Trial & Error: When Study Results Disappoint

Researchers studied female anorexia nervosa patients to see whether testosterone could be a potential treatment. Despite promising results in previous trials, the current study’s outcomes were not as hoped.

Anorexia nervosa (AN), a serious and potentially fatal eating disorder, affects up to 2% of women and carries with it a number of dangerous comorbidities, including a prevalence of up to 75% of major depressive disorder and anxiety, equally serious and potentially fatal psychiatric illnesses. Treatment for AN involves psychotherapeutic approaches, and severe cases require hospitalization in order to attempt to restore the patient to a healthy weight. However, there are currently no FDA-approved pharmaceutical treatments for AN.

Testosterone therapy has been shown to improve depressive symptoms in men suffering from hypogonadism, and male rats treated with testosterone after orchiectomy increased their food intake and gained weight. Researchers in Boston hypothesized that women with AN may benefit from testosterone therapy as well, since previous studies of women with severe androgen deficiency secondary to hypopituitarism and bilateral oophorectomy demonstrated antidepressant effects of low-dose testosterone therapy. The group, led by Karen K. Miller, MD, and Anne Klibanski, MD, both of Harvard Medical School and the Neuroendocrine Unit at Massachusetts General Hospital, designed a three-week, randomized, placebo-controlled pilot study in which they saw that testosterone therapy improved depression severity in women, compared to placebo.

So the team continued the work with a follow-up study, now testing the effects of low-dose testosterone in therapy in women with AN over 24 weeks. “Given the results of our three-week pilot study, we were hopeful that low-dose testosterone therapy to correct a relative testosterone deficiency in women with anorexia nervosa would be an effective endocrine-targeted treatment,” says the study’s first author, Allison Kimball, MD, also of Harvard Medical School and Massachusetts General Hospital’s Neuroendocrine Unit.

Treating AN can be challenging, and while this disorder might not always be in an endocrinologist’s wheelhouse, it’s still worth looking at whether an endocrinological solution to caring for patients with AN and its comorbidities is indicated.

Impact of Psychiatric Meds

For this current study, Kimball, Miller, and their team recruited 90 women with AN, aged 18 to 45 years old, through collaborating clinicians and through advertisements, and the researchers treated the participants with either a transdermal testosterone patch at 300 micrograms daily for 24 weeks or a transdermal placebo patch for 24 weeks. They published their results recently in The Journal of Clinical Endocrinology & Metabolism.

“Many factors may have contributed to the lack of sustained antidepressant effect of testosterone, including the high number of psychiatric medication changes or inefficacy of low-dose testosterone treatment in this population. Additionally, testosterone therapy was associated with less weight gain and did not lead to improvements in disordered eating symptoms compared to placebo.” – Allison Kimball, MD, Harvard Medical School; Neuroendocrine Unit, Massachusetts General Hospital, Boston

The researchers saw a trend toward greater improvement in depression symptom severity in the testosterone group compared to the placebo group at four weeks, which was consistent with the results of their three-week pilot study. However, no difference in depression symptom severity between groups was seen at 24 weeks. Additionally, testosterone therapy was associated with less weight gain and did not lead to improvements in disordered eating symptoms compared to placebo. “Many factors may have contributed to the lack of sustained antidepressant effect of testosterone, including the high number of psychiatric medication changes or inefficacy of low-dose testosterone treatment in this population,” Kimball says.

While it seems that these external factors may have influenced the effects Kimball, Miller, and their team observed, they didn’t have a say in which psychiatric medications their trial participants were taking, for obvious reasons. “As untreated anorexia nervosa can be life-threatening, subjects were required to be followed by a treatment team, and usual medical and psychiatric care was continued during the study,” Kimball says. “This resulted in initiation or discontinuation of psychiatric medications in nearly half of all subjects and psychiatric medication dose changes in nearly one-third of subjects. While the frequency of these medication changes was not different between the testosterone and placebo groups, the sheer number may have attenuated any effects of testosterone that could have been seen if psychiatric medications were held constant. For safety reasons, we allowed psychiatric medication changes at the discretion of the treatment team.”

Testosterone is considered a promising medication, and the researchers felt that it would be able to withstand whatever other medications these patients were prescribed. “We didn’t feel that it would be ethical to prohibit patients in the study from receiving whatever treatments that their healthcare providers felt was important for their health, which may have interfered with our ability to see an effect with our treatment,” Miller says. “That having been said, if there had been a large effect, I think we would have seen it through these [medication] changes, and we didn’t see it. It clearly doesn’t have a strong enough effect for us to be able to say we recommend it.”

Disappointing Study Results

Anorexia nervosa, especially if left untreated, has a high mortality rate. According to a 2011 meta-analysis in JAMA Psychiatry by Jon Arcelus, LMS, MSc, FRCPsych, PhD, et al., AN had a standard mortality rate of 5.86, and one in five people with AN who had died had committed suicide. “Individuals with eating disorders have significantly elevated mortality rates, with the highest rates occurring in those with AN,” Arcelus and his team wrote in their conclusion.

“The attractiveness of testosterone therapy was that we were positing that the correction of a relative androgen deficiency might be effective and have few side effects. We did see few side effects, but we did not see that it was powerful enough to be effective for the treatment of this serious disease.” – Karen K. Miller, MD, Harvard Medical School; Neuroendocrine Unit, Massachusetts General Hospital, Boston

And again, treating AN has proven to be difficult. By the very nature of the disorder, patients are afraid to gain weight, and this serious psychiatric illness itself is only compounded by its comorbidities. Further studies are absolutely needed to identify effective pharmacological therapies. For now, however, testosterone has to be added to the very long list of medications that are unable to treat AN. “It is very possible that testosterone is simply an ineffective treatment in this population,” Kimball says. “Another consideration is that anorexia nervosa and its comorbidities are very difficult to treat, so a ‘stronger’ medication may be necessary.”

Kimball goes on to say that the results of this study were disappointing, especially with the need for effective medications to treat AN. “Given the results of this study, testosterone therapy cannot be recommended to treat depression, anxiety, or eating disorder symptoms in women with anorexia nervosa,” she says.

Such is nature of science and medicine: the results don’t always support the hypothesis. Things are ruled out, lessons are learned, ideas are formed, new avenues are revealed.

“The attractiveness of testosterone therapy was that we were positing that the correction of a relative androgen deficiency might be effective and have few side effects,” Miller says. “We did see few side effects, but we did not see that it was powerful enough to be effective for the treatment of this serious disease.”

— Bagley is the senior editor of Endocrine News. He wrote the August cover story linking BPA exposure in pregnancy to the potential for hyperactive offspring.

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