Progesterone-induced immunosuppression is not mediated through the progesterone receptor

Endometriosis and subfertility: is the relationship resolved?

D'Hooghe TM et al., 2003 · Semin Reprod Med

There are many arguments to support the hypothesis that there is a causal relationship between the presence of endometriosis and subfertility. These arguments are reviewed in this article and include: (1) an increased prevalence of endometriosis in subfertile women compared with women of proven fertility; (2) a reduced monthly fecundity rate (MFR) in baboons with mild to severe (spontaneous or induced) endometriosis compared with those with minimal endometriosis or a normal pelvis; (3) a trend toward a reduced MFR in infertile women with minimal to mild endometriosis compared with women with unexplained infertility; (4) a dose-effect relationship: a negative correlation between the r-AFS stage of endometriosis and the monthly fecundity rate and crude pregnancy rate; (5) a reduced monthly fecundity rate and cumulative pregnancy rate after donor sperm insemination in women with minimal-mild endometriosis compared with those with a normal pelvis; (6) a reduced MFR after husband sperm insemination in women with minimal to mild endometriosis compared with those with a normal pelvis; (7) a reduced implantation rate per embryo after IVF in women with moderate to severe endometriosis compared with women with a normal pelvis; and (8) an increased monthly fecundity rate and cumulative pregnancy rate after surgical removal of minimal to mild endometriosis.

Implantation and the survival of early pregnancy

Norwitz ER et al., 2002 · N Engl J Med

The implantation of fertilized ova and the formation of the placenta are crucial steps in reproduction. This review summarizes current information about these steps, including some of the molecular mechanisms that mediate them and how they may go awry, with consequent loss of the pregnancy.

A randomized study comparing Crinone 8% and intramuscular progesterone supplementation in in vitro fertilization-embryo transfer cycles

Propst AM et al., 2001 · Fertil Steril

To compare the efficacy of Crinone 8% intravaginal progesterone gel vs. IM progesterone for luteal phase and early pregnancy support after IVF-ET. Randomized, open-label study. Academic medical center. PATIENT(S): Two hundred and one women undergoing IVF-ET. INTERVENTION(S): Women were randomized to supplementation with Crinone 8% (90 mg once daily) or IM progesterone (50 mg once daily) beginning the day after oocyte retrieval. MAIN OUTCOME MEASURE(S): Pregnancy, embryo implantation, and live birth rates. RESULT(S): The women randomized to luteal phase supplementation with IM progesterone had significantly higher clinical pregnancy (48.5% vs. 30.4%; odds ratio [OR], 2.16; 95% confidence interval [CI], 1.21, 3.87), embryo implantation (24.1% vs. 17.5%; OR, 1.89; 95% CI, 1.08, 3.30), and live birth rates (39.4% vs. 24.5%; OR, 2.00; 95% CI, 1.10, 3.70) than women randomized to Crinone 8%. CONCLUSION(S): In women undergoing IVF-ET, once-a-day progesterone supplementation with Crinone 8%, beginning the day after oocyte retrieval, resulted in significantly lower embryo implantation, clinical pregnancy, and live birth rates compared with women supplemented with IM progesterone.

Infertility in Novak's Gynecology, 12th Edition

Hornstin MD et al., 1996

Mechanism of immunosuppression of progesterone on maternal lymphocyte activation during pregnancy

Clemens LE et al., 1979 · J Immunol

Lymphocyte reactivity was measured in human mixed lymphocyte (MLC) and mitogen-stimulated cultures in the presence of various steroids. When present during the entire culture period at concentrations between 1 and 20 µg/ml progesterone, estradiol, and testosterone blocked 3H-thymidine (3H-TdR) incorporation. Estriol and 16 α-hydroxy progesterone were without suppressive effects. The kinetics of steroid mediated suppression of thymidine incorporation and DNA synthesis was investigated at various times during lymphocyte activation. When progesterone was present only at the beginning of culture, subsequent DNA content, but not thymidine incorporation was suppressed. However, if added late during the activation process, progesterone reduced thymidine incorporation independent of cellular DNA content. If present during the entire culture period both were suppressed. Cortisol, but not progesterone irreversibly inhibited lymphocyte thymidine incorporation if added during the first 12 hr of culture. A reversible blockade of lymphocyte thymidine uptake could be observed with progesterone even during the final hours of mitogen or MLC cultures. Thus, effects of steroid hormones on cellular DNA synthesis and thymidine incorporation appear to be independent processes. Cell fractionation experiments demonstrated that progesterone blocked the uptake of 3H-TdR into the lymphocyte nucleoside pool thereby reducing its availability for incorporation into DNA. This study is consistent with the hypothesis that lymphocyte proliferation at the maternal fetal-interface during pregnancy may be under specific regulation by progesterone. The relatively high local concentrations of the hormone produced by trophoblast are immunosuppressive whereas the substantially lower peripheral steroid levels are entirely inadequate to suppress systemic immunity. We suggest that at least one important role of progesterone in maintaining pregnancy is its regulation of cellular immunity in the maternal-fetal bed.

