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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1181
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 3 1428-1433
Copyright © 2005 by The Endocrine Society

Testosterone Administration in Women with Anorexia Nervosa

K. K. Miller, K. A. Grieco and A. Klibanski

Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Karen K. Miller, M.D., Neuroendocrine Unit, BUL 457B, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: kkmiller{at}partners.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Anorexia nervosa (AN) is complicated by severe bone loss, cognitive function deficits, and a high prevalence of major depression. We hypothesized that bone formation would increase and depressive symptoms and spatial cognition would improve with short-term physiological testosterone administration. We randomized 33 women with AN and relative testosterone deficiency to transdermal testosterone (Intrinsa, Procter and Gamble Pharmaceuticals, Cincinnati, OH), 150 µg, 300 µg, or placebo, for 3 wk. At baseline, free testosterone correlated with L4 bone density (r = 0.51, P < 0.001), body mass index (r = 0.39, P = 0.02), depressive symptoms (r = –0.44, P = 0.02), and spatial cognition (r = 0.45, P = 0.04). C-terminal propeptide of type 1 collagen levels were higher during testosterone administration than placebo (P = 0.03). The change in propeptide of type 1 collagen correlated with change in free testosterone over 3 wk (r = 0.50, P = 0.02). Osteocalcin and bone-specific alkaline phosphatase did not change. Depressed patients receiving testosterone improved from severely depressed to moderately depressed; the placebo group was unchanged (P = 0.02). Spatial cognition improved in the testosterone group, compared with placebo (P = 0.0015). Therefore, short-term low-dose testosterone may improve depressive symptoms and spatial cognition in women with AN. Low-dose testosterone may also prevent decreased bone formation in AN, but because testosterone did not affect all markers of bone formation studied, further data are needed.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ANOREXIA NERVOSA (AN), with a prevalence of 0.5–1% among college-age women (1, 2, 3, 4), is a psychiatric disorder complicated by severe bone loss (5, 6, 7); cognitive impairment (8, 9, 10); and a high prevalence of mood and anxiety disorders (11, 12, 13), including major depressive disorder (14, 15). Osteopenia is present in 92% and osteoporosis in 38% of young women with AN (5). There are no effective, available therapies for this severe bone loss, which is characterized by both decreased bone formation and increased resorption (16, 17). AN is also complicated by both a high prevalence of comorbid psychiatric disorders, including major depression (14, 15), and anxiety and obsessive compulsive disorders (18), and by deficits in cognitive function (8, 9, 10). Major depressive disorder is the most commonly diagnosed comorbid psychiatric disorder in women with AN (13), with a lifetime prevalence as high as 68% (11, 14). In addition, a majority of women with AN display subtle cognitive deficits, including impaired spatial skills (8, 9), despite above average intelligence, compared with healthy controls (19). There are few data regarding hormonal deficiencies that might contribute to comorbid major depression and cognitive dysfunction in AN and therefore might form the basis for development of new therapies.

