Progesterone Exposure Research Articles

Scientific Message Translation and the Heuristic Systematic Model: Insights for Designing Educational Messages About Progesterone and Breast Cancer Risks.

Results of ongoing scientific research on environmental determinants of breast cancer are not typically presented to the public in ways they can easily understand and use to take preventive actions. In this study, results of scientific studies on progesterone exposure as a risk factor for breast cancer were translated into high and low literacy level messages. Using the heuristic systematic model, this study examined how ability, motivation, and message processing (heuristic and systematic) influenced perceptions of risk beliefs and negative attitudes about progesterone exposure among women who read the translated scientific messages. Among the 1254 participants, those given the higher literacy level message had greater perceptions of risk about progesterone. Heuristic message cues of source credibility and perceived message quality, as well as motivation, also predicted risk beliefs. Finally, risk beliefs were a strong predictor of negative attitudes about exposure to progesterone. The results can help improve health education message design in terms of practitioners having better knowledge of message features that are the most persuasive to the target audiences on this topic.

STOPPIT Baby Follow-up Study: the effect of prophylactic progesterone in twin pregnancy on childhood outcome.

ObjectivesTo determine the long-term effects of in utero progesterone exposure in twin children.MethodsThis study evaluated the health and developmental outcomes of all surviving children born to mothers who participated in a double-blind, placebo-controlled trial of progesterone given for the prevention of preterm birth in twin pregnancies (STOPPIT, ISRCTN35782581). Follow-up was performed via record linkage and two parent-completed validated questionnaires, the Child Development Inventory and the Health Utilities Index.ResultsRecord linkage was successfully performed on at least one record in 759/781 (97%) children eligible for follow-up. There were no differences between progesterone-exposed and placebo-exposed twins with respect to incidence of death, congenital anomalies and hospitalisation, nor on routine national child health assessments. Questionnaire responses were received for 324/738 (44%) children. The mean age at questionnaire follow-up was 55.5 months. Delay in at least one developmental domain on the Child Development Inventory was observed in 107/324 (33%) children, with no evidence of difference between progesterone-exposed and placebo-exposed twins. There was no evidence of difference between the progesterone and placebo groups in global health status assessed using the Health Utilities Index: 89% of children were rated as having ‘excellent’ health and a further 8% as having ‘very good’ health.ConclusionsIn this cohort of twin children there was no evidence of a detrimental or beneficial impact on health and developmental outcomes at three to six years of age due to in utero exposure to progesterone.

Progesterone antagonizes the positive influence of estrogen on Chlamydia trachomatis serovar E in an Ishikawa/SHT-290 co-culture model.

Studies indicate that estrogen enhances Chlamydia trachomatis serovar E infection in genital epithelial cells. Hormones have direct and indirect effects on endometrial epithelial cells. Estrogen and progesterone exposure induces endometrial stromal cells to release effectors that subsequently regulate growth and maturation of uterine epithelial cells. Estrogen enhances C. trachomatis infection by aiding entry and intracellular development in endometrial epithelial cell (Ishikawa, IK)/SHT-290 stromal cell co-culture. Enhanced chlamydial infection was mediated by direct estrogen-stimulated signaling events in epithelial cells and indirectly via estrogen-induced stromal cell effectors. The current study investigates the effects of hormones on chlamydial development using culture conditions representative of the menstrual cycle. Chlamydia trachomatis-infected IK or IK/SHT-290 cultures were exposed to 10(-8) M estrogen (E2), 10(-7) M progesterone (P4) or a combination of both hormones (10(-8) M E2 followed by 10(-9) M E2/10(-7) M P4). Chlamydial infectivity and progeny production were significantly decreased (30-66%) in cultures exposed to progesterone or estrogen/progesterone combination compared to estrogen alone. Thus, progesterone antagonized the positive effects of estrogen on chlamydial infection. These data indicate the susceptibility of endometrial epithelial cells to C. trachomatis infection during the menstrual cycle is altered by phase specific actions of sex hormones in the genital tract.

