The role of progesterone and the progesterone receptor in human reproduction and cancer

Abstract

Insufficient progesterone, effect possibly more on immune factors rather than adequate endometrial development, can be an easy remedial cause of infertility by simply supplementing the luteal phase with either vaginal or intramuscular or oral (dydrogesterone) progesterone. Progesterone will also help to reduce miscarriage rates when follicle maturing drugs are used for those with regular menses but follicular maturation defects, or women with recurrent miscarriages. One mechanism of action seems to be related to production of an immunomodulatory protein, the progesterone-induced blocking factor either in the cytoplasm or in the circulation. PIBF inhibits cytotoxicity of natural killer cells. Cancer cells may ‘borrow’ the same mechanism to escape NK cell immunosurveillance.

Keywords::

• cancer
• growth factors
• immunosuppression
• infertility
• miscarriage
• preterm delivery
• progesterone
• progesterone receptor
• progesterone receptor antagonist
• progesterone-induced blocking factor

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Endometrial biopsy, measurement of progesterone receptors (PRs) and molecular markers have proven disappointing in detecting luteal phase deficiency.

• • Progesterone alone is able to interact with PRs on gamma/delta T cells to express a unique 34 kDa protein which suppresses natural killer (NK) cell cytolytic activity and causes a shift of thymic helper 1 (TH1) to thymic helper 2 (TH2) cytokines.

• • Purification of the progesterone-induced blocking factor (PIBF) protein and the development of a monoclonal antibody has led to the development of an ELISA assay. Thus, PIBF may be the next target to evaluate even if progesterone secretion is adequate for successful conception.

• • Follicular maturation studies should be used to determine if women with infertility and regular menses but suspected luteal phase deficiency should be treated exclusively with progesterone in the luteal phase or have the addition of follicle maturing drugs in the follicular phase.

• • Progesterone treatment is the main method by which a physician can help prevent miscarriage or preterm labor other than in vitro fertilization and transfer of embryos that are chromosomally normal using 24 chromosome analysis and trophectoderm biopsy.

• • The PIBF 90 kDa molecule has a centrosomal location near BRCA1 and BRCA2 but a split variant of 34–36 kDa is present in the cytoplasm of most rapidly proliferating cells. Intracytoplasmic PIBF may be most important in providing immune protection for cancer cells.

• • There is a complex relationship and cross-talk involving the estrogen receptor and PR and isoforms of the PR which through both genomic and non-genomic mechanisms control cell growth.

• • Mutations, for example, BRCA1, where there may be inadequate degradation of the PR by ubiquitination may lead to uncontrolled cell growth or the production of an excess of factors, for example, PIBF preventing immune destruction.

• • PR antagonists, for example, mifepristone, has been found to prolong life and diminish suffering not only in animal and human models where tumors are known to be PR+, but also in ones not known to have PRs.

• • New more specific PR antagonists that have little antiglucocorticoid receptor antagonists and ones that will not block progesterone effect at the endometrial level are in the pharmaceutical pipeline clinical trials for cancer are forthcoming.