Gestational progesterone restores menstrual cycle in PCOS patients via enhancing ovary estrogen production

Yang Q et al., 2026 · Life Metab · Free full text on PubMed Central

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age, typically characterized by irregular menstrual cycles. Our study found that postpartum menstrual cycles were largely restored in PCOS patients following assisted reproductive technology (ART) therapy. However, this recovery in menstrual cycles was not associated with any specific ART procedures. Using a PCOS mouse model, we demonstrated that elevated progesterone levels during pregnancy were responsible for normalizing estrous cyclicity. Elevated levels of progesterone induce granulosa cell apoptosis and deplete large follicles, which potentially contribute to ovarian function suppression during pregnancy. Mechanistic studies indicated that progesterone decreased follicle-stimulating hormone receptor (FSHR) expression in a GATA binding protein 2 (GATA2)-dependent manner. Interestingly, the capacity of granulosa cells to convert androgens to estrogens significantly increased after progesterone withdrawal, as evidenced by elevated cytochrome P450 family 19 subfamily A member 1 (Cyp19a1) expression in granulosa cells when stimulated with FSH. Additionally, we found that progesterone administration reduced the thickness of the uterine endometrium in PCOS mice. Our findings suggest that sustained high levels of progesterone during pregnancy can enhance ovarian reproductive endocrine capacity and improve endometrial function, thereby facilitating the recovery of postpartum menstrual cycles.

Progesterone function in human endometrium: clinical perspectives

Young SL et al., 2010 · Semin Reprod Med

Progesterone is essential for endometrial receptivity and successful establishment of pregnancy. Either an insufficient progesterone concentration or an insufficient response to progesterone, therefore can lead to infertility and pregnancy loss. Assessment of the role that either progesterone insufficiency or inadequate progesterone response plays in human reproductive failure has been difficult to assess because serum progesterone concentrations fluctuate markedly, limiting the ability to characterize sufficiency of progesterone, and there are no highly reliable markers of endometrial function available. Recent evidence demonstrates exquisite sensitivity of normal endometrium to very low levels of progesterone stimulation, suggesting that progesterone insufficiency should not be a common cause of reproductive failure. Further evidence suggests that women with endometriosis, and possibly polycystic ovarian syndrome, have an altered progesterone response, which may explain some of the clinical features of these disorders and supports the hypothesis that progesterone resistance underlies some cases of human reproductive failure.

Differential glucocorticoid receptor-mediated effects on immunomodulatory gene expression by progestin contraceptives: implications for HIV-1 pathogenesis

Hapgood JP et al., 2014 · Am J Reprod Immunol

Whether hormonal contraceptives increase HIV-1 acquisition, transmission and disease progression are critical questions. Clinical research has been hampered by a lack of understanding that different progestins used in contraception exhibit differential off-target effects via steroid receptors other than the progesterone receptor. Of particular, relevance is the relative effects of medroxyprogesterone acetate (MPA) and norethisterone enanthate (NET-EN), widely used as injectable contraceptives in sub-Saharan Africa. While most high-quality clinical studies find no increased risk for HIV-1 acquisition with oral contraception or injectable NET-EN, most do find an increase with MPA, particularly in young women. Furthermore, mounting evidence from animal, ex vivo and biochemical studies are consistent with MPA acting to increase HIV-1 acquisition and pathogenesis, via mechanisms involving glucocorticoid-like effects on gene expression, in particular genes involved in immune function. We report that MPA, unlike NET and progesterone, represses inflammatory genes in human PBMCs in a dose-dependent manner, via the glucocorticoid receptor (GR), at concentrations within the physiologically relevant range. These and published results collectively suggest that the differential GR activity of MPA versus NET may be a mechanism whereby MPA, unlike NET or progesterone, differentially modulates HIV-1 acquisition and pathogenesis in target cells where the GR is the predominant steroid receptor expressed.