Non-synchronized endometrium and its correction in non-ovulatory cryopreserved embryo transfer cycles

The aim of this case series study was to investigate the effect of adjusting the length of progesterone exposure on clinical pregnancy rates in cryopreserved embryo transfer cycles of patients with out-of-phase classic endometrial dating. Eighty infertile women with previous implantation failure and good-quality embryos underwent endometrial biopsy before cryopreserved embryo transfer and were included in this study. The main outcome measures were clinical pregnancy rate and histologic endometrial dating. After adjusting the length of progesterone exposure according to endometrial dating, a significantly higher implantation rate was observed in blastocyst transfers (P = 0.02) and the clinical pregnancy rate for all cycles was 36.4%, similar to that in patients with in-phase endometrium (22.5%). In conclusion, the use of classic histologic endometrial dating to estimate the timing of the window of implantation and to adjust progesterone exposure accordingly may increase the implantation rate in frozen embryo transfer cycles.

Risks of hormonally active pharmaceuticals to amphibians: a growing concern regarding progestagens.

Most amphibians breed in water, including the terrestrial species, and may therefore be exposed to water-borne pharmaceuticals during critical phases of the reproductive cycle, i.e. sex differentiation and gamete maturation. The objectives of this paper were to (i) review available literature regarding adverse effects of hormonally active pharmaceuticals on amphibians, with special reference to environmentally relevant exposure levels and (ii) expand the knowledge on toxicity of progestagens in amphibians by determining effects of norethindrone (NET) and progesterone (P) exposure to 0, 1, 10 or 100 ng l−1 (nominal) on oogenesis in the test species Xenopus tropicalis. Very little information was found on toxicity of environmentally relevant concentrations of pharmaceuticals on amphibians. Research has shown that environmental concentrations (1.8 ng l−1) of the pharmaceutical oestrogen ethinylestradiol (EE2) cause developmental reproductive toxicity involving impaired spermatogenesis in frogs. Recently, it was found that the progestagen levonorgestrel (LNG) inhibited oogenesis in frogs by interrupting the formation of vitellogenic oocytes at an environmentally relevant concentration (1.3 ng l−1). Results from the present study revealed that 1 ng NET l−1 and 10 ng P l−1 caused reduced proportions of vitellogenic oocytes and increased proportions of previtellogenic oocytes compared with the controls, thereby indicating inhibited vitellogenesis. Hence, the available literature shows that the oestrogen EE2 and the progestagens LNG, NET and P impair reproductive functions in amphibians at environmentally relevant exposure concentrations. The progestagens are of particular concern given their prevalence, the range of compounds and that several of them (LNG, NET and P) share the same target (oogenesis) at environmental exposure concentrations, indicating a risk for adverse effects on fertility in exposed wild amphibians.

Persistent genital hyperinnervation following progesterone administration to adolescent female rats.

Provoked vestibulodynia, a female pelvic pain syndrome affecting substantial numbers of women, is characterized by genital hypersensitivity and sensory hyperinnervation. Previous studies have shown that the risk of developing provoked vestibulodynia is markedly elevated following adolescent use of oral contraceptives with high progesterone content. We hypothesized that progesterone, a steroid hormone with known neurotropic properties, may alter genital innervation through direct or indirect actions. Female Sprague Dawley rats received progesterone (20 mg/kg subcutaneously) from Days 20-27; tissue was removed for analysis in some rats on Day 28, while others were ovariectomized on Day 43 and infused for 7 days with vehicle or 17beta estradiol. Progesterone resulted in overall increases in vaginal innervation at both Day 28 and 50 due to proliferation of peptidergic sensory and sympathetic (but not parasympathetic) axons. Estradiol reduced innervation in progesterone-treated and untreated groups. To assess the mechanisms of sensory hyperinnervation, we cultured dissociated dorsal root ganglion neurons and found that progesterone increases neurite outgrowth by small unmyelinated (but not myelinated) sensory neurons, it was receptor mediated, and it was nonadditive with NGF. Pretreatment of ganglion with progesterone also increased neurite outgrowth in response to vaginal target explants. However, pretreatment of vaginal target with progesterone did not improve outgrowth. We conclude that adolescent progesterone exposure may contribute to provoked vestibulodynia by eliciting persistent genital hyperinnervation via a direct effect on unmyelinated sensory nociceptor neurons and that estradiol, a well-documented therapeutic, may alleviate symptoms in part by reducing progesterone-induced sensory hyperinnervation.