Testosterone administration results in marked increases in bone density in hypogonadal men (20), and studies suggest that low-dose androgen therapy may increase bone formation (21) and bone density (22, 23) in postmenopausal women. Likewise, recent studies demonstrated that testosterone administration may improve depression in depressed eugonadal men (24). Testosterone administration has also been demonstrated to improve spatial skills in healthy women in two small studies (25, 26). We hypothesized that short-term (3-wk) low-dose testosterone replacement would increase bone formation, improve depression, and improve spatial ability in women with AN and relative androgen deficiency.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Thirty-eight women with AN, aged 18–50 yr, were enrolled in the study, which after five dropouts resulted in 33 evaluable subjects. All subjects fulfilled all Diagnostic and Statistical Manual of Mental Disorders IV criteria for AN, including percent ideal body weight less than 85% at the time of screening for study eligibility, amenorrhea for at least 3 months, and all psychiatric manifestations of the disease (27) when screened for the study. To participate in the study, a serum free testosterone level less than the median of the reference range for premenopausal women was required at the time of screening. None of the subjects had received oral contraceptives, progesterone derivatives, glucocorticoids, anabolic agents, or any medications known to affect bone metabolism within the 3 months before study enrollment. None of the subjects had had a fracture within 1 yr of study participation. 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 collaborating physicians and advertisements in community newspapers. At screening visit, a complete medical history and physical examination were performed. Serum was drawn for total and free testosterone levels. Nutritional evaluation including weight in a gown, height, and frame size were measured and percent ideal body weight (IBW) (28) and body mass index (BMI) were calculated by research dietitians for all study participants. Each eligible subject returned for a baseline visit during which blood was drawn for determination of markers of bone metabolism and hormones, and a repeat nutritional evaluation was performed. The Beck Depression Inventory (BDI) was administered to all subjects (29) at the baseline visit. Antidepressant use was recorded for each patient and categorized as current use or nonuse. Visuospatial ability was assessed by the Vandenberg and Kuse adaptation of Shepard and Metzler’s three-dimensional mental rotations test (MRT) (30). The 20-item test consists of a target drawing and four test drawings, with subjects asked to indicate which two of the four test drawings depicted the target drawing in rotated positions. The test was scored by adding one point if the subject identified both correct answers (31). Quality of life was assessed by administering the Psychological General Well-Being Index (32). Body hair was evaluated using the Lorenzo scale (33).

A pregnancy test was performed before randomization to transdermal testosterone (Intrinsa, Procter & Gamble Pharmaceuticals, Cincinnati, OH) 150 µg, 300 µg, or placebo. Randomization was blinded to investigators and subjects. Each patient returned for study visits at 10 d and 3 wk after the baseline. All testing performed at baseline was repeated at 10 d and 3 wk, except for measurement of spatial cognition, which was performed at baseline and again at 3 wk.

Laboratory methods

Total testosterone was measured by column chromatography (Esoterix Endocrinology, Calabassas Hills, CA). The sensitivity of this assay is 0.1 nmol/liter with an intraassay coefficient of variation (CV) of less than 8.1%. Free testosterone concentration was determined as the product of percent free testosterone, measured by equilibrium dialysis (Esoterix Endocrinology), and the 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%. Estradiol was determined using a RIA kit [Diagnostic Systems Laboratories (DSL), Webster, TX], with a sensitivity of 0.008 nmol/liter and an intraassay CV of 6.5–8.9%. Dehydroepiandrosterone sulfate was measured by a RIA kit (DSL), with a sensitivity of 68 nmol/liter and percent intraassay CV of 1.8–5.2%. IGF-I was measured using a RIA kit (Nichols Institute Diagnostics, San Clemente, CA), with an intraassay CV of 2.4–3.0% and a sensitivity of 1.8 nmol/liter. SHBG was measured by immunoradiometric assay (Esoterix Endocrinology) with an intraassay CV of 2.42–3.91%. C-terminal propeptide of type 1 collagen (PICP) was determined by an ELISA procedure (Metra Biosystems, Inc., Mountain View, CA) with a sensitivity of 2.4 µg/liter and an intraassay CV of 5.5–6.8%. Osteocalcin was determined by using two monoclonal antibodies reactive with osteocalcin (CIS Bio International, Gif-sur-Yvette, France) with an intraassay CV of 3.8–3.9% and interassay CV of 8–16%. Serum N-telopeptide was determined by a competitive-inhibition ELISA (Ostex International, Inc., Seattle, WA) with a sensitivity of 5.0 nM bone collagen equivalent and an intraassay CV of 10–23%.

