Evidence for a role for the neurosteroid allopregnanolone in the modulation of reproductive function in female rats

Abstract

The present study investigated the effect of allopregnanolone (5 alpha-pregnan-3 alpha-ol-20-one) or of passive immunoneutralization of brain allopregnanolone, the most potent steroid produced by neurons, on ovulation rate and sexual behavior in female rats. Allopregnanolone was injected intracerebroventricularly in rats on diestrus and proestrus and tests were done on estrus. The intracerebroventricular injection of allopregnanolone significantly decreased the number of oocytes collected on estrus (p < 0.01). To support a physiological involvement, antiserum to allopregnanolone was injected centrally to block the activity of the endogenous neurosteroid. When administered on diestrus and proestrus or only on proestrus, the antiserum was shown to be correlated with a significant increase (p < 0.01) in oocytes retrieved on estrus. In female rats treated with antiserum to allopregnanolone, the lordosis intensity was augmented significantly as compared to controls. Finally, the possible changes of medial basal hypothalamus concentration of allopregnanolone throughout the estrous cycle and at the time of ovulation were investigated. Hypothalamic extracts were eluted on high-pressure liquid chromatography and allopregnanolone concentration was measured by radioimmunoassay. Brain cortex was used as control tissue. Hypothalamic allopregnanolone concentration on proestrus morning and afternoon was found to be significantly lower than in the remaining phases of the estrous cycle (p < 0.01), while no significant changes were observed in brain cortex concentration of allopregnanolone. The present results suggest that hypothalamic allopregnanolone may be involved in the mechanism of ovulation, affecting hormonal and behavioral events.

Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function

“…The androgenic neurosteroid, 3α-diol, also showed cycle-dependent variation in cortical homogenates, with levels being lowest in diestrus I (0.08 ng/g) and rising steadily as the cycle progresses to a maximum of 0.33 ng/g during estrus (Kellogg and Frye, 1999). With respect to the hypothalamus, allopregnanolone levels were also shown to vary across the estrous cycle, but, in contrast to cortex, the lowest levels were reported on the evening of proestrus (~40 pg/mg protein) and the highest levels during the morning of diestrus I (~95 pg/mg protein) (Genazzani et al, 1995). The differences in concentrations of progestin-and testosterone-derived neurosteroids as a function of hormonal state contrasts with that for THDOC which shows only a small increase from ~1.5 ng/g during estrus to ~ 3ng/g in late pregnancy (Concas et al, 1998).…”

“…With respect to other measures of reproductive function, Genazzani et al (1995) report that intracerebroventricular (i.c.v.) injection of two doses of allopregnanolone (20 μg, on diestrus II and the morning of proestrus) decreases the number of oocytes retrieved at estrus, and that female rats injected i.c.v.…”

Aging is associated with changes in allopregnanolone concentrations in brain, endocrine glands and serum in male rats

“…Rat hypothalamic and hippocampal contents of allopregnanolone show significant changes during the estrous cycle (7,8). No data on brain allopregnanolone content are available in aged rats.…”

“…No data on brain allopregnanolone content are available in aged rats. The observation that allopregnanolone modulation of the stress response is impaired in aged rats (8) and that the plasma levels of other neuroactive steroids, such as dehydroepiandrostenedione (DHEA) undergo changes with aging in rats and in man (9-11), led us to investigate possible age-related variations in allopregnanolone levels in different brain areas, endocrine glands, and serum of male rats.…”

An Essential Component in Steroid Synthesis, the Steroidogenic Acute Regulatory Protein, Is Expressed in Discrete Regions of the Brain

“…The brain synthesizes neurosteroids de novo, especially within glia (Corpechot et al, 1981;Koenig et al, 1995;Zwain and Yen, 1999;Compagnone and Mellon, 2000;Tsutsui et al, 2000), but the relative roles of locally produced neuroactive steroids and those converted from circulating precursors remain to be defined. Alterations in levels of locally produced neurosteroids in the hypothalamus, hippocampus, and other regions may serve as crucial paracrine modulators of essential brain functions, including sexual drive, learning, and memory (Majewska et al, 1986;Genazzani et al, 1995;Frye et al, 1996;Calogero et al, 1998;Akwa et al, 2001). Deficits in neurosteroid production may contribute to a variety of disorders, including dementia, epilepsy, premenstrual syndrome, and postpartum depression (Vallee et al, 1997;Smith et al, 1998;Beyenburg et al, 1999).…”