Progesterone inhibits endometrial cancer invasiveness by inhibiting the TGFβ pathway.

Increased expression of TGFβ isoforms in human endometrial cancer correlates with decreased survival and poor prognosis. Progesterone has been shown to exert a chemoprotective effect against endometrial cancer, and previous animal models have suggested that these effects are accompanied by changes in TGFβ. The goal of this study was to characterize the effect of progesterone on TGFβ signaling pathway components and on TGFβ-induced protumorigenic activities in endometrial cancer cell lines. Progesterone significantly decreased expression of three TGFβ isoforms at 72 hours after treatment except for TGFβ2 in HEC-1B and TGFβ3 in Ishikawa cells. Progesterone treatment for 120 hours attenuated expression of the three isoforms in all cell lines. Progesterone exposure for 72 hours reduced expression of TGFβ receptors in HEC-1B cells and all but TGFβR1 in Ishikawa cells. Progesterone reduced TGFβR3 expression in RL-95 cells at 72 hours, but TGFβR1 and βR2 expression levels were not affected by progesterone at any time point. SMAD2/3 and pSMAD2/3 were substantially reduced at 72 hours in all cell lines. SMAD4 expression was reduced in RL-95 cells at 24 hours and in HEC-1B and Ishikawa cells at 72 hours following progesterone treatment. Furthermore, progesterone effectively inhibited basal and TGFβ1-induced cancer cell viability and invasion, which was accompanied by increased E-cadherin and decreased vimentin expression. An inhibitor of TGFβRI blocked TGFβ1-induced effects on cell viability and invasion and attenuated antitumor effects of progesterone. These results suggest that downregulation of TGFβ signaling is a key mechanism underlying progesterone inhibition of endometrial cancer growth.

Abstract 4096: A pilot study was initiated to determine if the immunomodulatory protein, the progesterone-induced blocking factor (PIBF), is present in higher quantity in the sera of patients with gynecologic cancer as compared to controls without cancer

Abstract PIBF is a unique protein that is secreted by gamma/delta T cells and precipitously rises in the sera following progesterone (P) exposure. The 34 kDa protein protects the fetal semi-allograft from immune surveillance by reducing cytoxicity of natural killer (NK) cells by stabilizing perforin granules. The parent 90 kDa form occupies a centrosomal position close to BRCA-1. PIBF can be found in most rapidly dividing cells. One study found an over-expression of the mRNA for the PIBF protein in all 29 leukemia cell lines tested. The P receptor antagonist mifepristone was found to down-regulate PIBF protein. Mifepristone provided significant palliative benefit to a large variety of spontaneous murine and human cancers. P could also be responsible for converting the 90 kDa parent form to a 34-36 kDa split variant in the cytoplasm which may be the immunosuppressive form in cancer cells. Alternatively, some P-like secretion by the tumor could influence gamma/delta T cells in the tumor microenvironment to secrete PIBF and possibly spill over to the sera. The aim of this study was to determine if there is any increase in serum PIBF in women with gynecologic cancer as opposed to controls. Serum was obtained from women about to have surgery for gynecologic problems including malignant and benign disorders. The samples would then be measured for PIBF using a new non-commercial enzyme linked immunoabsorbent assay (ELISA) for PIBF and serum progesterone. The PIBF levels (ng/mL) from lowest to highest in women with various gynecologic cancers (in all cases serum progesterone (P) <2ng/mL) were 10.06, 17.35, 32.59, 35.62, 54,7, and 57.17. The average serum PIBF was 34.6 ng/mL. There were 3 women with benign gynecologic tumors and the serum PIBF was 14.76, 15.7, and 36.64 their average serum PIBF was 22.5 ng/mL). There were 2 women with no tumors having gynecologic surgery and their serum PIBF levels (ng/mL) were 9.56 and 35.27 (with an average of 22.4 ng/mL). At least for gynecologic cancers if PIBF is conferring immune protection it is more likely operating through its intracytoplasmic presence rather than working through sera levels. In women or men exposed to exogenous or endogenous P for just 6 days it is not unusual to see sera PIBF rise to 300 to >800ng/mL. Citation Format: Jerome H. Check, Mojirayo Sarumi, Ann DiAntonio, Krystal Hunter, Gunda Simpkins, Marie Duroseau. A pilot study was initiated to determine if the immunomodulatory protein, the progesterone-induced blocking factor (PIBF), is present in higher quantity in the sera of patients with gynecologic cancer as compared to controls without cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4096. doi:10.1158/1538-7445.AM2014-4096

