Progesterone and Medroxyprogesterone Acetate Effects on Central and Peripheral Allopregnanolone and Beta-Endorphin Levels

Abstract

The increased use of hormonal therapies has led to the study of the properties of different progestin molecules and their effects on the central nervous system. The central and peripheral levels of neurosteroid allopregnanolone and the opioid peptide β-endorphin (β-END) are regulated by estrogens. The aim of the present study was to investigate the effects of a 2-week oral treatment with micronized progesterone or medroxyprogesterone acetate (MPA) alone or in addition to estradiol valerate (E2V) on central and peripheral allopregnanolone and β-END levels in ovariectomized (OVX) female rats. Thirteen groups of Wistar OVX rats received one of the following treatments: oral progesterone (2, 4 or 8 mg/kg/day); oral MPA (0.05, 0.1 or 0.2 mg/kg/day); E2V (0.05 mg/kg/day); E2V + progesterone (0.05 mg/kg/day + 2, 4 or 8 mg/kg/day), or E2V + MPA (0.05 mg/kg/day + 0.05, 0.1 or 0.2 mg/kg/day) for 14 days. One group of fertile and one group of OVX rats were used as controls. The concentration of allopregnanolone was assessed in the frontal and parietal lobes, hypothalamus, hippocampus, anterior pituitary, adrenals and serum, while the β-END content was assessed in the frontal and parietal lobes, hypothalamus, hippocampus, anterior and neurointermediate pituitary, and plasma. E2V administration reverted the ovariectomy-induced reduction in allopregnanolone and β-END. Progesterone and MPA increased allopregnanolone levels in all tissues except in the adrenal gland. The combined administration of progesterone or MPA and E2V determined a further increase in allopregnanolone levels with respect to E2V alone except in the adrenal gland and hippocampus only after MPA treatment. Progesterone did not affect β-END levels in the frontal and parietal lobes, hippocampus and anterior pituitary, while it caused an increase plasma, hypothalamic and neurointermediate pituitary β-END levels. MPA only affected β-END levels in the hippocampus and in the neurointermediate lobe. The combined administration of progesterone or MPA and E2V did not alter the effect of estradiol or it determined a further dose-dependent increase in β-END levels. In conclusion, this study demonstrates that progesterone and MPA have a similar but not identical effect on central and peripheral allopregnanolone and β-END levels. Their association with an estrogenic compound does not interfere with the positive effects produced by estrogen on allopregnanolone and β-END brain content.

Dydrogesterone increases allopregnanolone in selected brain areas and in serum of female rats

“…We previously showed that the administration of progesterone had a huge impact on the opiatergic system, especially when it was coadministered with an estrogen molecule (10). On the contrary, the neutral effect exerted by DYD suggests a differential impact of this synthetic progestin (when compared with the natural progesterone) on the cell system responsible for the synthesis/release of b-endorphin.…”

“…Allopregnanolone is a potent endogenous steroid that rapidly affects the excitability of neurons and glia cells through the direct modulation of the activity of g-aminobutyric acid A receptors (5, 6). Allopregnanolone exerts neuropharmacologic actions, with hypnotic/sedative, anxiolytic, anesthetic, and analgesic functions, and it enhances the myelination/remyelination process (7, 8).In addition, it has been demonstrated that chronic intraperitoneal treatment with progesterone or different progestins (medroxyprogesterone acetate [MPA], norethisterone acetate, desogestrel) as well as oral administration of active progestogens (MPA and drospirenone) directly influences the central nervous system's levels of b-endorphin in ovariectomized female rats (3,(9)(10)(11). Beta-endorphin exerts several behavioral, analgesic, thermoregulatory, and neuroendocrine properties (12).…”

“…In addition, it has been demonstrated that chronic intraperitoneal treatment with progesterone or different progestins (medroxyprogesterone acetate [MPA], norethisterone acetate, desogestrel) as well as oral administration of active progestogens (MPA and drospirenone) directly influences the central nervous system's levels of b-endorphin in ovariectomized female rats (3,(9)(10)(11). Beta-endorphin exerts several behavioral, analgesic, thermoregulatory, and neuroendocrine properties (12).…”

Effects of medroxyprogesterone acetate on cerebral oedema and spatial learning performance after traumatic brain injury in rats

“…In one recent report, addition of MPA to conjugated equine oestrogens caused an increased insulin resistance in adipose tissue whereas oestrogen alone did not [19]. Bernardi et al [20] found that natural progesterone and MPA do not have the same effects on the expression of central and peripheral allopregnanolone and beta-endorphin levels, suggesting somewhat different receptor mechanisms of action. An in vitro study, Nilsen et al [21] added MPA to a cell culture medium and found increased cytotoxicity and neuronal death after exposure to glutamate.…”

Qualitative Histological Analysis of Adrenal Cortex Following Application of Medroxyprogesterone Acetate

“…Their association with an estrogenic compound does not interfere with the positive effects produced by estrogen on allopregnanolone and beta-END brain content [28]. It was published a case report of a patient with pedophilia who was treated over a 4-year period with medroxyprogesterone acetate (MPA) at a dose of 300 mg/day and as a consequence developed Cushing's Syndrome and adrenal insufficiency, for which he was treated and from which he recovered.…”