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International Journal of Molecular... Dec 2023C11-oxy C and C11-oxy C steroids have been identified as novel steroids but their function remains unclear. This study aimed to investigate the pre-receptor regulation...
C11-oxy C and C11-oxy C steroids have been identified as novel steroids but their function remains unclear. This study aimed to investigate the pre-receptor regulation of C11-oxy steroids by 11β-hydroxysteroid dehydrogenase (11βHSD) interconversion and potential agonist and antagonist activity associated with the androgen (AR) and progesterone receptors (PRA and PRB). Steroid conversions were investigated in transiently transfected HEK293 cells expressing 11βHSD1 and 11βHSD2, while CV1 cells were utilised for agonist and antagonist assays. The conversion of C11-hydroxy steroids to C11-oxo steroids by 11βHSD2 occurred more readily than the reverse reaction catalysed by 11βHSD1, while the interconversion of C11-oxy C steroids was more efficient than C11-oxy C steroids. Furthermore, 11-ketodihydrotestosterone (11KDHT), 11-ketotestosterone (11KT) and 11β-hydroxydihydrotestosterone (11OHDHT) were AR agonists, while only progestogens, 11β-hydroxyprogesterone (11βOHP4), 11β-hydroxydihydroprogesterone (11βOHDHP4), 11α-hydroxyprogesterone (11αOHP4), 11α-hydroxydihydroprogesterone (11αOHDHP4), 11-ketoprogesterone (11KP4), 5α-pregnan-17α-diol-3,11,20-trione (11KPdione) and 21-deoxycortisone (21dE) exhibited antagonist activity. C11-hydroxy C steroids, 11βOHP4, 11βOHDHP4 and 11αOHP4 exhibited PRA and PRB agonistic activity, while only C11-oxo steroids, 11KP4 and 11-ketoandrostanediol (11K3αdiol) demonstrated PRB agonism. While no steroids antagonised the PRA, 11OHA4, 11β-hydroxytestosterone (11OHT), 11KT and 11KDHT exhibited PRB antagonism. The regulatory role of 11βHSD isozymes impacting receptor activation is clear-C11-oxo androgens exhibit AR agonist activity; only C11-hydroxy progestogens exhibit PRA and PRB agonist activity. Regulation by the downstream metabolites of active C11-oxy steroids at the receptor level is apparent-C11-hydroxy and C11-oxo metabolites antagonize the AR and PRB, progestogens the former, androgens the latter. The findings highlight the intricate interplay between receptors and active as well as "inactive" C11-oxy steroids, suggesting novel regulatory tiers.
Topics: Humans; Progesterone; Receptors, Progesterone; Androgens; Progestins; HEK293 Cells; Steroids; Receptors, Steroid; 11-beta-Hydroxysteroid Dehydrogenases
PubMed: 38203272
DOI: 10.3390/ijms25010101 -
The Oncologist May 2024The optimal treatment approach for hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2-negative MBC) with aggressive characteristics remains... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The optimal treatment approach for hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2-negative MBC) with aggressive characteristics remains controversial, with lack of randomized trials comparing cyclin-dependent kinase (CDK)4/6-inhibitors (CDK4/6i) + endocrine therapy (ET) with chemotherapy + ET.
MATERIALS AND METHODS
We conducted an open-label randomized phase II trial (NCT03227328) to investigate whether chemotherapy + ET is superior to CDK4/6i + ET for HR+/HER2-negative MBC with aggressive features. PAM50 intrinsic subtypes (IS), immunological features, and gene expression were assessed on baseline samples.
RESULTS
Among 49 randomized patients (median follow-up: 35.2 months), median progression-free survival (mPFS) with chemotherapy + ET (11.2 months, 95% confidence interval [CI]: 7.7-15.4) was numerically shorter than mPFS (19.9 months, 95% CI: 9.0-30.6) with CDK4/6i + ET (hazard ratio: 1.41, 95% CI: 0.75-2.64). Basal-like tumors under CDK4/6i + ET exhibited worse PFS (mPFS: 11.4 months, 95% CI: 3.00-not reached [NR]) and overall survival (OS; mOS: 18.8 months, 95% CI: 18.8-NR) compared to other subtypes (mPFS: 20.7 months, 95% CI: 9.00-33.4; mOS: NR, 95% CI: 24.4-NR). In the chemotherapy arm, luminal A tumors showed poorer PFS (mPFS: 5.1 months, 95% CI: 2.7-NR) than other IS (mPFS: 13.2 months, 95% CI: 10.6-28.1). Genes/pathways involved in BC cell survival and proliferation were associated with worse outcomes, as opposite to most immune-related genes/signatures, especially in the CDK4/6i arm. CD24 was the only gene significantly associated with worse PFS in both arms. Tertiary lymphoid structures and higher tumor-infiltrating lymphocytes also showed favorable survival trends in the CDK4/6i arm.