Exposure to paper mill effluent at a site in North Central Florida elicits molecular-level changes in gene expression indicative of progesterone and androgen exposure.

Endocrine disrupting compounds (EDCs) are chemicals that negatively impact endocrine system function, with effluent from paper mills one example of this class of chemicals. In Florida, female Eastern mosquitofish (Gambusia holbrooki) have been observed with male secondary sexual characteristics at three paper mill-impacted sites, indicative of EDC exposure, and are still found at one site on the Fenholloway River. The potential impacts that paper mill effluent exposure has on the G. holbrooki endocrine system and the stream ecosystem are unknown. The objective of this study was to use gene expression analysis to determine if exposure to an androgen receptor agonist was occurring and to couple this analysis with in vitro assays to evaluate the presence of androgen and progesterone receptor active chemicals in the Fenholloway River. Focused gene expression analyses of masculinized G. holbrooki from downstream of the Fenholloway River paper mill were indicative of androgen exposure, while genes related to reproduction indicated potential progesterone exposure. Hepatic microarray analysis revealed an increase in the expression of metabolic genes in Fenholloway River fish, with similarities in genes and biological processes compared to G. holbrooki exposed to androgens. Water samples collected downstream of the paper mill and at a reference site indicated that progesterone and androgen receptor active chemicals were present at both sites, which corroborates previous chemical analyses. Results indicate that G. holbrooki downstream of the Fenholloway River paper mill are impacted by a mixture of both androgens and progesterones. This research provides data on the mechanisms of how paper mill effluents in Florida are acting as endocrine disruptors.

Hormonal Changes During Menopause and the Impact on Fluid Regulation

Reproductive surgeries leave women more susceptible to postoperative hypervolemic hyponatremia because during this period women can retain water at an accelerated pace and much faster than they do sodium. This review proposes that estrogen and progestogen exposure play an important role in the increased risk of hyponatremia in menopausal women. Estrogen and progesterone exposure have important effects on both body fluid regulation and cardiovascular function and both of these reproductive hormones impact blood pressure responses to sodium loads. This article provides information on the effects of female reproductive hormones and hormone therapy (HT) on fluid regulation and cardiovascular function during menopause. Thirst- and fluid-regulating hormones respond to both osmotic and volume stimuli. Aging women maintain thirst sensitivity to osmotic stimuli but lose some thirst sensitivity to changes in central body fluid volume. Thus, older adults are more at risk of dehydration because they may replenish fluids at a slower rate. Estrogen therapy increases osmotic sensitivity for mechanisms to retain body water so may help menopausal women control body fluids and avoid dehydration. Some progestogens can mitigate estradiol effects on water and sodium retention through competition with aldosterone for the mineralocorticoid receptor and attenuating aldosterone-mediated sodium retention in the distal tubule. However, some progestogens can increase cardiovascular risks. Appropriate balance of these hormones within HT is important to avoid the negative consequences of body fluid and sodium retention, including edema and hypertension.

