed at baseline, as measured by the BDI. Forty-six percent had total Derogatis T scores more than 2 SD and 68% more than 1 SD below the normal mean.
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.) One participant did not receive placebo as assigned because it was learned after randomization that she was no longer eligible for study participation due to recent discontinuation of GH replacement therapy (Fig. 1.) One participant in the placebo group was excluded from analysis when it was learned that she had not met inclusion criteria (data were obtained that demonstrated primary, not secondary, adrenal insufficiency); she had discontinued study participation after the 1-month visit because of an unrelated illness (Fig. 1.)
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Mean free testosterone was below normal for women of reproductive age (Esoterix Endocrinology), with undetectable levels in 28 of 51 women (55%) at baseline, and increased into the normal range during testosterone administration (Fig. 2). Nine of 24 (37.8%) of subjects randomized to receive 300 µg of testosterone were dose reduced to 150 µg testosterone daily because of free testosterone levels above the upper limit of normal for women of reproductive age. Estradiol, IGF-I, and SHBG did not change with testosterone administration vs. placebo.
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Bone density increased significantly at the hip and radius [P = 0.023 and P = 0.007, respectively, by ANCOVA). The mean percent changes at the hip in the testosterone and placebo groups were 0.9 ± 0.5 and –1.2 ± 0.6%, respectively, and at the radius 0.8 ± 0.2 and –0.5 ± 0.4%, respectively (Fig. 3). There was no significant change in PA spine bone density in patients receiving testosterone vs. placebo (Fig. 3). There was a trend toward an association between percent increase bone mineral density (BMD) and both percent increase fat-free mass (R = 0.37, P = 0.073) and percent increase thigh muscle area (R = 0.35, P = 0.091) at the hip but not at the spine or radius.
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Fat-free mass, as measured by DXA, increased significantly in patients receiving testosterone vs. placebo (P = 0.040 by ANCOVA), with a mean increase of 3.4 ± 0.9 and 0.6 ± 0.9% in the testosterone and placebo groups, respectively (Fig. 4). Cross-sectional CT of the thigh demonstrated a significant increase in muscle area, compared with placebo (P = 0.038 by ANCOVA), with a mean increase in the testosterone group of 6.6 ± 1.4%, compared with 1.5 ± 1.3% in the placebo group (Fig. 4). There was no change in fat mass, as measured by DXA [1.4 ± 3.4% (placebo) vs. 4.8 ± 2.2% (testosterone), P = 0.83]. Total, intraabdominal and sc fat cross-sectional area, as measured by CT, did not change significantly with testosterone compared with placebo, nor did body weight.
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Mood, as measured by BDI, improved in study subjects receiving testosterone, compared with those receiving placebo (P = 0.029) (Fig. 5). Sexual function improved in subjects receiving testosterone, compared with those receiving placebo (P = 0.044) (Fig. 6). The following subscales also improved in patients receiving testosterone, compared with placebo: arousal (P = 0.047) and behavior/experience (P = 0.025). There was no change in the following subscales: orgasm, cognition/fantasy, or drive/relationship (Fig. 6).
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Side effects
Side effects in the testosterone and placebo groups are compared in Table 3. One third of patients receiving testosterone reported increased acne, compared with only one participant (4%) who received placebo (P = 0.004). There were no other differences in side effects between the groups. Sixty-five percent of subjects (33 of 51) experienced mild local irritation at patch sites, and three of these subjects (6% of the total number) dropped out of the study because of severe patch reactions (Table 3); patch reactions were distributed equally between the testosterone and placebo groups. All rashes were local. Reasons for discontinuation of nine additional patients are delineated in Table 3.
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There was a trend toward a decrease in mean ALT in women receiving testosterone (P = 0.083), compared with placebo.
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Discussion |
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To our knowledge, there are two previously published randomized, controlled trials investigating the effects of testosterone on bone density in women. Both demonstrated improvements in bone density in women receiving testosterone. They differ from the current study in that both investigated postmenopausal women, an older and less severely androgen-deficient population, and they both used modes of testosterone delivery that resulted in transient supraphysiologic free testosterone levels. Davis et al. (25) randomized 30 postmenopausal women to testosterone plus estradiol implants vs. estradiol alone in a single-blind study and reported an increase in hip and spine bone density at 24 months in women receiving the testosterone, compared with those receiving estradiol alone. Miller et al. (26) demonstrated increases in hip, but not spine, bone density in postmenopausal women receiving sublingual testosterone in addition to micronized hormone replacement therapy (HRT), compared with micronized HRT alone. In the current study, we demonstrate increases in hip bone density in young women with severe androgen deficiency with testosterone replacement to physiologic levels for healthy women of reproductive age.