Statistical analysis

JMP Statistical Discoveries (version IV, SAS Institute Inc., Cary, NC) was used for statistical analysis. 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 assess statistical significance. A two-way repeated-measures ANOVA was employed to assess mean serum hormone concentrations, serum bone markers, and mood at baseline, 10 d, and 3 wk. When responses to the 150 and 300 µg doses were analyzed separately, no statistically significant effect or dose response could be detected. Therefore, data from the 150 and 300 µg testosterone groups were pooled for the purposes of analysis of treatment effects. Percent change in markers of bone metabolism were compared using an analysis of covariance, controlling for age of subject. Analysis of the Vandenberg and Kuse MRT used analysis of covariance to adjust for the following factors that could potentially influence cognitive performance: age, years of education, percent IBW, and duration of AN. Variables lacking normal distribution underwent natural logarithmic transformation before analysis. A Beck score of more than 10 was selected based on the data of Beck et al. (34) to separate those patients with mild to severe depression from those with no or minimal depression (Beck score ≤ 10). Statistical significance was defined as a two-tailed P ≤ 0.05. Data are reported as mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline clinical characteristics

There was no difference observed at baseline between patients who received placebo and those who received testosterone in age, weight, BMI, percent IBW, duration of amenorrhea, free or total testosterone, markers of bone metabolism, bone density, severity of depression, or spatial cognition (Table 1Go). Fifty-four percent of subjects with AN were depressed, as assessed by the BDI. Free testosterone at baseline correlated with L4 bone mineral density (r = 0.51, P < 0.001), BMI (r = 0.39, P = 0.04), BDI (r = –0.44, P = 0.02), Psychological General Well-Being Index (r = 0.41, P = 0.04), and MRT (r = 0.45, P = 0.02) (Fig. 1Go).


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  		TABLE 1. Clinical characteristics of study subjects at baseline: testosterone vs. placebo

 


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  		FIG. 1. BMI (A), L4 bone mineral density by quantitative computed tomography (B), BDI (C) and MRT (D) results correlated with serum free testosterone at baseline in women with AN.

 
Treatment responses

Serum hormone levels. Serum total and free testosterone levels increased significantly in patients receiving testosterone (Table 2Go and Fig. 2Go). Approximately 50% of subjects randomized to receive 150 µg and 67% of subjects administered 300 µg experienced an increase in free testosterone at 3 wk to levels that exceeded the upper limit of the normal premenopausal range. In contrast, estradiol, SHBG, dehydroepiandrosterone sulfate, and IGF-I (Table 2Go) did not change with testosterone administration vs. placebo. For subjects randomized to receive testosterone, lower-weight patients had less of an increase in serum free testosterone than higher-weight subjects. Change in free testosterone correlated significantly with baseline percent IBW (r = 0.39, P = 0.03). Weight did not change over 3 wk in any group.


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  		TABLE 2. Hormone data: pretreatment vs. posttreatment with testosterone or placebo

 


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  		FIG. 2. Serum free testosterone (picomoles per liter) at baseline and 3 wk after administration of placebo patches and 150 µg testosterone and 300 µg testosterone patches. Dotted lines delineate the normal range for women of reproductive age.

 
Markers of bone metabolism

PICP levels were higher during testosterone administration than with placebo (P = 0.03) (Fig. 3Go). Change in PICP correlated with change in free testosterone over 3 wk (r = 0.50, P = 0.02). Serum osteocalcin, bone-specific alkaline phosphatase, and serum N-telopeptide levels did not change significantly over the 3 wk in the group receiving testosterone, compared with placebo.



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  		FIG. 3. A, PICP levels were higher during testosterone administration (black line) than with placebo (gray line) (*, P = 0.03). B, Change in PICP correlated with change in serum free testosterone (r = 0.50, P = 0.02).