CONCLUSIONS
The KENDO trial, although closed prematurely, adds further evidence supporting CDK4/6i + ET use in aggressive HR+/HER2-negative MBC instead of chemotherapy. PAM50 IS, genomic, and immunological features are promising biomarkers to personalize therapeutic choices.
Topics: Humans; Female; Breast Neoplasms; Cyclin-Dependent Kinase 4; Middle Aged; Cyclin-Dependent Kinase 6; Biomarkers, Tumor; Receptor, ErbB-2; Aged; Adult; Protein Kinase Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Receptors, Estrogen; Receptors, Progesterone
PubMed: 38175669
DOI: 10.1093/oncolo/oyad337 -
Addiction Neuroscience Dec 2023Opioid use and opioid use disorder are characterized by sex and gender differences, and some of these differences may be mediated by differences in the hormonal milieu...
Opioid use and opioid use disorder are characterized by sex and gender differences, and some of these differences may be mediated by differences in the hormonal milieu within and across individuals. This review focuses on the role of ovarian hormones, and particularly estradiol, on the endogenous mu opioid receptor system. There is an abundance of data indicating that estradiol influences the activity of endogenous mu opioid peptides, the activation of mu opioid receptors, and the internalization and desensitization of mu opioid receptors. These effects have functional consequences on behaviors mediated by endogenous mu opioid receptor activity and on sensitivity to mu opioid agonists and antagonists. Recent behavioral data suggest these consequences extend to mu opioid reward, and preclinical studies report that estradiol decreases self-administration of mu opioid receptor agonists across a range of experimental conditions. Data collected in human laboratory studies suggest that estradiol may have functionally similar effects in clinical populations, and thus estrogen receptors may be a potential target in the development of novel therapeutics. This review summarizes data from cellular assays to clinical trials to explore how estradiol influences mu opioid receptor activity, as well as potential ways in which estrogen receptors may be targeted to address the problems of opioid use.
PubMed: 38155959
DOI: 10.1016/j.addicn.2023.100139 -
Frontiers in Pharmacology 2023Preterm birth is the leading cause of infant morbidity and mortality. There has been an interest in developing prostaglandin F (PGF) antagonists as a new treatment for...
Preterm birth is the leading cause of infant morbidity and mortality. There has been an interest in developing prostaglandin F (PGF) antagonists as a new treatment for preterm birth, although much of the rationale for their use is based on studies in rodents where PGF initiates labour by regressing the corpus luteum and reducing systemic progesterone concentrations. How PGF antagonism would act in humans who do not have a fall in systemic progesterone remains unclear. One possibility, in addition to an acute stimulation of contractions, is a direct alteration of the myometrial smooth muscle cell state towards a pro-labour phenotype. In this study, we developed an immortalised myometrial cell line, MYLA, derived from myometrial tissue obtained from a pregnant, non-labouring patient, as well as a novel class of PGF receptor (FP) antagonist. We verified the functionality of the cell line by stimulation with PGF, resulting in Gα-specific coupling and Ca release, which were inhibited by FP antagonism. Compared to four published FP receptor antagonists, the novel FP antagonist N582707 was the most potent compound [F 7.67 ± 0.63 (IC 21.26 nM), AUC 7.30 ± 0.32 (IC 50.43 nM), and frequency of Ca oscillations 7.66 ± 0.41 (IC 22.15 nM)]. RNA-sequencing of the MYLA cell line at 1, 3, 6, 12, 24, and 48 h post PGF treatment revealed a transforming phenotype from a fibroblastic to smooth muscle mRNA profile. PGF treatment increased the expression of , , and as well as the pro-labour genes , , and , which were inhibited by FP antagonism. Concomitant with the inhibition of a smooth muscle, pro-labour transition, FP antagonism increased the expression of the fibroblast marker genes , , and . Our findings suggest that in addition to the well-described acute contractile effect, PGF transforms myometrial smooth muscle cells from a myofibroblast to a smooth muscle, pro-labour-like state and that the novel compound N582707 has the potential for prophylactic use in preterm labour management beyond its use as an acute tocolytic drug.
