Studies by researchers in the U.S. suggest that a metabolite of progesterone may represent a new therapeutic target for depression and anxiety in otherwise treatment-resistant groups of patients, including those with anorexia nervosa. Collaborating scientists at Massachusetts General Hospital, the University of Illinois at Chicago, and Boston University School of Medicine found low levels of the neuroactive steroid allopregnanolone (3α-5α-tetrahydroprogesterone, or “allo”) in both obese women and those with anorexia nervosa, and showed that levels of allo correlated with the severity of depression and anxiety symptoms.

“We are beginning to see more and more evidence that low allo levels are tightly linked to depression, anxiety, post-traumatic stress disorder (PTSD), and other mood disorders,” comments co-researcher Graziano Pinna, Ph.D., associate professor of psychiatry at the University of Illionois at Chicago College of Medicine. “To see women with anorexia nervosa and obesity have low levels adds to the picture that the role of allo is under-recognized in mood disorders.”

The researchers report their findings in the online edition of Neuropsychopharmacology, in a paper entitled “Neuroactive Steroids and Affective Symptoms in Women Across the Weight Spectrum.”

More than 50% of women with anorexia nervosa and 43% of obese adults have depression or anxiety. The progesterone metabolite allo binds to gamma-aminobutyric acid (GABA) receptors in the brain, which are also the targets of anxiolytic drugs. Previous studies have linked low levels of allo with anxiety and depression, but the relationship between allo and mood in anorexic and obese women hadn’t previously been investigated.

The new research, headed by Karen Miller, M.D., professor of medicine at Harvard Medical School, included 12 women with anorexia nervosa and amenorrhea who had a body mass index (BMI) of less than 18.5, another 12 obese women with BMIs of more than 25, and 12 normal-weight women with BMIs of 19 to 24. The average age was 26 years. None of the participants had received a diagnosis of depression or had ever taken antidepressants. 

Each of the women completed questionnaires to assess depression and anxiety scores. Levels of allo and other hormones in their blood were tested using highly sensitive gas chromatography and mass spectrometry-based technology that had previously been developed by Dr. Pinna’s laboratory to detect very low levels of sex hormones and their metabolites in body fluids.

The results showed that levels of allo were 50% lower in obese women and those with anorexia nervosa than in the women with normal BMIs, and women who were clinically obese had 60% lower levels of allo than control participants. Importantly, in all the patient groups, the lower the level of allo, the more severe the depression and anxiety scores, even though progesterone levels were low across all the groups. “Allopregnanolone, but not progesterone, was negatively associated with depression and anxiety symptom severity, independent of BMI,” the authors write. “Women with anorexia nervosa had low progesterone because they were amenorrheic, and the other two groups also had low progesterone levels because their blood was taken in the follicular phase when progesterone is naturally low,” Pinna adds.

Interestingly, there was no similar relationship between levels of the testosterone metabolite 5α-androstane-3α,17β-diol (known as 3α-androstanediol) and depression or anxiety, “despite a significant negative association between free testosterone levels and both anxiety and depression severity,” the authors state.“That we found that obese women had lower allo levels than normal weight participants adds to growing evidence that this steroid is involved in depression and anxiety regardless of how much progesterone is available to begin with,” Pinna adds.

Pinna suggests that the fault may lie in enzymes that convert progesterone into allo, leading to lower levels of the metabolite, which adversely impact on mood disorders. “Drugs that increase the efficacy of these enzymes may be useful in helping to boost allo levels,” he notes. “But more research is needed to figure out exactly the deficit in the metabolism of progesterone into allo so that precision medicines using allo as a biomarker can be developed.”

Pinna is now carrying out preclinical studies with drugs that are designed to increase allo levels using different pharmacological approaches and have already demonstrated promising effects in mouse models of depression and PTSD. “Neuroactive steroids such as allopregnanolone may be potential therapeutic targets for depression and anxiety in traditionally treatment-resistant groups, including anorexia nervosa,” he states.

“Depression is an incredibly prevalent problem, especially in women, and also particularly at the extremes of the weight spectrum,” Dr. Miller comments. “The hope is that a greater understanding of mechanisms contributing to these disorders—including abnormalities in the regulation of hormones and their neuroactive metabolites—may lead to new targeted therapies in the future.”

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