Testosterone Therapy Disappoints for Anorexia

Batya Swift Yasgur, MA, LSW

June 28, 2019

Low-dose testosterone does not lead to sustained improvements in depression, anxiety, or disordered eating in women with anorexia nervosa (AN), new research shows.

Investigators compared a transdermal testosterone patch with a placebo patch in 90 adult women with AN who had free testosterone levels below the median.

At the end of 24 weeks, they found that mean depression and anxiety scores decreased similarly in both groups, and that there were no significant differences in eating disorder scores between the groups.

Moreover, although testosterone was safe and well tolerated, it was associated with less weight gain than placebo.

"Despite prior research showing positive mood effects of testosterone administration in some groups of men and women with testosterone deficiency — including a 3-week study of our group in women with anorexia nervosa — we showed in this 6-month study that testosterone treatment in women with anorexia nervosa resulted in less weight gain and did not lead to sustained improvements in depression, anxiety, or disordered eating symptoms," lead author Allison Kimball, MD, a fellow in the Neuroendocrine Unit at Massachusetts General Hospital in Boston, told Medscape Medical News.

"Testosterone therapy [therefore] cannot be recommended to treat eating disorder, depressive, or anxiety symptoms in women with anorexia nervosa," she added.

The study was published online June 20 in the Journal of Clinical Endocrinology & Metabolism.

No Approved Medications

Depression and anxiety symptoms are associated with worse outcomes in eating disorders, and antidepressants have not proven effective in alleviating these symptoms in patients with AN, the investigators note.

Relative androgen deficiency is "common" in women with AN and results from decreased production of testosterone and testosterone precursors from the ovaries.

Prior studies have shown that levels of testosterone in women with AN are inversely associated with depression and anxiety severity, "therefore, relative androgen deficiency may be a promising treatment target in AN," the investigators write.

Several population-based studies have also suggested that testosterone administration may exert antidepressant effects, and research using animal models suggests that testosterone may modulate food intake and body weight, the authors say.

"Anorexia nervosa is a psychiatric illness with serious comorbidities, including a greater than 50% prevalence of depression, but there are no FDA-approved pharmacologic therapies," said Kimball.

"As prior studies have suggested an antidepressant effect of testosterone administration, including in women with AN over a 3-week period, we sought to determine whether low-dose testosterone therapy would be an effective treatment for women with anorexia nervosa," she said.

To investigate the question, the researchers enrolled 90 women with AN (ages 18-45 years) who had either low weight or normal weight (but achieved the psychological criteria for AN ["atypical" AN]); 88 of the women were included in the analysis.

Participants were required to have a serum free testosterone level less than the medium of reference range for premenopausal women and had to use contraception for the duration of the study.

Individuals with unstable medical or psychiatric illnesses or recent substance use disorder were excluded.

Baseline testing included medical history, physical examination, nutritional evaluation, measure of weight, and an array of blood tests (androgens, free thyroxine [T4], complete blood count (CBD), alanine aminotransferase (ALT), creatinine, lipids, and urine toxicology.

Subjects also completed the Structured Clinical Interview for DSM-IV (SCID-IV), the Hamilton Depression Rating Scale (HAM-D), the Hamilton Anxiety Rating Scale (HAM-A), the Eating Disorder Examination-Questionnaire (EDE-Q), and the Eating Disorder Inventory-2 (EDI-2).

Participants were then randomly assigned to receive either transdermal testosterone (300 mcg) or placebo, applied twice weekly for 24 weeks, returning for study visits at 4, 12, 18, 24, and 32 weeks after the baseline visit.

The primary outcome (body mass index [BMI]) and secondary outcomes (scores on the HAM-D, the HAM-A, the EDE-Q, and the EDI-2) were assessed at all visits.

Contrary to Hypothesis

Of the subjects, 42% met criteria for atypical AN (ie, BMI>18.5 kg/m2 (P = 1.00 for testosterone vs placebo), and of these, 67% had a previous history of low weight (BMI<18.5 kg/m2, P = .29 for testosterone vs placebo).

