-
Reproductive Sciences (Thousand Oaks,... Mar 2016Uterine leiomyoma are a common benign pelvic tumors composed of modified smooth muscle cells and a large amount of extracellular matrix (ECM). The proteoglycan...
Uterine leiomyoma are a common benign pelvic tumors composed of modified smooth muscle cells and a large amount of extracellular matrix (ECM). The proteoglycan composition of the leiomyoma ECM is thought to affect pathophysiology of the disease. To test this hypothesis, we examined the abundance (by immunoblotting) and expression (by quantitative real-time polymerase chain reaction) of the proteoglycans biglycan, decorin, and versican in leiomyoma and normal myometrium and determined whether expression is affected by steroid hormones and menstrual phase. Leiomyoma and normal myometrium were collected from women (n = 17) undergoing hysterectomy or myomectomy. In vitro studies were performed on immortalized leiomyoma (UtLM) and normal myometrial (hTERT-HM) cells with and without exposure to estradiol and progesterone. In leiomyoma tissue, abundance of decorin messenger RNA (mRNA) and protein were 2.6-fold and 1.4-fold lower, respectively, compared with normal myometrium. Abundance of versican mRNA was not different between matched samples, whereas versican protein was increased 1.8-fold in leiomyoma compared with myometrium. Decorin mRNA was 2.4-fold lower in secretory phase leiomyoma compared with proliferative phase tissue. In UtLM cells, progesterone decreased the abundance of decorin mRNA by 1.3-fold. Lower decorin expression in leiomyoma compared with myometrium may contribute to disease growth and progression. As decorin inhibits the activity of specific growth factors, its reduced level in the leiomyoma cell microenvironment may promote cell proliferation and ECM deposition. Our data suggest that decorin expression in leiomyoma is inhibited by progesterone, which may be a mechanism by which the ovarian steroids affect leiomyoma growth and disease progression.
Topics: Adult; Cell Line, Transformed; Cell Line, Tumor; Decorin; Estradiol; Female; Humans; Leiomyoma; Middle Aged; Myometrium; Progesterone; Promegestone; Proteoglycans; Uterine Neoplasms
PubMed: 26423601
DOI: 10.1177/1933719115607994 -
British Medical Journal (Clinical... Feb 1985
Topics: Abortifacient Agents, Steroidal; Abortion, Induced; Animals; Cushing Syndrome; Estrenes; Female; Humans; Labor, Induced; Menstruation; Mifepristone; Pregnancy; Progesterone; Rabbits
PubMed: 3918678
DOI: 10.1136/bmj.290.6468.580 -
Journal of Smooth Muscle Research =... 2013Various studies have shown that pregnancy is associated with gastrointestinal complaints that might result from disturbance of the normal contractile pattern of smooth...
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.
Topics: Acetylcholine; Animals; Cells, Cultured; Depression, Chemical; Male; Muscle Contraction; Muscle, Smooth; Progesterone; Rats; Stomach; rho-Associated Kinases
PubMed: 24133695
DOI: 10.1540/jsmr.49.55 -
The Journal of Clinical Endocrinology... Jan 2018Polycystic ovary syndrome (PCOS) and adolescent hyperandrogenism (HA) are characterized by rapid luteinizing hormone (LH) pulse frequency. This partly reflects impaired...
CONTEXT
Polycystic ovary syndrome (PCOS) and adolescent hyperandrogenism (HA) are characterized by rapid luteinizing hormone (LH) pulse frequency. This partly reflects impaired gonadotropin-releasing hormone pulse generator (hypothalamic) sensitivity to progesterone (P4) negative feedback. We assessed whether metformin may improve P4 sensitivity in adolescent HA, for which it is prescribed widely.
OBJECTIVE
To test the hypothesis that metformin improves hypothalamic P4 sensitivity in adolescent HA.
DESIGN
Nonrandomized, interventional trial.
SETTING
Academic clinical research unit.
PARTICIPANTS
Ten adolescent girls with HA.
INTERVENTION
The girls underwent LH sampling every 10 minutes for 11 hours, at study baseline and after 7 days of oral P4 and estradiol (E2). Participants then took metformin (1 g twice daily) for 9.4 to 13.7 weeks, after which participants again underwent frequent LH sampling before and after 7 days of oral P4 and E2 (while continuing metformin). Total and free testosterone (T) and fasting insulin were assessed at each admission. At admissions 1 and 3, 2-hour oral glucose tolerance tests were performed.
