A Putative Stimulatory Role of Progesterone Acting via Progesterone Receptors in the Steroidogenic Cells of the Human Corpus Luteum1

Abstract

To further explore the proposed auto-regulatory role of progesterone action in the human corpus luteum (CL), the expression and functional roles of progesterone receptor (PR) isoforms A and B during the luteal phase (LP) of the menstrual cycle were investigated. A total of 27 otherwise healthy patients previously scheduled for surgery were recruited after informed consent. An LH rise was detected, and CL were grouped according to age (Days 2-5 post-LH-rise, early LP; Days 6-10, mid LP; Days 11-14, late LP). Using a semiquantitative reverse transcription-polymerase chain reaction assay, the PR-B mRNA levels, which were 100- to 1000-fold lower than PR-A/B mRNA, were 46% lower (P < 0.05, n = 24) in mid LP, compared to early and late LP. CL tissue levels of progesterone and PR-A/B protein levels were inversely correlated to increasing CL age; i.e., significantly reduced levels were observed in the late LP (r(2) = 0.34, P < 0.01, n = 23). Expression of PR-A/B mRNA as well as PR-A/B protein were detected by in situ hybridization and immunohistochemistry, respectively. Both methods revealed a clear and distinct localization to cells in the steroidogenic layer of the CL. Freshly obtained mid-luteal CL cells were cultured in vitro, and media were analyzed for progesterone concentrations after treatment by incremental doses of hCG and the stable PR antagonist mifepristone, alone or in combination. Mifepristone did not per se alter progesterone synthesis, but when it was added in conjunction with hCG, a dose-related inhibitory response was seen, with a maximal 47% reduction in progesterone output at a 10 microM addition (P < 0.05, n = 3). Collectively, these data implicate a stimulatory role of progesterone receptor-mediated action in the steroidogenic cells of the human CL, which may serve as an important pathway for maintaining functional homeostasis during early pregnancy.

The effect of human chorionic gonadotrophin on the expression of progesterone receptors in human luteal cells in vivo and in vitro

“…We have confirmed the published observations in women (Iwai et al 1990, Ottander et al 2000, rhesus monkeys (Hild-Petito et al 1988) and baboons (Hild-Petito & Fazleabas 1997) on luteal PR immunostaining. Where PR expression has been quantified there is a clear trend to its reduction in the late-luteal phase in most published studies.…”

“…Where PR expression has been quantified there is a clear trend to its reduction in the late-luteal phase in most published studies. This is the case using immunohistochemistry and protein assays in women (Iwai et al 1990, Ottander et al 2000 and immunohistochemistry and Western blotting in non-human primates , Hild-Petito & Fazleabas 1997. Using wellcharacterised human corpora lutea we have confirmed that the PR immunostaining is reduced in the late-luteal phase.…”

“…In the primate corpus luteum, Western blotting suggested that the major PR variant is the B isoform . In human corpora lutea, however, PR A/B mRNA was found in higher concentrations than PR B mRNA (Misao et al 1998, Ottander et al 2000 and PR A was confirmed to be higher using Western blotting (Misao et al 1998). It seems clear, however, that both PR isoforms are expressed in the corpus luteum.…”

“…It has been suggested that a specific PR-mediated action in the steroidogenic cells of the human corpus luteum may maintain function during early pregnancy (Ottander et al 2000). The fall in PR expression during the late-luteal phase may therefore be involved in the luteolytic process by augmenting progesterone withdrawal.…”

The human corpus luteum: life cycle and function in natural cycles

“…In addition, P has been implicated in the control of tissue inhibitors of metalloproteinase-1 expression in luteinized granulosa cells (78). In humans, it is well known that the CL expresses PR-A and PR-B mRNA, and PR-A was found to be more abundant than PR-B (79,80). Both receptor isoforms decrease in late luteal phase CL.…”