Endometrial progesterone resistance and PCOS

Polycystic ovary syndrome (PCOS) is a state of altered steroid hormone production and activity. Chronic estrogen exposure or lack of progesterone due to ovarian dysfunction can result in endometrial hyperplasia and carcinoma. A key contributor to our understanding of progesterone as a critical regulator for normal uterine function has been the elucidation of progesterone receptor (PR) expression, regulation, and signaling pathways. Several human studies indicate that PR-mediated signaling pathways in the nucleus are associated with progesterone resistance in women with PCOS. The aim of this review is to provide an overview of endometrial progesterone resistance in women with PCOS; to present the PR structure, its different isoforms, and their expression in the endometrium; to illustrate the possible regulation of PR and PR-mediated signaling in progesterone resistance in women with PCOS; and to discuss current clinical treatments for atypical endometrial hyperplasia and endometrial carcinoma in women with PCOS and accompanying progesterone resistance.

Abstract P1-05-02: COX-2 expression in normal mammary epithelium is estrogen responsive and predicts expression in DCIS and invasive ductal carcinoma

Abstract Background: Cyclooxygenase-2 (COX-2) overexpression is implicated in the poor prognosis of young women's breast cancer. Understanding the regulation of COX-2 expression in normal premenopausal breast tissue and its relationship to malignancy is anticipated to provide insight into COX-2 as a potential therapeutic target for young breast cancer patients. Methods: To investigate COX-2 regulation and expression, quantitative COX-2 immunohistochemistry was performed on adjacent normal and breast cancer tissues from 83 premenopausal women with known clinical reproductive histories as well as on rat mammary glands with distinct estradiol and progesterone exposures. To determine the stability of COX-2 expression over time, a small cohort of women with serial breast biopsies 2-3 weeks apart was evaluated. Results: COX-2 expression in normal adjacent breast tissue was predominantly epithelial, varied >40-fold between individual women, and was independent of proximity to tumor and tumor biology. COX-2 upregulation occurred in alveoli during pregnancy and with estradiol and progesterone exposure in the rat. Though these data demonstrate ovarian hormone regulation, COX-2 expression was relatively stable for each individual premenopausal woman over a 2-3 week assessment window. Furthermore, COX-2 expression levels in normal epithelium independently predicted COX-2 expression levels in tumors. Conclusions: COX-2 expression in the adjacent normal breast epithelium is highly variable across premenopausal women, and may be further modified by ovarian hormone exposure. Moreover, COX-2 expression in the normal breast independently predicts COX-2 expression in tumors, implicating women with high COX-2 expression in the normal breast epithelium as high risk patients who may benefit from COX-2 inhibitor therapy. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-05-02.

Progesterone exposure of seasonally anoestrous ewes alters the expression of angiogenic growth factors in preovulatory follicles

Small-dose, multiple injections of GnRH given to seasonally anoestrous ewes induce final stages of the preovulatory follicle development, but result in an high incidence of defective CL unless animals are primed with progesterone, which completely eliminates luteal dysfunction. Progesterone priming upregulates luteal vascularization; however, its effect on follicular angiogenesis is poorly understood. This study tested the hypothesis that progesterone priming of seasonally anoestrous ewes treated with dose multiple injections of GnRH eliminates defective luteal function by altering the expression of vascular endothelial growth factor (VEGF), VEGF receptor-2, angiopoietin (ANG)-1, ANG-2, and TIE-2 during early and late preovulatory follicle development. Ten seasonally anoestrous ewes were given 20 mg of progesterone im 3 days before the start of GnRH treatment; 10 other animals served as controls. Intravenous injections of 500 ng GnRH were given to all animals every 2 hours for 28 hours, followed at 30 hours with a 300-μg GnRH bolus injection to synchronize the preovulatory LH surge. Ovaries were collected at 24 and 46 hours after the start of GnRH treatment. Small (2–2.5 mm) and large (>2.5 mm) follicles were analyzed for protein and mRNA expression of the angiogenic factors using immunohistochemistry and in situ hybridization assays. Progesterone priming did not have an influence on angiogenic factor levels in small follicles. However, progesterone-primed animals showed significantly (P ≤ 0.05) higher levels of VEGF, VEGFR-2, ANG-1, and ANG-2 in large follicles compared with nonprimed ones. These data suggest that progesterone priming alters the expression of angiogenic factors in large preovulatory follicles, ensuring adequate luteal development and function.