MAIN OUTCOME MEASURE
Metformin-related change in hypothalamic P4 sensitivity index [percent change in LH pulse frequency (before vs after P4 and E2) divided by day 7 P4 level].
RESULTS
Free T levels decreased by 29% with metformin (P = 0.0137). Measures of hyperinsulinemia and P4 sensitivity index did not significantly change with metformin use.
CONCLUSION
Short-term metformin use improved biochemical hyperandrogenemia, but did not improve hypothalamic sensitivity to P4 suppression, in adolescent girls.
Topics: Adolescent; Feedback, Physiological; Female; Follow-Up Studies; Glucose Tolerance Test; Humans; Hyperandrogenism; Hypoglycemic Agents; Insulin Resistance; Luteinizing Hormone; Metformin; Progesterone; Prognosis; Pulsatile Flow
PubMed: 29095983
DOI: 10.1210/jc.2017-02068 -
Nature Jul 2015Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-α (ERα) function and breast cancer prognosis. Here we show that PR is not merely an...
Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-α (ERα) function and breast cancer prognosis. Here we show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited oestrogen-mediated growth of ERα(+) cell line xenografts and primary ERα(+) breast tumour explants, and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PGR, the gene coding for PR, is a common feature in ERα(+) breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.
Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Chromatin; DNA Copy Number Variations; Disease Progression; Estrogen Receptor alpha; Estrogens; Female; Gene Expression Regulation, Neoplastic; Humans; Ligands; Mice; Progesterone; Protein Binding; Receptors, Progesterone; Transcription, Genetic; Xenograft Model Antitumor Assays
PubMed: 26153859
DOI: 10.1038/nature14583 -
Biochemical and Biophysical Research... Apr 1995This study investigated whether gonadal steroids modulate the expression of the cytokine Interleukin-1 receptor antagonist in monocytes. Human male peripheral monocytes...
This study investigated whether gonadal steroids modulate the expression of the cytokine Interleukin-1 receptor antagonist in monocytes. Human male peripheral monocytes were isolated and cultured in serum free media with serially diluted concentrations of estradiol and progesterone. mRNA expressions with increasing steroid concentrations were compared by reverse transcription-polymerase chain reaction for intracellular and secretory interleukin-1 receptor antagonist specific primers and glyceraldehyde 3-phosphate dehydrogenase primers. Monocyte expression of secretory Interleukin-1 receptor antagonist mRNA was significantly elevated in the presence of normal physiological levels of estradiol (10(-11) M) and progesterone (10(-8) M), while expression was suppressed by higher concentrations of steroids. Intracellular receptor antagonist was also detected. This study is the first to describe the dose related response of cytokine interleukin-1 receptor antagonist to gonadal steroids.
Topics: Base Sequence; Cells, Cultured; DNA Primers; Estradiol; Gene Expression Regulation; Glyceraldehyde-3-Phosphate Dehydrogenases; Humans; Interleukin 1 Receptor Antagonist Protein; Male; Molecular Sequence Data; Monocytes; Polymerase Chain Reaction; Progesterone; RNA, Messenger; Receptors, Interleukin-1; Sialoglycoproteins
PubMed: 7726847
DOI: 10.1006/bbrc.1995.1500 -
Revista Da Associacao Medica Brasileira... Sep 2019Melatonin is known for its effects on both the sleep and reproductive system of mammals. The latter has melatonin receptors type 1 and 2, which act to regulate, among...
Melatonin is known for its effects on both the sleep and reproductive system of mammals. The latter has melatonin receptors type 1 and 2, which act to regulate, among other things, cyclic AMP. Notwithstanding all the literature data, there is still no sound knowledge or a clear understanding of the hormone's action on the physiology of ovarian follicular cells. OBJECTIVE To review and evaluate studies about melatonin action on the ovarian granulosa/theca interna cells from the literature. METHODS The systematic review was carried out according to the PRISMA recommendations. The MEDLINE and Cochrane primary databases were consulted with the use of specific terms. There was no limitation on language or publication year. RESULTS Seven papers about melatonin action on granulosa cells were selected. The following can be attributed to the hormone's effects: a) progesterone increase in culture medium; b) increased estrogen production; c) antagonistic action on estrogen; d) improvement in cell quality resulting in improved embryo and higher pregnancy rates; e) improved cell proliferation via MAPK; f) reduction of free radicals. Nevertheless, there are contrarian papers reporting a reduction in progesterone production. Melatonin interferes in sex steroid production, boosting progesterone output. Such action may help improve oocyte quality.