There are also few published studies investigating the effects of other androgens on bone density in women. Two double-blind, controlled studies of the effects of methyltestosterone, a synthetic oral compound active at androgen receptors, plus conjugated equine estrogen (CEE), compared with CEE alone in women with bilateral oophorectomy, yielded conflicting results. Barrett-Connor et al. (27) demonstrated increases in bone density in women with bilateral oophorectomy receiving methyltestosterone at the higher of the two doses used. However, Watts et al. (28) failed to detect a significant increase in bone density in the group that received this same higher dose of methyltestosterone. Methyltestosterone is not converted to testosterone but binds to androgen receptors (29) and may increase bioavailable testosterone by suppressing SHBG levels (30). Because the compound is not endogenously produced, it cannot be readily assessed whether such therapy approximates normal physiology, nor can the results be compared directly with those of our study.
In the current study, hip bone density increased with 1 yr of physiologic testosterone replacement, compared with placebo, as did radial bone density, whereas spine bone density did not. These findings suggest that testosterone replacement, at the low doses that are appropriately physiologic for women, may be more effective in increasing cortical than trabecular bone density. This is consistent with our previously reported strong cross-sectional correlations of androgen levels with hip, but not spine, bone density in women with hypopituitarism (31). This is also consistent with the results of the study by Miller et al. (26) that showed an increase in hip, but not spine, bone density in postmenopausal women randomized to sublingual estradiol with or without progesterone plus micronized testosterone, compared with micronized HRT alone. Additional studies are necessary to investigate this hypothesis further.
We demonstrate increased fat-free mass with physiologic testosterone replacement in women with severe androgen deficiency due to hypopituitarism. Although testosterone replacement at male replacement doses, i.e. much higher than used in the current study of women, has been shown to increase lean body mass in men with hypogonadism (1, 3), there are few studies investigating these end points in women. In a previous report from our group, body composition did not change in women with AIDS wasting treated with the same testosterone preparation as in our current report (32). Likewise, Davis et al. (33) were not able to demonstrate changes in body composition in postmenopausal women receiving testosterone plus estradiol implants, compared with estradiol alone, although they did report increases in fat-free mass, as measured by DXA, within the testosterone group when compared with baseline. Moreover, there are scant published data regarding the effects of administration of other compounds with androgenic action on body composition in women. Methyltestosterone administration has been investigated in postmenopausal women by Dobs et al. (34) in a randomized, placebo-controlled study that demonstrated an increase in fat-free mass, a decrease in percent body fat, and an increase in lower body strength in women receiving methyltestosterone plus CEE vs. CEE alone. In another study, the addition of nandrolone decanoate, an anabolic steroid with weak androgenic activity, to caloric restriction resulted in an increase in lean body mass and decrease in total body fat, compared with diet alone (35). Although these two synthetic compounds have androgenic activity, they are not equivalent to testosterone replacement. Nevertheless, their effects on body composition are consistent with our results.
Our study was not powered or designed to determine whether the combination of testosterone and GH replacement might have an additive or synergistic effect on BMD or muscle. Patients receiving GH were accepted for participation only if they had been receiving stable GH replacement for at least 2 yr. The effect of combination therapy is an important area of investigation for future trials.
This is the first study to demonstrate improvements in mood and sexual function in women with severe androgen deficiency due to hypopituitarism, which is consistent with effects of testosterone in other female populations. Shifren et al. (5) demonstrated improved libido, sexual function, mood and quality of life in women with androgen deficiency due to bilateral oophorectomy. Only the group that received the higher dose of testosterone, 300 µg daily, experienced improvement, compared with placebo, and subjects with supraphysiologic testosterone levels were not dose reduced. This resulted in a mean free testosterone level for the group near the upper limit of normal, raising the question of whether strict physiologic dosing would be efficacious in women (5). Three subsequent recent randomized, placebo-controlled reports (6, 7, 8) confirmed those of Shifren et al. (5) with respect to the effectiveness of testosterone, 300 µg daily by patch, to improve sexual function and libido in women with bilateral oophorectomy. Other, less profoundly hypoandrogenic populations have also been demonstrated to experience improvements in libido and/or sexual function with testosterone administration, including postmenopausal women (25) and premenopausal women with decreased libido (36). In the latter study, Goldstat et al. (36) also reported improvements in mood and quality of life with testosterone therapy. Lobo et al. (30) showed improved sexual function with methyltestosterone plus oral esterified estrogens, compared with esterified estrogens alone in postmenopausal women with hypoactive sexual desire.