Comparative breast cancer research, lessons from companion animals.

Comparative breast cancer research, lessons from companion animals.

The Demonstration that the Immunomodulatory Protein the Progesterone Induced Blocking Factor Significantly Rises in Males with Short Term Progesterone Exposure Provides New Insights Into the Immunology of Pregnancy

The Demonstration that the Immunomodulatory Protein the Progesterone Induced Blocking Factor Significantly Rises in Males with Short Term Progesterone Exposure Provides New Insights Into the Immunology of Pregnancy

Protocols with Different Time of Progesterone Exposure on Superestimulatory Response and Embryo Production of Locally Adapted Curraleiro Pé-Duro Cows

The purpose of this study was to evaluate embryo production and embryonic quality of locally adapted Curraleiro Pe-duro cows, using protocols with different progesterone exposure. Cows were divided in three groups: Control, P24 and P36. All cows had the estrus previously synchronized and in the fifth day of the estrus cycle, the cows of the groups P24 and P36 received an intravaginal progesterone device and estradiol benzoate. Starting from the ninth day of the cycle, all cows received eight decreasing doses of FSH and two doses of Dcloprostenol together with the two last doses of FSH. Treatments P24 and P36 had the progesterone device removed 24 and 36 hours after the first application of D-cloprostenol, respectively. All cows received lecireline in the thirteenth day, with the inseminations accomplished 12 and 24 hours later. There was no difference (P > 0.05) for superestimulatory response among treatments. The number of total structures was greater (P < 0.05) in P24 than in the Control and the number of viable structures was greater (P < 0.05) in both P24 and P36 than in the Control. The use of exogenous progesterone in superovulation protocols improved embryo production and quality of locally adapted Curraleiro Pe-duro cows.

If Progesterone Is Blamed for Breast Cancer Development, Why Are We Still Using Tamoxifen?

To the Editor: Breast cancer is the most commonly seen cancer in women and rates increase with advancing age [1]. Tamoxifen was found to be an effective drug in estrogen receptor positive breast cancer and it has been shown to be associated with prolonged survival [2]. In recent long term randomized population studies, breast cancer rates were higher in women under estrogen+progesterone therapy while there was no increase in breast cancer rate in group with estrogen only therapy [3,4]. Another controversy is increase rates of breast cancer in women with long term anovulatory cycles like polycystic ovary syndrome [5]. Additive effect or potentialization may be the mechanism under this controversy. We suggest to analyze effect of progesterone only therapy on breast cancer development. And also the effect of antiprogesterone therapy in breast cancer needs to be analyzed. Although a retrospective data showed no association between previous progesterone exposure and invasive breast cancer [6], we thought that women using subdermal implants for long term contraception are the best candidates to assess role of progesterone in breast cancer development and determine duration and dosage leading to cancer in a prospective manner. Effect of mifepristone on breast cell proliferation was analyzed and study concluded that the ability of mifepristone that block breast epithelial cell proliferation in premenopausal women may be beneficial [7]. Therefore tamoxifen may be combined with a safe drug mifepristone, a progesterone receptor antagonist, as an adjunctive therapy in hysterectomized women to determine efficacy of antiprogesterone therapy in breast cancer.