Topics: Cells, Cultured; Female; Granulosa Cells; Humans; Melatonin; Oocytes; Ovarian Follicle; Pregnancy; Progesterone; Theca Cells
PubMed: 31531613
DOI: 10.1590/1806-9282.65.8.1122 -
American Journal of Physiology.... Nov 2009Progesterone (P4) inhibits the gastrointestinal muscle contraction by downregulating Galpha(q/11) proteins that mediate contraction, by upregulating Galpha(s) proteins...
Progesterone (P4) inhibits the gastrointestinal muscle contraction by downregulating Galpha(q/11) proteins that mediate contraction, by upregulating Galpha(s) proteins that mediate relaxation, and by altering the pattern of cyclooxygenase (COX) enzymes and prostaglandins. We aimed to examine whether P4 treatment of guinea pigs in vivo affects basal colon motility [basal motility index (MI)] by altering the levels and actions of PGF(2alpha) and PGE(2). Guinea pigs were treated with intramuscular (IM) P4 for 4 days. The BASAL MI, the PGF(2alpha)-induced contraction, and PGE(2)-induced inhibition of contraction were examined in muscle strips and cells. The levels of PGF(2alpha) and PGE(2) were measured by radioimmunoassay. Treatment with P4 reduced the basal MI, the levels of PGF(2alpha), and PGF(2alpha)-induced contraction. P4 increased PGE(2) levels, and PGE(2) induced relaxation. Pretreatment with IM RU-486 (10 mg/kg per day), a P4 receptor antagonist, 1 h before P4 blocked the actions of P4. The PGF(2alpha) antagonist Al-1180 abolished basal MI and PGF(2alpha)-induced contraction. N-ethylmaleimide, which blocks unoccupied membrane receptors, blocked Ach and VIP actions but had no effect on PGF(2alpha) and PGE(2) effects. A COX-1 inhibitor decreased and a COX-2 inhibitor increased PGF(2alpha) levels; GTPgammaS increased and GDPbetaS decreased the levels of PGF(2alpha). Galpha(q/11) protein antibodies (Abs) reduced PGF(2alpha) levels, and Galpha(i3) Abs blocked its motor actions. Galphas Abs increased PGF(2alpha) but decreased PGE(2) levels. We concluded that P4 decreases basal MI by reducing PGF(2alpha) levels caused by downregulation of Galpha(q/11) and that PGF(2alpha)-induced contraction was blocked by downregulating Galpha(i3). P4 also decreased the basal MI by increasing PGE(2) levels, and PGE(2) induced relaxation by upregulating Galpha(s) proteins.
Topics: Acetylcholine; Animals; Antibodies; Colon; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Ethylmaleimide; GTP-Binding Protein alpha Subunits, Gi-Go; GTP-Binding Protein alpha Subunits, Gq-G11; GTP-Binding Proteins; Gastrointestinal Motility; Guinea Pigs; In Vitro Techniques; Male; Mifepristone; Muscle Contraction; Muscle, Smooth; Myocytes, Smooth Muscle; Pertussis Toxin; Progesterone; Prostaglandins; Receptors, Prostaglandin; Vasoactive Intestinal Peptide
PubMed: 20501437
DOI: 10.1152/ajpgi.00184.2009 -
The Prostate Jun 2019Intratumoral steroidogenesis and its potential relevance in castration-resistant prostate cancer (CRPC) and in cytochrome P450, family 17, subfamily A, polypeptide 1...
BACKGROUND
Intratumoral steroidogenesis and its potential relevance in castration-resistant prostate cancer (CRPC) and in cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1)-inhibitor treated hormone-naïve and patients with CRPC are not well established. In this study, we tested if substrates for de novo steroidogenesis accumulating during CYP17A1 inhibition may drive cell growth in relevant preclinical models.
