Progesterone

Progesterone is a critical hormone for the maintenance of pregnancy, menstrual cycle,  endometrium and functions with its receptor [1].
Progesterone plays an important role in establishing uterine receptivity for embryo implantation. Cooperated with nuclear progesterone receptor, progesterone could damper the action(s) of E2 and BPA on Egr1 expression [2]. When tested with mouse melanoma (B16F10) cells and human melanoma (BLM) cells, progesterone treatment could significantly inhibit mouse melanoma cell growth [3]. In MCF-7 cells, progesterone activated GLI-1 in RANKL dependent manner to regulate estrogen-induced mammary carcinogenesis [4].
When tested with rats (pretreated subcutaneous progesterone or peanut oil for 5 days beginning on pregnancy day 17 and control ones), progesterone (400 and 500 μg per day) treatment enhanced maternal behavior inhibited by opioidergic [1].
Progesterone also has been shown to exhibit neuroprotective effects via modulating the phosphorylation of Akt which plays pivotal role in promoting cell growth in the brain. To assess the effects of progesterone on Akt phosphorylation, when tested with closed-skull traumatic brain injury C57BL/6 mice, after progesterone treatment phosphorylation of Akt in hippocampus increased compared to traumatic brain injury vehicle [5]. When tested with female rats, progesterone treatment asymmetricly modulated the expression of GABA (A) receptor α4 subunit in the olfactory bulb [6].
References:
[1].    Cruz, A.M., M.H. Sukikara, and F.F. L, Late pregnancy progesterone treatment as a modulatory signal for postpartum behavior. Pharmacol Biochem Behav, 2014. 27(14): p. 00348-7.
[2].    Kim, H.R., et al., Egr1 is rapidly and transiently induced by estrogen and bisphenol A via activation of nuclear estrogen receptor-dependent ERK1/2 pathway in the uterus. Reprod Toxicol, 2014. 50: p. 60-7.
[3].    Ramaraj, P. and J.L. Cox, In vitro effect of progesterone on human melanoma (BLM) cell growth. Int J Clin Exp Med, 2014. 7(11): p. 3941-53.
[4].    Boopalan, T., et al., RANKL signaling promotes progesterone mediated estrogen induced mammary carcinogenesis. Cancer Sci, 2014. 21(10): p. 12571.
[5].    Garling, R.J., et al., Does progesterone show neuroprotective effects on traumatic brain injury through increasing phosphorylation of Akt in the hippocampus? Neural Regen Res, 2014. 9(21): p. 1891-6.
[6].    Arbo, B.D., et al., Asymmetric effects of low doses of progesterone on GABA(A) receptor alpha4 subunit protein expression in the olfactory bulb of female rats. Can J Physiol Pharmacol, 2014. 92(12): p. 1045-9.

Sex differences in the effect of progesterone after controlled cortical impact in adolescent mice: a preliminary study.[Pubmed:25280093]

J Neurosurg. 2014 Dec;121(6):1337-41.

OBJECT: While Progesterone has been well studied in experimental models of adult traumatic brain injury (TBI), it has not been evaluated in pediatric models. The study of promising interventions in pediatric TBI is important because children have the highest public health burden of such injuries. Therapies that are beneficial in adults may not necessarily be effective in the pediatric population. The purpose of this study was to evaluate whether Progesterone treatment improves outcomes in an experimental model of pediatric TBI. METHODS: The authors determined whether Progesterone administered after controlled cortical impact (CCI) improves functional and histopathological outcomes in 4-week-old mice. Both male and female mice (58 mice total) were included in this study, as the majority of prior studies have used only male and/or reproductively senescent females. Mice were randomized to treatment with Progesterone or vehicle and to CCI injury or sham injury. Motor (wire grip test) and memory (Morris water maze) testing were performed to determine the effect of Progesterone on TBI. Lesion volume was also assessed. RESULTS: Compared with their vehicle-treated counterparts, the Progesterone-treated CCI-injured male mice had improved motor performance (p < 0.001). In contrast, Progesterone-treated CCI-injured female mice had a worse performance than their vehicle-treated counterparts (p = 0.001). Progesterone treatment had no effect on spatial memory performance or lesion volume in injured male or female mice. CONCLUSIONS: These data suggest a sex-specific effect of Progesterone treatment after CCI in adolescent mice and could inform clinical trials in children.

Progesterone-induced stimulation of mammary tumorigenesis is due to the progesterone metabolite, 5alpha-dihydroprogesterone (5alphaP) and can be suppressed by the 5alpha-reductase inhibitor, finasteride.[Pubmed:25595041]

J Steroid Biochem Mol Biol. 2015 May;149:27-34.

