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

Evidence that exposure to progesterone alone is a sufficient stimulus to cause a precipitous rise in the immunomodulatory protein the progesterone induced blocking factor (PIBF)

“…Despite clinical evidence of its efficacy, there does not appear to be at this present time, except at extremely low serum levels of P, a good method to determine who requires supplementation and who does not [26]. Equally important, if certain women are found to need progesterone, how can one determine if the amount given has corrected the problem?…”

“…Progesterone has been found to not only increase the serum PIBF but to also increase the level of a PIBF intracellular splice variant (that is similar in size to circulating PIBF) in rapidly growing cells, e.g., the cells of the fetal placental unit (or cancer cells) [1,25,26]. The progesterone receptor modulator abortifacient mifepristone has been found to decrease intracytoplasmic PIBF production of the 34-36-kDa intracytoplasmic splice variant [25].…”

“…If such a correlation is found, and if intracytoplasmic levels of the 34-36-kDa splice variant are found to be the more important factor for the fetal semi-allograft to escape immune surveillance, then knowing which P vehicle stimulates the most serum PIBF could be important in choosing the right type of P supplementation. Of course, even to the present time, there still exists debate about the importance of supplementing extra progesterone to improve the chances of a live delivery [26,28,29].…”

Mifepristone Extends Both Length and Quality of Life in a Patient With Advanced Non-small Cell Lung Cancer that Has Progressed Despite Chemotherapy and a Check-point Inhibitor

“…The second case examined in this study, which is reported here, had non-small cell lung cancer that progressed despite multiple courses of chemotherapy or immunotherapy with nivolumab. This case report documents a positive response to single agent mifepristone, which activates the immune destruction of the tumor by inhibiting intracytoplasmic PIBF by blocking extranuclear membrane P receptors (7,16).…”

“…The hypothesized mechanism of action of mifepristone is that this progesterone receptor modulator suppresses a progesterone-associated immunomodulatory protein that is unique to rapidly growing cells in the fetal placental unit, including embryonic, mesenchymal, and trophoblast cells, and in rapidly growing cancer cells. This protein is called the progesterone induced blocking factor (PIBF) (5)(6)(7)(8).…”