“Rapid actions of the neurosteroid allopregnanolone on ovarian and hypothalamic steroidogenesis: Central and peripheral modulation”

Abstract

The present study aimed to determine whether an i.c.v. administration of allopregnanolone (ALLO) rapidly modifies the hypothalamic and ovarian 3β‐hydroxysteroid dehydrogenase (3β‐HSD) enzymatic activity and gene expression in in vivo and ex vivo systems in pro‐oestrus (PE) and dioestrus I (DI) rats. Animals were injected with vehicle, ALLO, bicuculline or bicuculline plus ALLO and were then killed. In the in vivo experiment, the hypothalamus, ovaries and serum were extracted and analysed. In the ex vivo experiment, the superior mesenteric ganglion ‐ ovarian nerve plexus ‐ ovary system was extracted and incubated during 120 minutes at 37 ºC. The serum and ovarian compartment fluids were used to determine progesterone by radioimmunoanalysis. In the in vivo experiments, ALLO caused a decrease in hypothalamic and ovarian 3β‐HSD enzymatic activity during PE. During DI, ALLO increased hypothalamic and ovarian 3β‐HSD activity and gene expression. The ovarian 3β‐HSD activity increased in both stages in the ex vivo system; gene expression increased only during DI. ALLO induced an increase in serum progesterone only in D1 and in the ovarian incubation liquids in both stages. All findings were reversed by an injection of bicuculline before ALLO. Ovarian steroidogenic changes could be attributed to signals coming from ganglion neurones, which are affected by the acute central neurosteroid stimulation. The i.c.v. administration of ALLO via the GABAergic system altered 3β‐HSD activity and gene expression, modulating the neuroendocrine axis. The present study reveals the action that ALLO exerts on the GABAA receptor in both the central and peripheral nervous system and its relationship with hormonal variations. ALLO is involved in the “fine tuning” of neurosecretory functions as a potent modulator of reproductive processes in female rats.

Superior mesenteric ganglion neural modulation of ovarian angiogenesis, apoptosis and proliferation by the neuroactive steroid allopregnanolone

“…ALLO is a 5α‐pregnane metabolite of progesterone, and a neuroactive steroid with important functions in the PNS 1,26‐28 . We have previously shown that a central administration of ALLO 6 µ m was capable of rapidly modifying ovarian steroidogenesis through a neural pathway that involves the SMG‐ONP system 71 . In the present study, we evaluated the effect of a low nanomolar and a high micromolar (0.06 µ m = 60 n m and 6 µ m ) ALLO concentration on an ex vivo culture that comprised the SMG‐ONP‐ovary system and the contralateral DO in the estrous stage.…”

“…1,[26][27][28] We have previously shown that a central administration of ALLO 6 µm was capable of rapidly modifying ovarian steroidogenesis through a neural pathway that involves the SMG-ONP system. 71 In the present study, we evaluated the effect of a low nanomolar and a high micromolar (0.06 µm = 60 nm and 6 µm) ALLO concentration on an ex vivo culture that comprised the SMG-ONP-ovary system and the contralateral DO in the estrous stage. This methodological approach allows to emulate in vivo conditions by preserving the neural connection between the SMG and the ovary, as well as autocrine and paracrine mechanisms, without the humoral influence.…”

“…In a previous study, 71 we showed that ALLO 6 µ m central administration can rapidly modify the neuroendocrine axis and the peripheral neural control that regulates ovarian steroidogenesis, altering progesterone secretion. These effects involve the central GABAergic system and the SMG‐ONP pathway in a time‐ and cycle‐dependent manner 71 . In the present study, we analyzed the direct effects of a low nanomolar and a high micromolar (0.06 µ m = 60 n m and 6 µ m ) dose of ALLO, on the ovarian peripheral neural modulation of key physiological processes, deeply involved in the estrous day of the cycle and closely related to ovarian pathologies such as polycystic ovary and cancer.…”

“…In a previous study, 71 we showed that ALLO 6 µm central administration can rapidly modify the neuroendocrine axis and the peripheral neural control that regulates ovarian steroidogenesis, altering progesterone secretion. These effects involve the central GABAergic system and the SMG-ONP pathway in a time-and cycle-dependent manner.…”

“…These effects involve the central GABAergic system and the SMG-ONP pathway in a time-and cycle-dependent manner. 71 In the present study, we analyzed the direct effects of a low nanomolar and a high micromolar (0.06 µm = 60 nm and 6 µm) dose of ALLO, on the ovarian peripheral neural modulation of key physiological processes, deeply involved in the estrous day of the cycle and closely related to ovarian pathologies such as polycystic ovary and cancer. To differentiate ALLO actions, we used an ex vivo culture of the SMG-ONP-ovary system and the incubation of the contralateral ovary alone, without neural influence (denervated ovary [DO]).…”