Progesterone has long been linked to breast cancer but its actual role as a cancer promoter has remained in dispute. Previous in vitro studies have shown that Progesterone is converted to 5alpha-dihydroProgesterone (5alphaP) in breast tissue and human breast cell lines by the action of 5alpha-reductase, and that 5alphaP acts as a cancer-promoter hormone. Also studies with human breast cell lines in which the conversion of Progesterone to 5alphaP is blocked by a 5alpha-reductase inhibitor, have shown that the in vitro stimulation in cell proliferation with Progesterone treatments are not due to Progesterone itself but to the metabolite 5alphaP. No similar in vivo study has been previously reported. The objective of the current studies was to determine in an in vivo mouse model if the presumptive Progesterone-induced mammary tumorigenesis is due to the Progesterone metabolite, 5alphaP. BALB/c mice were challenged with C4HD murine mammary cells, which have been shown to form tumors when treated with Progesterone or the progestin, medroxyProgesterone acetate. Cells and mice were treated with various doses and combinations of Progesterone, 5alphaP and/or the 5alpha-reductase inhibitor, finasteride, and the effects on cell proliferation and induction and growth of tumors were monitored. Hormone levels in serum and tumors were measured by specific RIA and ELISA tests. Proliferation of C4HD cells and induction and growth of tumors was stimulated by treatment with either Progesterone or 5alphaP. The Progesterone-induced stimulation was blocked by finasteride and reinstated by concomitant treatment with 5alphaP. The 5alphaP-induced tumors expressed high levels of ER, PR and ErbB-2. Hormone measurements showed significantly higher levels of 5alphaP in serum from mice with tumors than from mice without tumors, regardless of treatments, and 5alphaP levels were significantly higher (about 4-fold) in tumors than in respective sera, while Progesterone levels did not differ between the compartments. The results indicate that the stimulation of C4HD tumor growth in BALB/c mice treated with Progesterone is due to the Progesterone metabolite 5alphaP formed at elevated levels in mammary cells as a result of the 5alpha-reductase action on Progesterone. The results provide the first in vivo demonstration that stimulation of breast cell tumorigenesis and tumor growth accompanying Progesterone treatment is due to the Progesterone metabolite 5alphaP, and that breast tumorigenesis can be blocked with the 5alpha-reductase inhibitor, finasteride.

Effects of exogenous progesterone on fetal nuchal translucency: an observational prospective study.[Pubmed:25305408]

Am J Obstet Gynecol. 2015 Mar;212(3):335.e1-7.

OBJECTIVE: Nuchal translucency (NT) seen ultrasonographically at 11-14 weeks' gestation is a sensitive marker for Down syndrome. Despite its important role for Down syndrome screening, its use is still considered controversial due to high false-positive rates. We speculated that Progesterone could lead to abnormal blood flow patterns and, subsequently, to increased NT. Our primary endpoint was to evaluate the effects of exogenous Progesterone on NT thickness compared to controls. The secondary endpoint was to evaluate these effects in a subgroup at low risk for fetal aneuploidies, identifying the strongest factors influencing NT variation. The tertiary endpoint was to evaluate, within the treatment group, if there is any difference in NT according to the type of Progesterone administered, route of administration, and dose regimen. STUDY DESIGN: All women who came to measure NT at 11-14 weeks' gestation (crown-rump length between 45-84 mm) were considered eligible. We divided patients into 2 groups: women receiving exogenous Progesterone and controls. Afterwards, 3 NT scans were performed for each case, and the largest value, accurate to 2 decimal points, was recorded. RESULTS: In all, 3716 women were enrolled and analyzed. In a crude analysis, NT (P < .05) increased in the exogenous Progesterone group. The same results were obtained in the low-risk group (P < .05). The factorial analysis of variance model confirmed a correlation between altered NT and gestational age (P < .0001) and Progesterone exposure (P < .05). The characteristics of treatment (route, formulation, dose) were examined separately and no statistically significant differences among the subgroups were observed. CONCLUSION: Exogenous Progesterone increases NT.

Progesterone-induced activation of membrane-bound progesterone receptors in murine macrophage cells.[Pubmed:25472814]

J Endocrinol. 2015 Feb;224(2):183-94.

Parturition is an inflammatory process mediated to a significant extent by macrophages. Progesterone (P4) maintains uterine quiescence in pregnancy, and a proposed functional withdrawal of P4 classically regulated by nuclear Progesterone receptors (nPRs) leads to labor. P4 can affect the functions of macrophages despite the reported lack of expression of nPRs in these immune cells. Therefore, in this study we investigated the effects of the activation of the putative membrane-associated PR on the function of macrophages (a key cell for parturition) and discuss the implications of these findings for pregnancy and parturition. In murine macrophage cells (RAW 264.7), activation of mPRs by P4 modified to be active only extracellularly by conjugation to BSA (P4BSA, 1.0x10(-7) mol/l) caused a pro-inflammatory shift in the mRNA expression profile, with significant upregulation of the expression of cyclooxygenase 2 (COX2 (Ptgs2)), Il1B, and Tnf and downregulation of membrane Progesterone receptor alpha (Paqr7) and oxytocin receptor (Oxtr). Pretreatment with PD98059, a MEK1/2 inhibitor, significantly reduced P4BSA-induced expression of mRNA of Il1B, Tnf, and Ptgs2. Inhibition of protein kinase A (PKA) by H89 blocked P4BSA-induced expression of Il1B and Tnf mRNA. P4BSA induced rapid phosphorylation of MEK1/2 and CREB (a downstream target of PKA). This phosphorylation was inhibited by pretreatment with PD98059 and H89, respectively, revealing that MEK1/2 and PKA are two of the components involved in mPR signaling. Taken together, these results indicate that changes in membrane Progesterone receptor alpha expression and signaling in macrophages are associated with the inflammatory responses; and that these changes might contribute to the functional withdrawal of P4 related to labor.

