The dialectic role of progesterone

Progesterone is known to be metabolized into various metabolites exerting various effects, predominantly into 5α-pregnanes and 4-pregnenes. Studies on uterine tissues showed numerous progesterone-converting enzymes such as 5α-reductase (5αR), 5β-reductase, 3α-, 3β-, 20α-, and 20β-hydroxysteroid oxidoreductases and others. The main progesterone-metabolizing enzymes in human breast tissues are 5αR, 3α-HSO 3β-HSO, and 20α-HSO. Tumor genesis in the breast has been shown to be enhanced by high 5αR activity and suppression of 3α-HSO and 20α-HSO. A major determinant of 5αR, the breast's gate-keeping enzyme activity is the genetic variation in the enzyme's gene. Two polymorphisms within the steroid 5αR type 2 gene, Ala > Thr at codon 49 and Val > Leu at codon 89 have been reported to strongly affect the enzyme's activity, even in regard to breast cancer risk. As steroid hormones are known to be converted into many other steroids occupying different receptors and thereby exerting various different effects, progesterone receptors are important factors when mediating the hormone's effects. The progesterone receptor (PR) gene is transcribed from one gene by two alternative promoters and translated into PR-B, a potent transcriptional activator, and PR-A, the shorter isoform, necessary to oppose the effects of PR-B. In addition, endocrine reactions are modulated by epigenetics. The expression of progesterone receptors has been shown to be up- and downregulated by various epigenetic mechanisms. Many factors must be also taken into account in hormonal (replacement) therapy. Thus natural steroids should not be disparaged as treatment options for gender-specific diseases. An update on endocrinological knowledge and experience is rather mandatory for gynaecologists.