PubMed: 38155905
DOI: 10.3389/fphar.2023.1285779 -
Frontiers in Pharmacology 2023Progesterone has been shown to have neuroprotective capabilities against a wide range of nervous system injuries, however there are negative clinical studies that have...
Progesterone has been shown to have neuroprotective capabilities against a wide range of nervous system injuries, however there are negative clinical studies that have failed to demonstrate positive effects of progesterone therapy. Specifically, we looked into whether progesterone receptors or its metabolizing enzymes, cytochrome P450c17 and 5α-reductase, are involved in the effects of progesterone on neuropathic pain after chronic constriction injury (CCI) of the sciatic nerve in mice. Intrathecal progesterone administration during the induction phase of chronic pain enhanced mechanical allodynia development and spinal glial fibrillary acidic protein (GFAP) expression, and this enhancement was inhibited by administration of ketoconazole, a P450c17 inhibitor, but not finasteride, a 5α-reductase inhibitor. Furthermore, phospho-serine levels of P450c17 in the spinal cord were elevated on day 1 after CCI operation, but not on day 17. In contrast, intrathecal progesterone administration during the maintenance phase of chronic pain decreased the acquired pain and elevated GFAP expression; this inhibition was restored by finasteride administration, but not by ketoconazole. The modification of mechanical allodynia brought on by progesterone in CCI mice was unaffected by the administration of mifepristone, a progesterone receptor antagonist. Collectively, these findings imply that progesterone suppresses spinal astrocyte activation via 5α-reductase activity during the maintenance phase of chronic pain and has an analgesic impact on the mechanical allodynia associated with the growing neuropathy. Progesterone, however, stimulates spinal astrocytes during the induction stage of peripheral neuropathy and boosts the allodynic impact caused by CCI through early spinal P450c17 activation.
PubMed: 38152690
DOI: 10.3389/fphar.2023.1253901 -
BMC Pharmacology & Toxicology Dec 2023Feminizing gender-affirming hormone therapy (GAHT) for transgender individuals traditionally includes estradiol and androgen deprivation. Research has demonstrated that... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Feminizing gender-affirming hormone therapy (GAHT) for transgender individuals traditionally includes estradiol and androgen deprivation. Research has demonstrated that breast size as a result of GAHT in transgender women is often limited. Therefore, transgender women often choose to undergo breast augmentation surgery. Progesterone is important for breast development in cisgender women during puberty. A potential role for progesterone in breast development in transgender women has not been investigated in a randomized controlled experimental set-up. The primary objective of this study is to explore the effects on breast volume of addition of oral progesterone to GAHT with estradiol in transgender women after vaginoplasty or orchiectomy. Secondary objectives include assessment of safety, satisfaction, mood, sleep and sexual pleasure.
METHODS
This is a non-blinded, non-placebo, randomized controlled trial using a factorial design in adult transgender individuals assigned male sex at birth who have undergone GAHT for at least one year and underwent vaginoplasty or orchiectomy. The study design allows for rapid assessment of potential synergistic effects of various dose combinations of estradiol and progesterone on breast volume change: Ninety participants will be randomized into six groups of 15 subjects each, receiving either the baseline dose of estradiol, the baseline dose of estradiol and progesterone 200 mg daily, the baseline dose of estradiol and progesterone 400 mg daily, twice the baseline dose of estradiol, twice the baseline dose of estradiol and progesterone 200 mg daily or twice the baseline dose of estradiol and progesterone 400 mg daily, all for a duration of 12 months. The main study parameters include changes in breast volume as determined by 3D measurements. Participants will be followed-up with laboratory testing including serum progesterone concentrations as well as surveys for satisfaction, mood, sleep quality and sexual pleasure.
DISCUSSION
This study will indicate whether progesterone is safe and of additional value with regard to breast volume change in transgender individuals receiving feminizing GAHT. The results of this study will be useful for innovation of feminizing GAHT.
TRIAL REGISTRATION
WHO International Clinical Trials Registry Platform: EUCTR2020-001952-16-NL; date of registration: 12 December 2020 https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2020-001952-16-NL .