Progesterone-induced down-regulation of hormone sensitive lipase (Lipe) and up-regulation of G0/G1 switch 2 (G0s2) genes expression in inguinal adipose tissue of female rats is reflected by diminished rate of lipolysis.[Pubmed:25448749]

J Steroid Biochem Mol Biol. 2015 Mar;147:31-9.

Decreased lipolytic activity in adipose tissue may be one of the reasons behind excess accumulation of body fat during pregnancy. The aim of this study was to analyze the effect of Progesterone on the expression of: (a) Lipe (encoding hormone-sensitive lipase, HSL), (b) Pnpla2 (encoding adipose triglyceride lipase, ATGL), (c) abhydrolase domain containing 5 (Abhd5), and (d) G0/G1 switch 2 (G0s2) genes in white adipose tissue (WAT), as potential targets for Progesterone action during the course of pregnancy. Administration of Progesterone to female rats, which was reflected by approximately 2.5-fold increase in circulating Progesterone concentration, is associated with a decrease in Lipe gene expression in the inguinal WAT. The expression of Pnpla2 gene in all main fat depots of females and males remained unchanged after Progesterone administration. Administration of Progesterone resulted in an increase in the expression of Abhd5 gene (whose product increases ATGL activity) and G0s2 gene (whose product decreases ATGL activity) in the inguinal WAT of female rats. Mifepristone, a selective antagonist of Progesterone receptor, abolished the effect of Progesterone on Lipe, Abhd5 and G0s2 genes expression in the inguinal WAT. The decrease in Lipe and the increase in Abhd5 and G0s2 genes expression was associated with lower rate of stimulated lipolysis. Administration of Progesterone exerted no effect on Lipe, Abhd5 and G0s2 genes expression and stimulated lipolysis in the retroperitoneal WAT of females, as well as in the inguinal, epididymal and retroperitoneal WAT of males. In conclusion, our findings suggest that Progesterone decreases the rate of lipolysis in the inguinal WAT of female rats, inhibiting the activity of both ATGL (by stimulating synthesis of G0S2 - specific inhibitor of the enzyme) and HSL (due to inhibition of Lipe gene expression).

Roles for estrogen and progesterone in breast cancer prevention.[Pubmed:17381827]

Breast Cancer Res. 2007;9(2):102.

Prevention has long been the holy grail of breast cancer research. The significant reduction in breast cancer risk afforded by a full-term pregnancy early in life suggests the great potential of preventive strategies. In contrast to the risks associated with prolonged exposures, exogenous estrogen and Progesterone for short durations can mimic the protective effects of pregnancy in carcinogen-induced mammary tumor models. Rajkumar and coworkers have now demonstrated that these hormones protect mice from mammary tumors initiated by a spectrum of oncogenic alterations that are common in breast cancers. Although differences between rodent models and humans remain, the results reveal that exogenous estrogen and Progesterone potently inhibit tumorigenesis through multiple pathways and establish a foundation for strategies to prevent breast cancer.

Characterization of a new class of selective nonsteroidal progesterone receptor agonists.[Pubmed:15072922]

Steroids. 2004 Mar;69(3):201-17.

The identification of a new series of selective nonsteroidal Progesterone receptor (PR) agonists is reported. Using a high-throughput screening assay based on the measurement of transactivation of a mouse mammary tumor virus promoter-driven luciferase reporter (MMTV-Luc) in human breast cancer T47D cells, a benzimidazole-2-thione analog was identified. Compound 1 showed an apparent EC50 of 53 nM and efficacy of 93% with respect to Progesterone. It binds to PR with high affinity (Ki nM), but had no or very low affinity for other steroid hormone receptors. Structure-activity relationship studies of a series of benzimidazole-2-thione analogs revealed critical positions for high PR binding affinity and transactivation potency as well as receptor selectivity, as exemplified by 25. Compound 25 binds to human PR with high affinity (Ki nM) and had at least > 1000-fold selectivity for PR versus other steroid receptors. Molecular modeling studies suggested that these agonists overlap favorably with Progesterone in the ligand-binding domain of PR. In T47D cells, compound 25 acted as a full agonist in the MMTV-Luc reporter assay, as well as in the induction of endogenous alkaline phosphatase activity with apparent EC50 values of 4 and 9 nM, respectively. In the immature rat model, compound 25 provided a significant suppression of estrogen-induced endometrium hypertrophy as measured by luminal epithelial height. In contrast, compound 25 was inactive in the luteinizing hormone release assay in young ovariectomized rats. These benzimidazole-2-thione analogs constitute a new series of nonsteroidal PR agonists with an excellent steroid receptor selectivity profile. The differential activities observed in the in vivo progestogenic assays in rat models suggest that these analogs can act as selective PR modulators.