 
Mood, spatial cognition, and well-being

Mood, as measured by BDI, improved in depressed patients receiving testosterone, compared with those receiving placebo (P = 0.02) (Fig. 4Go), such that the mean BDI score at baseline improved from the severely depressed range (20.4 ± 2.1) into the moderately depressed range (15.1 ± 2.6) after 3 wk of testosterone administration. There was no change in BDI in the placebo group over the 3-wk study (baseline: 19.8 ± 3.8; 3 wk: 19.3 ± 5.2). There was no difference in the percent of patients receiving testosterone vs. placebo who were taking antidepressants at baseline. In addition, subjects did not report any change in antidepressant usage or dosage during the 3 wk of the study. In a forward stepwise regression analysis, with change in BDI as the dependent variable and randomization group, change in weight, change in IGF-I levels, and antidepressant use as the independent variables, randomization to testosterone or placebo (P = 0.03) was the only significant predictor of change in BDI. After 3 wk of testosterone administration, testosterone-treated subjects performed significantly better on the MRT, compared with those on placebo (P = 0.0015) (Fig. 5Go). There was no improvement in well-being as measured by the Psychological General Well-Being Index at 10 d or 3 wk in patients receiving testosterone, compared with placebo.



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  		FIG. 4. Severity of depressive symptoms, as measured by the BDI, improved in depressed patients with AN who received testosterone (black line), compared with placebo (gray line) (*, P = 0.02).

 


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  		FIG. 5. Change in spatial cognition, as measured by the Vanderberg and Kuse MRT, improved in patients with AN who received testosterone (black line), compared with placebo (gray line) (*, P = 0.0015).

 
Side effects

The patches were generally well tolerated. Three subjects randomized to testosterone and one subject in the placebo group developed mild skin irritation at the patch site, but this did not prompt discontinuation from the study in any subject. No significant changes in hirsutism scores were observed during the 3-wk study. One subject randomized to receive testosterone, with a history of affective disorder, reported increased depression and anxiety at the 10-d visit and improvement in these symptoms with benzodiazepine administration. One subject in the placebo group was treated by her primary care physician for increased fatigue and vertigo. Five subjects were either discontinued or withdrew from the study, including one subject who became pregnant and another subject with multiple fractures after an automobile accident. Two subjects (one on placebo and one on testosterone) were discontinued from the study by the investigator due to life-threatening weight loss. One placebo subject withdrew from the study due to nausea. An additional subject in the testosterone group reported nausea but did not drop out of the study. There were no significant changes in lipids or lipoprotein levels, including high-density lipoprotein (HDL), or serum transaminases in subjects receiving testosterone.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
AN is complicated by severe bone loss, for which there are no effective, available therapies. AN-associated bone loss is characterized by decreased bone formation in addition to the increased resorption observed in menopause (16, 17). For this reason, anabolic therapies directed at decreased formation may be particularly important for this population. Bone formation has been shown to increase in postmenopausal women receiving testosterone plus estrogen, compared with women receiving estrogen alone (21). However, to our knowledge, this is the first study to examine markers of bone metabolism in women receiving testosterone alone, without concurrent estrogen administration. Our data suggest that low-dose testosterone administration may increase bone formation in this undernourished population. However, because only one of three formation markers studied responded, further data are needed to determine whether testosterone increases bone formation and bone density in this population.

Testosterone administration also resulted in an improvement in mood in depressed patients with AN. Depression is a common complication of AN, with 54% of patients in this study scoring in the depressed range on the BDI. Depression has been shown to improve in men after higher dose testosterone administration (35) than those given in this study. Studies in women are few, but androgens and preandrogens have been demonstrated to improve mood in a few small studies (36, 37, 38). These include a randomized, placebo-controlled study by Shifren et al. (38) in which testosterone administration, using the same transdermal preparation used in this study, resulted in an improvement in mood and general well-being in oophorectomized women given 300, but not 150, µg/d. In another randomized, placebo-controlled study, Arlt et al. (37) demonstrated that dehydroepiandrosterone replacement improves mood in patients with adrenal insufficiency. Androgen receptors have been located in the brain, as have aromatases, estradiol receptors, and 5{alpha}-reductases. Therefore, in addition to direct effects of testosterone on the brain, testosterone-related brain function effects may be mediated by conversion to estrogens and/or dihydrotestosterone. Further study is needed to confirm these findings. However, if confirmed, low-dose testosterone replacement therapy might have a role in the treatment of mood disorders in women with anorexia nervosa.

