As demonstrated in progesterone receptor-deficient mice, the physiological effects of progesterone depend completely on the presence of the human progesterone receptor (hPR), a member of the steroid-receptor superfamily of nuclear receptors. The single-copy human (hPR) gene uses separate promoters and translational start sites to produce two isoforms, hPR-A and -B, which are identical except for an additional 165 amino acids present only in the N terminus of hPR-B.  Although hPR-B shares many important structural domains with hPR-A, they are in fact two functionally distinct transcription factors, mediating their own response genes and physiological effects with little overlap. Selective ablation of PR-A in a mouse model, resulting in exclusive production of PR-B, unexpectedly revealed that PR-B contributes to, rather than inhibits, epithelial cell proliferation both in response to estrogen alone and in the presence of progesterone and estrogen. These results suggest that in the uterus, the PR-A isoform is necessary to oppose estrogen-induced proliferation as well as PR-B-dependent proliferation.
The Mesterolone hormone is not estrogenic. It does not aromatize and it carries no progestin nature. As a result, the side effects of Proviron will not include any related effects such as gynecomastia or excess water retention. Such adverse effects are impossible with this steroid. This will also greatly reduce the risk of high blood pressure as high blood pressure associated with anabolic steroid use is often due to extreme water retention. In fact, Proviron should provide an anti-estrogenic effect by preventing testosterone to estrogen conversion or at least tremendously slow it down.
Estradiol likely acts at both the hypothalamus and pituitary gland to exert negative and positive feedback effects on GnRH secretion and gonadotropin release. Within the hypothalamus, altered GnRH pulsatility may be a result of direct or indirect effects on the GnRH neurons. For many years, it was believed that GnRH neurons lacked estrogen receptor expression, suggesting that all effects on these neurons were achieved via connecting interneurons. However, more recent studies have demonstrated that the estrogen receptor, ERb, is expressed by at least a subset of GnRH neurons. The presence of ERa is more controversial, although ERa mRNA has been clearly identified in some studies. 20 , 21 Some of these discrepancies may be attributable to species differences. There is also substantial evidence to support a direct negative effect by estrogens at the pituitary level. 22 For example, studies have been performed in women with GnRH deficiency who were treated with pulsatile GnRH followed by estradiol. Estradiol was able to blunt GnRH-mediated increases in gonadotropin expression, despite a lack of potential feedback at the hypothalamus. 23