Increased Response of Plasma Allopregnanolone to Corticotropin-Releasing Hormone in Obese Patients

Abstract

Allopregnanolone is a neuroactive steroid present in the brain, but also measurable in systemic circulation. It exhibits anxiolytic and anticonvulsant effects and is able to produce hyperphagia. Since eating behavior disturbances and increased peripheral basal sympathetic activity have been reported in obese subjects, the present study investigated allopregnanolone and catecholamine (epinephrine and norepinephrine) responses to corticotropin-releasing hormone (CRH) in obese subjects. Blood was sampled from 39 obese (14 men and 25 women) and 57 normal-weight subjects (20 men and 37 women) and assayed for cortisol, allopregnanolone and catecholamines concentrations. In addition, 13 obese patients (5 men and 8 women) and 18 control subjects (9 men and 9 women) were submitted to a CRH test. Plasma allopregnanolone and norepinephrine levels were significantly higher in obese than in control subjects (p < 0.01), but plasma cortisol and epinephrine concentrations were comparable in both groups. No correlation was found in any group between plasma allopregnanolone and norepinephrine or epinephrine levels. Acute CRH administration significantly stimulated allopregnanolone secretion, with peak levels at 15 min in obese subjects, whereas maximal concentrations were reached after 60 min only in controls. In obese patients the allopregnanolone secretory incremental area was significantly higher than in controls (p < 0.02). CRH injection increased cortisol levels to a comparable extent in both groups. Plasma norepinephrine or epinephrine levels did were not significantly affected by CRH test in either group. In conclusion, obese subjects present higher allopregnanolone levels and a greater response to CRH than normal subjects. Since allopregnanolone has hyperphagic effects in rats, hypersecretion of the hormone in obese patients may represent one of the mechanisms underlying obesity.

Neurosteroids in the context of stress: Implications for depressive disorders

“…Moreover, for the entire sample of women, higher luteal phase allopregnanolone tended to be associated with lower luteal phase cortisol concentrations (r=−0.32, P=0.05). Although it should be pointed out that higher allopregnanolone concentrations in obese subjects in response to a CRF challenge test was not found to be related to plasma cortisol concentrations (Menozzi et al, 2002).…”

“…Suppression of adrenal steroidogenesis with dexamethasone markedly reduced allopregnanolone, indicating that in humans both ovary and adrenal cortex are major sources of circulating allopregnanolone. Subsequent work by this group has yielded a similar time course to peak plasma allopregnanolone response to the endocrine CRF challenge in healthy male and female controls, although not in women with hypothalamic amenorrhea who fail to show any increase in allopregnanolone (Meczekalski et al, 2000) or in obese men and women who show an exaggerated allopregnanolone response to CRF infusions with an earlier peak (Menozzi et al, 2002). Taken together, the results of these endocrine challenge studies suggest that neuroactive steroids may increase in response to stress in healthy humans as they do in animals.…”

High basal serum allopregnanolone levels in overweight girls

“…The relationship between adrenal secretion and obesity remains unclear, as increased basal cortisol secretion was also reported in obese subjects. 42,43 Although a single morning measurement of serum cortisol (such as all the other hormones with a known circadian rhythm) is not representative of the circadian activity of the HPA axis, the finding of normal morning cortisol levels suggests that changes in DHEAS in our pubertal obese girls were not owing to an overactive CRH/ACTH system, prompting a dissociation in the adrenal secretion of DHEAS and cortisol.…”

Neuroactive Steroids and Affective Symptoms in Women Across the Weight Spectrum

“…In contrast to this hypothesis, a few small studies have demonstrated higher allopregnanolone levels in women with AN vs healthy controls (Galderisi et al, 2003;Monteleone et al, 2001). Studies of neuroactive steroids in obesity are limited; two studies, one in women alone and one in both sexes combined, reported higher levels of allopregnanolone in obese than normal-weight individuals without consideration of comorbid psychiatric symptomatology (Menozzi et al, 2002;Monteleone et al, 2003). However, all these studies were limited by the use of immunoassays to measure allopregnanolone levels, which are particularly vulnerable to cross-reactivity with similarly structured steroid hormone metabolites (Cheney et al, 1995a;Siekmann, 1979).…”

“…However, all these studies were limited by the use of immunoassays to measure allopregnanolone levels, which are particularly vulnerable to cross-reactivity with similarly structured steroid hormone metabolites (Cheney et al, 1995a;Siekmann, 1979). Additionally, while some studies exclude women on oral contraceptives (Monteleone et al, 2001;Monteleone et al, 2003) and control for the follicular phase of the menstrual cycle (Menozzi et al, 2002;Monteleone et al, 2001;Monteleone et al, 2003), others (Galderisi et al, 2003) do not specify these conditions, which are critical in the assessment of neuroactive steroids.…”