Testosterone administration also resulted in an improvement in spatial cognition in subjects with AN. Studies have demonstrated impaired cognitive function in women with AN, including spatial abilities (8, 9). In studies of cognitive function in healthy volunteers, mental rotation spatial testing demonstrates the largest gender differences (31, 39). A more direct association of spatial abilities with testosterone levels has been reported in correlational cross-sectional human and rodent studies (40, 41, 42). For example, Silverman et al. (43) demonstrated a positive association between MRT results and serum testosterone levels in men. In addition, castration impairs maze performance in male rodents (44), suggesting that reductions in testosterone may impair spatial abilities. Few studies have investigated the causal effects of testosterone administration on spatial abilities, particularly in women. However, in two small studies investigating the effects of a single dose of 0.5 mg of sublingual testosterone on spatial cognition in women, spatial abilities improved significantly after testosterone administration, compared with placebo (25, 26). Therefore, our finding of improved spatial cognition in AN after administration of testosterone, compared with placebo, is consistent with previously published data regarding the effects of testosterone administration on cognitive function and has particular relevance to the AN population, which has been demonstrated to have impaired spatial cognition.

Low-dose testosterone replacement therapy was well tolerated in this population. We did not detect development of hirsutism, acne, decreases in HDL, or increases in transaminases. The most prevalent side effect was local irritation at patch sites. Our side effect and safety data are consistent with previous reports from our group and others (38, 45), in which no adverse effects on lipids, lipoproteins, or transaminases have been detected when testosterone is administered transdermally, therefore avoiding first-pass liver metabolism. In contrast, oral androgens and preandrogens have consistently been demonstrated to decrease serum HDL (21, 46). In addition, longer-term studies have reported low rates of development of signs of hyperandrogenemia when low replacement doses of androgens have been administered to women (47), but studies lasting longer than 24 months have not been reported. Likewise, our study was very short, and longer studies are needed to evaluate tolerability with chronic use. Of importance, in our study, serum free testosterone levels were supraphysiological in about 50% of subjects randomized to receive 150 µg and 67% of subjects administered 300 µg. Whether doses that are not strictly physiological will result in hyperandrogenism, particularly over the long term, is not known and is an important area for future investigation.

We could not detect effects of testosterone when we did not pool data from women receiving both doses (150 and 300 µg daily). This can likely be explained by the low number of patients studied, the short duration of the study (3 wk), and the low dose of testosterone administered. Although our results are not definitive, they do provide a basis for further study, which will be important, because there is little known about the mechanisms underlying bone loss or mood disorders in women with AN as well as few effective therapies.

In conclusion, low-dose testosterone replacement therapy may stimulate bone formation and improve depression and spatial cognition in women with AN. Given the severe bone loss (5) and frequent psychiatric comorbidity (11, 12, 13), these findings could be the basis for development of new therapies for women with AN. However, it should be noted that this study was carried out in a relatively small number of patients and for only 3 wk. Therefore, these findings need to be confirmed in larger, longer, randomized, placebo-controlled studies, and testosterone therapy is not recommended for women with AN at this time.


   Acknowledgments
 
We thank the nurses and bionutritionists at Massachusetts General Hospital and the patients for participation in the study.


   Footnotes
 
This work was supported in part by National Institutes of Health Grants RO1-DK52625, MO1-RR01066-27, MO1-RR01066-27S1, and RO3-DK59297.

First Published Online December 21, 2004

Abbreviations: AN, Anorexia nervosa; BDI, Beck Depression Inventory; BMI, body mass index; CV, coefficient of variation; HDL, high-density lipoprotein; IBW, ideal body weight; MRT, mental rotations test; PICP, C-terminal propeptide of type 1 collagen.

Received June 21, 2004.

Accepted December 12, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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