Both groups had a similar number of subjects taking combined hormonal contraceptives or progestin-only contraceptives.

There were no significant differences between the two groups in any of the pre-treatment variables, including mean HAM-D and HAM-A scores, EDE-Q global score, and EDI-2 subscales.

Both study groups started out with a mean serum free testosterone at baseline below the median for healthy women of reproductive age. However, in the testosterone group, serum free testosterone increased by 1.1 ± 0.9 ng/dL from 0 to 4 weeks and remained significantly higher than serum free testosterone in the placebo group during the 24 weeks of testosterone administration (P < .001).

By contrast, estradiol and insulin-like growth factor 1 (IGF-1) levels did not change with testosterone administration vs placebo.

Mean DHEAS level in the testosterone group and in the placebo groups decreased by 4.0 μg/dL and 18.4 μg/dL, respectively.

Over the 24-week study period, mean BMI in the testosterone and placebo groups increased by 0.0 ± 1.0 kg/m2 and 0.5 ± 1.1 kg/m2, respectively (P = .03).

Although there was a trend at 4 weeks toward a greater decrease in mean depression severity score in the testosterone vs placebo group (-1.6 ± 2.8 vs -0.7 ± 3.0, respectively, P = .09), no difference was found at 4 weeks between the groups in the mean HAM-A score (-1.8 ± 3.1 vs -1.6 ± 3.1, respectively, P = .59].

Moreover, at 24 weeks, both groups showed a similar decrease in HAM-D and HAM-A scores from baseline.

Within-group analyses found that over the 24-week study duration, BMI did not change within the testosterone group (P = .93) and actually increased within the placebo group (P = .01).

Both groups showed a decrease in depression severity score and anxiety severity score from baseline to 24 weeks (P < .001).

At 24 weeks, self-reported frequency of overexercising decreased in the testosterone vs the placebo group (3.0 ± 7.7 vs 1.2 ± 5.7 episodes respectively, P = .05).

By contrast, there was no difference in mean self-reported frequency of vomiting between the 2 groups and also no significant differences in mean change in EDE-Q global score, EDE-Q subscales, or EDI-2 scores over 24 weeks.

Testosterone was "generally well-tolerated," with no differences between groups in the frequency of self-reported androgenic side effects (eg, patch site irritation, oily skin, increased acne, or increased facial hair).

"Contrary to our hypothesis, we found that testosterone administration resulted in less weight gain, only modest and non-sustained improvements in depression, and no improvements in anxiety or disordered eating symptoms, compared with placebo," the researchers write.

Complex Disorder

Commenting on the study for Medscape Medical News, Anthony P. Winston, medical lead for eating disorders, Coventry and Warwickshire Partnership Trust, Warwick, United Kingdom, noted that it "was carried out by a group which has already done a substantial amount of research into endocrine changes."

Previous studies suggested that increasing testosterone had a positive effect on depression and anxiety in other patient groups and "the researchers hypothesized that it would have the same effect in anorexia nervosa [and] also hoped that it would be beneficial in terms of weight gain and the psychological symptoms of anorexia nervosa," said Winston, who was not involved with the current study.

"Unfortunately," he added, the study results do not support these hypotheses.  

"Anorexia nervosa is a complex disorder with multiple endocrine effects and more research is needed to establish whether hormonal intervention has a role to play in its treatment," he said.

Lead study author Kimball called their findings "important" because they "ensure that an ineffective treatment will not be recommended for women with anorexia nervosa."

The study was supported by grants from the National Institutes of Health (NIH), the Harvard Catalyst/The Harvard Clinical and Translational Science Center, the National Center for Advancing Translational Science, and the National Center for Research Resources. Kimball declares no conflicting interests. The other authors' disclosures are listed on the original article. Winston has disclosed no relevant financial relationships.

J Clin Endocrinol Metab. Published online June 20, 2019. Abstract

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