Other studies have investigated the effects of DHEA in women with androgen deficiency due to adrenal insufficiency (37, 38, 39, 40, 41, 42) or hypopituitarism (43, 44). Of note, DHEA, a compound classified by the U.S. Food and Drug Administration as a food supplement, is converted endogenously to testosterone, estradiol, and other hormones (45). Arlt et al. (37) studied women with adrenal insufficiency, primary or secondary, and demonstrated an improvement in libido, sexual function, and mood in subjects receiving DHEA, 50 mg daily, compared with placebo. Subsequent studies (38, 39, 40, 41, 42, 43, 44) showed less dramatic results. Some, but not all, of these studies used lower doses or combined men and women in their data analysis, which may explain some of the variance with the results of Arlt et al.. Trials comparing DHEA and testosterone directly will be required to determine whether one is more effective than the other.
Testosterone was well tolerated in this study, with a significant increase in acne, but not hirsutism or alopecia, in the group of women receiving testosterone, compared with placebo. A small increase in mean total cholesterol was detected, but only two subjects in the testosterone group increased from normal to slightly elevated, compared with one subject in the placebo group. There were no changes in HDL, which has been shown to decrease with oral preparations of androgens and preandrogens (37, 46), and no increase in LDL or triglycerides to explain an increase in total cholesterol. The particular preparation used in this study caused local irritation in many subjects, severe enough in some women (6% of the total) to prompt discontinuation from the study. Most of the rashes were mild, all were local, and the majority of subjects who experienced them chose to remain in the study. The irritation was not likely caused by the testosterone itself because it was experienced by similar numbers of women in both groups.
Our data demonstrate that physiologic testosterone replacement increased hip and radial bone density, fat-free mass, and thigh muscle area and improved mood, sexual function, and some aspects of quality of life in women with severe androgen deficiency due to hypopituitarism in response to physiologic testosterone replacement. In addition, testosterone at physiologic replacement levels was well tolerated with few side effects. Further studies will be needed to determine long-term efficacy and safety of such a replacement strategy.
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Acknowledgments |
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Footnotes |
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K.K.M. and A.K. have both received consulting fees from Procter & Gamble Pharmaceuticals. B.M.K.B., C.B., J.G.L., J.J., D.S., J.C.S., B.S., and J.L. have nothing to disclose.
First Published Online February 14, 2006
Abbreviations: ALT, Alanine aminotransferase; ANCOVA, analysis of covariance; BDI, Beck Depression Inventory; BMD, bone mineral density; CEE, conjugated equine estrogen; CT, computed tomography; CV, coefficient of variation; DHEA, dehydroepiandrosterone; DXA, dual x-ray absorptiometry; HDL, high-density lipoprotein; HRT, hormone replacement therapy; LDL, low-density lipoprotein; NHP, Nottingham Health Profile; PA, posteroanterior; PGWB, Psychologic General Well-Being; WASI, Wechsler Abbreviated Scale of Intelligence.
Received November 30, 2005.
Accepted February 6, 2006.
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References |
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-methyltestosterone in vitro to human sex hormone binding globulin and rat ventral prostate androgen receptors. Ther Drug Monit 17:377–380[Medline]This article has been cited by other articles:
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  J. A. Schlechte Update in Endocrinology Ann Intern Med, October 16, 2007; 147(8): 563 - 572. [Full Text] [PDF]
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 K. K. Miller, B. M. K. Biller, A. Schaub, K. Pulaski-Liebert, G. Bradwin, N. Rifai, and A. Klibanski Effects of Testosterone Therapy on Cardiovascular Risk Markers in Androgen-Deficient Women with Hypopituitarism J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2474 - 2479. [Abstract] [Full Text] [PDF]
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K. K. Miller, E. A. Lawson, V. Mathur, T. L. Wexler, E. Meenaghan, M. Misra, D. B. Herzog, and A. Klibanski Androgens in Women with Anorexia Nervosa and Normal-Weight Women with Hypothalamic Amenorrhea J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1334 - 1339. [Abstract] [Full Text] [PDF]
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W. Rosner, R. J. Auchus, R. Azziz, P. M. Sluss, and H. Raff Utility, Limitations, and Pitfalls in Measuring Testosterone: An Endocrine Society Position Statement J. Clin. Endocrinol. Metab., February 1, 2007; 92(2): 405 - 413. [Abstract] [Full Text] [PDF]
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M. E. Wierman, R. Basson, S. R. Davis, S. Khosla, K. K. Miller, W. Rosner, and N. Santoro Androgen Therapy in Women: An Endocrine Society Clinical Practice Guideline J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 3697 - 3710. [Abstract] [Full Text] [PDF]
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) or placebo (
). Horizontal dotted lines delineate the normal range for women of reproductive age.