METHODS
PCa cell lines and their respective CRPC sublines were used to model CRPC in vitro. Precursor steroids pregnenolone (Preg) and progesterone (Prog) served as substrate for de novo steroid synthesis. TAK700 (orteronel), abiraterone, and small interfering RNA (siRNA) against CYP17A1 were used to block CYP17A1 enzyme activity. The antiandrogen RD162 was used to assess androgen receptor (AR) involvement. Cell growth was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. AR-target gene expression was quantified by reverse transcription polymerase chain reaction (RT-PCR). Nuclear import studies using cells with green fluorescent protein (GFP)-tagged AR were performed to assess the potential of precursor steroids to directly activate AR.
RESULTS
Preg and Prog stimulated cell proliferation and AR target gene expression in VCaP, DuCaP, LNCaP, and their respective CRPC sublines. The antiandrogen RD162, but not CYP17A1 inhibition with TAK700, abiraterone or siRNA, was able to block Preg- and Prog-induced proliferation. In contrast to TAK700, abiraterone also affected dihydrotestosterone-induced cell growth, indicating direct AR binding. Furthermore, Prog-induced AR translocation was not affected by treatment with TAK700 or abiraterone, while it was effectively blocked by the AR antagonist enzalutamide, further demonstrating the direct AR activation by Prog.
CONCLUSION
Activation of the AR by clinically relevant levels of Preg and Prog accumulating in abiraterone-treated patients may act as a driver for CRPC. These data provide a scientific rationale for combining CYP17A1 inhibitors with antiandrogens, particularly in patients with overexpressed or mutated-AR.
Topics: Abiraterone Acetate; Cell Growth Processes; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Male; Pregnenolone; Progesterone; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Signal Transduction; Steroid 17-alpha-Hydroxylase; Steroids
PubMed: 31017696
DOI: 10.1002/pros.23799 -
Stem Cell Research & Therapy Sep 2010The physiological signals that direct the division and differentiation of the zygote to form a blastocyst, and subsequent embryonic stem cell division and...
INTRODUCTION
The physiological signals that direct the division and differentiation of the zygote to form a blastocyst, and subsequent embryonic stem cell division and differentiation during early embryogenesis, are unknown. Although a number of growth factors, including the pregnancy-associated hormone human chorionic gonadotropin (hCG) are secreted by trophoblasts that lie adjacent to the embryoblast in the blastocyst, it is not known whether these growth factors directly signal human embryonic stem cells (hESCs).
METHODS
Here we used hESCs as a model of inner cell mass differentiation to examine the hormonal requirements for the formation of embryoid bodies (EB's; akin to blastulation) and neuroectodermal rosettes (akin to neurulation).
RESULTS
We found that hCG promotes the division of hESCs and their differentiation into EB's and neuroectodermal rosettes. Inhibition of luteinizing hormone/chorionic gonadotropin receptor (LHCGR) signaling suppresses hESC proliferation, an effect that is reversed by treatment with hCG. hCG treatment rapidly upregulates steroidogenic acute regulatory protein (StAR)-mediated cholesterol transport and the synthesis of progesterone (P4). hESCs express P4 receptor A, and treatment of hESC colonies with P4 induces neurulation, as demonstrated by the expression of nestin and the formation of columnar neuroectodermal cells that organize into neural tubelike rosettes. Suppression of P4 signaling by withdrawing P4 or treating with the P4-receptor antagonist RU-486 inhibits the differentiation of hESC colonies into EB's and rosettes.
CONCLUSIONS
Our findings indicate that hCG signaling via LHCGR on hESC promotes proliferation and differentiation during blastulation and neurulation. These findings suggest that trophoblastic hCG secretion and signaling to the adjacent embryoblast could be the commencement of trophic support by placental tissues in the growth and development of the human embryo.
Topics: Biological Transport; Cell Differentiation; Cell Proliferation; Cells, Cultured; Cholesterol; Chorionic Gonadotropin; Embryonic Stem Cells; Female; Hormone Antagonists; Humans; Mifepristone; Nestin; Neural Plate; Neurulation; Phosphoproteins; Pregnancy; Progesterone; Receptors, LH; Receptors, Progesterone; Rosette Formation; Signal Transduction
PubMed: 20836886
DOI: 10.1186/scrt28