Topics: Adult; Humans; Male; Androgen Antagonists; Estradiol; Progesterone; Transgender Persons; Female
PubMed: 38124194
DOI: 10.1186/s40360-023-00724-4 -
Oncology Letters Jan 2024Breast cancer expressing the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) is known as triple-positive (TPBC)....
Breast cancer expressing the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) is known as triple-positive (TPBC). TPBC represents 9-11% of breast cancer cases worldwide and is a heterogeneous subtype. Notably, TPBC presents a therapeutic challenge due to the crosstalk between the hormonal (ER and PR) and HER2 pathways. Patients with TPBC are treated with trastuzumab (TTZ); however, several patients treated with TTZ tend to relapse. The present study aimed to investigate the effect of the PR on inhibitory effect of TTZ on cell viability. BT474 cells (a model of TPBC) and BT474 PR-silenced cells were treated with either TTZ, progesterone (Pg), the PR antagonist mifepristone (RU486) or estradiol (E2) alone or in combination for 144 h (6 days). Cell viability assays and western blotting were subsequently performed. The results showed that Pg and E2 interfered with the inhibitory effect of TTZ on cell viability and this effect was potentiated when both hormones were combined. Pg was revealed to act through the PR, mainly activating the PR isoform B (PR-B) and inducing the protein expression levels of CDK4 and cyclin D1; however, it did not reactivate the HER2/Akt pathway. By contrast, E2 was able to increase PR isoform A (PR-A) expression, which was inhibited by Pg. Notably, in most of the experiments, RU486 did not antagonize the effects of Pg. In conclusion, Pg and E2 may interfere with the inhibitory effect of TTZ on cell viability through PR-B activation and PR-A inactivation.
PubMed: 38034484
DOI: 10.3892/ol.2023.14152 -
Frontiers in Endocrinology 2023The delayed-start gonadotropin-releasing hormone antagonist protocol seems effective for patients who are poor ovarian responders, but there are insufficient data on...
Original delayed-start ovarian stimulation protocol with a gonadotropin-releasing hormone antagonist, medroxyprogesterone acetate, and high-dose gonadotropin for poor responders and patients with poor-quality embryos.
INTRODUCTION
The delayed-start gonadotropin-releasing hormone antagonist protocol seems effective for patients who are poor ovarian responders, but there are insufficient data on whether it is also effective for patients with poor-quality embryos and low rates of good blastocyst formation. Specifically, the effectiveness of delayed-start gonadotropin-releasing hormone antagonists with progesterone has not been adequately investigated. Therefore, we compared the efficacy of the original delayed-start gonadotropin-releasing hormone antagonist protocol using medroxyprogesterone acetate (MPA) and high-dose gonadotropin in patients with poor ovarian response.
METHODS
Overall, 156 patients with recurrent assisted reproductive technology failure who underwent the original protocol were included. They received cetrorelix acetate (3 mg) and MPA (10 mg) on cycle day 3, and high-dose gonadotropin was initiated on day 11. When the leading follicle reached 14 mm, ganirelix acetate (0.25 mg) was administered until the trigger day. The number of oocytes retrieved, metaphase II (MII) oocytes, two pronuclear (2PN) zygotes, and good blastocysts and live birth rates were compared between the previous (Cycle A) and original (Cycle B) cycles in three groups (Group A, all patients; Group B, poor responders; and Group C, patients with poor-quality embryos).
RESULTS
In Group A (n=156), the number of MII oocytes (3.6 ± 3.3 versus 4.5 ± 3.6), 2PN zygotes (2.8 ± 2.9 versus 3.8 ± 3.1), good blastocysts (0.5 ± 0.9 versus 1.2 ± 1.6), and live birth rates (0.6 versus 24.4) significantly increased in Cycle B. Similar results were obtained in Group B (n=83; 2PN zygotes [1.7 ± 1.7 versus 2.3 ± 1.8], good blastocysts [0.4 ± 0.7 versus 0.9 ± 1.3], live birth rates [0 versus 18.1]) and Group C (n=73; MII oocytes [5.1 ± 3.8 versus 6.6 ± 4.0], 2PN zygotes [4.0 ± 3.4 versus 5.4 ± 3.4], good blastocysts [0.7 ± 1.1 versus 1.6 ± 1.9], and live birth rates [1.4 versus 31.5]).