Non-genomic effects of progesterone on Rho kinase II in rat gastric smooth muscle cells

Various studies have shown that pregnancy is associated with gastrointestinal complaints that might result from disturbance of the normal contractile pattern of smooth muscle. Progesterone is an important steroid hormone, which plays a crucial role in female pregnancy. Progesterone affects muscle cells by genomic mechanisms, through nuclear receptors, and non-genomic mechanisms, through unidentified pathways. Non-genomic actions were defined as those occurring within 10 min of progesterone exposure. The aim of the present study was to investigate the non-genomic effect of progesterone on Rho kinase II activity in gastric smooth muscle. Single smooth muscle cells of the stomach obtained from Sprague Dawley rats were used. Dispersed gastric smooth muscle cells were treated with progesterone or acetylcholine (ACh) separately. Cells designated for progesterone treatment were incubated with 1 μM progesterone for 10 min. Rho kinase II expression and both basal and ACh-induced Rho kinase II activity were measured via specifically designed enzyme-linked immunosorbent assay (ELISA) and activity assay kits respectively in both control and progesterone-treated groups. Progesterone inhibited the ACh-induced, but not the basal, Rho kinase II activity in dispersed gastric smooth muscle cells without affecting its expression level. This study suggested that progesterone can rapidly affect the contractile activity of isolated gastric smooth muscle cells in rats via inhibition of the Rho kinase II pathway.

Activation of enteroendocrine membrane progesterone receptors promotes incretin secretion and improves glucose tolerance in mice.

Glucagon-like peptide-1 (GLP-1) secretion is classically regulated by ingested nutrients. To identify novel molecular targets controlling incretin secretion, we analyzed enteroendocrine cell pathways important for hormone biosynthesis and secretion. We demonstrate that progesterone increases GLP-1 secretion and extracellular signal–related kinase 1/2 (ERK1/2) phosphorylation in enteroendocrine GLUTag cells via mechanisms sensitive to the mitogen-activated protein kinase inhibitor U0126. The stimulatory effects of progesterone (P4) or the synthetic progestin R5020 on ERK1/2 phosphorylation were independent of the classical progesterone receptor antagonist RU486. Furthermore, a cell-impermeable BSA–progesterone conjugate rapidly increased ERK1/2 phosphorylation and GLP-1 secretion. Knockdown of the membrane progesterone receptors Paqr5 or Paqr7 in GLUTag cells eliminated the stimulatory effect of R5020 and progesterone on GLP-1 secretion. Enteral progesterone administration increased plasma levels of GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and insulin, and improved oral glucose tolerance in an RU486-insensitve manner in mice: however, systemic progesterone exposure did not improve glucose homeostasis. Unexpectedly, the glucoregulatory actions of enteral progesterone did not require classical incretin receptor signaling and were preserved in Glp1r−/− and Glp1r−/−:Gipr−/− mice. Intestine-restricted activation of membrane progesterone receptors may represent a novel approach for stimulation of incretin hormone secretion and control of glucose homeostasis.

Blood pressure and water regulation: understanding sex hormone effects within and between men and women

Cardiovascular disease remains the leading cause of death for both men and women. Hypertension is less prevalent in young women compared with young men, but menopausal women are at greater risk for hypertension compared with men of similar age. Despite these risks, women do not consistently receive first line treatment for the early stages of hypertension, and the greater morbidity in menopause reflects this neglect. This review focuses on ovarian hormone effects on the cardiovascular and water regulatory systems that are associated with blood pressure control in women. The study of ovarian hormones within young women is complex because these hormones fluctuate across the menstrual cycle, and these fluctuations can complicate conclusions regarding sex differences. To better isolate the effects of oestrogen and progesterone on the cardiovascular and water regulation systems, we developed a model to transiently suppress reproductive function followed by controlled hormone administration. Sex differences in autonomic regulation of blood pressure appear related to ovarian hormone exposure, and these hormonal differences contribute to sex differences in hypertension and orthostatic tolerance. Oestrogen and progesterone exposure are also associated with plasma volume expansion, and a leftward shift in the osmotic operating point for body fluid regulation. In young, healthy women, the shift in osmoregulation appears to have only a minor effect on overall body water balance. Our overarching conclusion is that ovarian hormone exposure is the important underlying factor contributing to differences in blood pressure and water regulation between women and men, and within women throughout the lifespan.