CONCLUSION
This original protocol increased the number of MII oocytes retrieved, 2PN zygotes, good blastocysts, and live birth rates in both poor responders and in patients with poor-quality embryos.
Topics: Pregnancy; Female; Humans; Medroxyprogesterone Acetate; Pregnancy Rate; Gonadotropins; Gonadotropin-Releasing Hormone; Ovulation Induction; Hormone Antagonists
PubMed: 38027155
DOI: 10.3389/fendo.2023.1277873 -
Immunity, Inflammation and Disease Nov 2023Coronavirus disease 2019 (COVID-19) is a pandemic disease caused by severe acute respiratory syndrome CoV type 2 (SARS-CoV-2). COVID-19 is higher in men than women and... (Review)
Review
BACKGROUND
Coronavirus disease 2019 (COVID-19) is a pandemic disease caused by severe acute respiratory syndrome CoV type 2 (SARS-CoV-2). COVID-19 is higher in men than women and sex hormones have immune-modulator effects during different viral infections, including SARS-CoV-2 infection. One of the essential sex hormones is progesterone (P4).
AIMS
This review aimed to reveal the association between P4 and Covid-19.
RESULTS AND DISCUSSION
The possible role of P4 in COVID-19 could be beneficial through the modulation of inflammatory signaling pathways, induction of the release of anti-inflammatory cytokines, and inhibition release of pro-inflammatory cytokines. P4 stimulates skew of naïve T cells from inflammatory Th1 toward anti-inflammatory Th2 with activation release of anti-inflammatory cytokines, and activation of regulatory T cells (Treg) with decreased interferon-gamma production that increased during SARS-CoV-2 infection. In addition, P4 is regarded as a potent antagonist of mineralocorticoid receptor (MR), it could reduce MRs that were activated by stimulated aldosterone from high AngII during SARS-CoV-2. P4 active metabolite allopregnanolone is regarded as a neurosteroid that acts as a positive modulator of γ-aminobutyric acid (GABA ) so it may reduce neuropsychiatric manifestations and dysautonomia in COVID-19 patients.
CONCLUSION
Taken together, the anti-inflammatory and immunomodulatory properties of P4 may improve central and peripheral complications in COVID-19.
Topics: Male; Humans; Female; COVID-19; Progesterone; SARS-CoV-2; Cytokines; Anti-Inflammatory Agents
PubMed: 38018575
DOI: 10.1002/iid3.1100 -
Endocrine-related Cancer Feb 2024Progesterone receptors (PRs) are biomarkers used as prognostic and predictive factors in breast cancer, but they are still not used as therapeutic targets. We have...
Progesterone receptors (PRs) are biomarkers used as prognostic and predictive factors in breast cancer, but they are still not used as therapeutic targets. We have proposed that the ratio between PR isoforms A and B (PRA and PRB) predicts antiprogestin responsiveness. The MIPRA trial confirmed the benefit of 200 mg mifepristone, administered to patients with tumors with a high PRA/PRB ratio, but dose-ranging has not been conducted. The aim of this study was to establish the plasma mifepristone levels of patients from the MIPRA trial, along with the resultant steroid profiles, and compare these with those observed in mifepristone-treated mice using therapeutic schemes able to induce the regression of experimental mammary carcinomas with high PRA/PRB ratios: 6 mg pellets implanted subcutaneously, or daily doses of 12 mg/kg body weight. The plasma levels of mifepristone and other 19 plasma steroids were measured by liquid chromatography-tandem mass spectometry. In mifepristone-treated mice, plasma levels were lower than those registered in mifepristone-treated patients (i.e. day 7 after treatment initiation, pellet-treated mice: 8.4 ± 3.9 ng/mL; mifepristone-treated patients: 300.3 ± 31.7 ng/mL (mean ± s.d.; P < 0.001)). The increase in corticoid related steroids observed in patients was not observed in mifepristone-treated mice. The increase in progesterone levels was the most significant side effect detected in mifepristone-treated mice after 14 or 21 days of treatment, probably due to an ovarian compensatory effect not observed in postmenopausal patients. We conclude that in future clinical trials using mifepristone, the possibility of lowering the standard daily dose of 200 mg should be considered.
Topics: Humans; Mice; Animals; Female; Mifepristone; Breast Neoplasms; Receptors, Progesterone; Hormone Antagonists; Prognosis
PubMed: 37962553
DOI: 10.1530/ERC-23-0238