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Clinical Cancer Research : An Official... Mar 2023The presurgical window of opportunity trial (WOT) MIPRA provides evidence that neoadjuvant treatment with the progesterone receptor (PR) antagonist mifepristone (RU486)...
The presurgical window of opportunity trial (WOT) MIPRA provides evidence that neoadjuvant treatment with the progesterone receptor (PR) antagonist mifepristone (RU486) may benefit patients with estrogen receptor-positive (ER+) breast cancer characterized by a high ratio of PR-A versus PR-B isoform (>1.5), suggesting that PR may be targeted in a subset of patients. See related article by Elía et al., p. 866.
Topics: Humans; Female; Mifepristone; Receptors, Progesterone; Breast Neoplasms; Hormone Antagonists
PubMed: 36547665
DOI: 10.1158/1078-0432.CCR-22-3374 -
Expert Opinion on Emerging Drugs Dec 2023Endometriosis is an estrogen-dependent disease that gives rise to pelvic pain and infertility. Although estroprogestins and progestins currently stand as the first-line... (Review)
Review
INTRODUCTION
Endometriosis is an estrogen-dependent disease that gives rise to pelvic pain and infertility. Although estroprogestins and progestins currently stand as the first-line treatments for this condition, demonstrating efficacy in two-thirds of patients, a significant portion of individuals experience only partial relief or symptom recurrence following the cessation of these therapies. The coexistence of superficial, deep endometriosis, and ovarian endometriomas, as three distinct phenotypes with unique pathogenetic and molecular characteristics, may elucidate the current heterogeneous biological response to available therapy.
AREAS COVERED
The objective of this review is to furnish the reader with a comprehensive summary pertaining to phase II-III hormonal treatments for endometriosis.
EXPERT OPINION
Ongoing research endeavors are directed toward the development of novel hormonal options for this benign yet debilitating disease. Among them, oral GnRH antagonists emerge as a noteworthy option, furnishing rapid therapeutic onset without an initial flare-up; these drugs facilitate partial or complete estrogen suppression, and promote prompt ovarian function recovery upon discontinuation, effectively surmounting the limitations associated with previously employed GnRH agonists. Limited evidence supports the use of selective estrogen and progesterone receptor modulators. Consequently, further extensive clinical research is imperative to garner a more profound understanding of innovative targets for novel hormonal options.
Topics: Female; Humans; Endometriosis; Hormone Antagonists; Progestins; Estrogens; Gonadotropin-Releasing Hormone; Clinical Trials, Phase II as Topic
PubMed: 38099328
DOI: 10.1080/14728214.2023.2296080 -
Seminars in Reproductive Medicine May 2020There is no approved medical therapy for adenomyosis and limited evidence to guide treatments in part due to the complexity of nonhistologic diagnosis and the prevalence... (Review)
Review
There is no approved medical therapy for adenomyosis and limited evidence to guide treatments in part due to the complexity of nonhistologic diagnosis and the prevalence of concomitant gynecologic conditions. Most available evidence focuses on the treatment of heavy menstrual bleeding, painful menses, and pelvic pain. Data evaluating fertility outcomes, sexual function, and quality of life following treatment are lacking. Additionally, there is no disease-specific measure of quality of life for adenomyosis. The levonorgestrel-releasing intrauterine system appears to be the most effective first-line therapy based on efficacy compared with oral agents, maintenance of steady-state hormonal levels, and contraceptive benefit. In areas where it is marketed, the progestin dienogest appears superior to combined oral contraceptives. Long-acting gonadotropin-releasing hormone agonists are effective and should be considered second-line therapy but are limited by hypogonadal effects. Additional data regarding oral gonadotropin-releasing hormone antagonists are required. While aromatase inhibitors demonstrate improvement in heavy menstrual bleeding and pelvic pain, further research is needed to determine their role in the management of adenomyosis. Progesterone receptor modulators may have a role for this disease if released again to market with appropriate safety parameters. Finally, modulation of prolactin and/or oxytocin may provide novel nonsteroidal treatment options.
Topics: Adenomyosis; Dysmenorrhea; Female; Hormone Antagonists; Humans; Levonorgestrel; Menorrhagia; Nandrolone; Pain Measurement; Quality of Life
PubMed: 33124017
DOI: 10.1055/s-0040-1719016 -
Reproductive Biology and Endocrinology... Jan 2023Ovarian stimulation (OS) is one of the key factors in the success of in vitro fertilization-embryo transfer (IVF-ET), by enabling the recruitment of numerous healthy... (Review)
Review
Ovarian stimulation (OS) is one of the key factors in the success of in vitro fertilization-embryo transfer (IVF-ET), by enabling the recruitment of numerous healthy fertilizable oocytes and, thereby, multiple embryos. The Stop GnRH-agonist/GnRH-antagonist (GnRH-ag/GnRH-ant), which offers all the advantages of using long suppressive GnRH-ag, with GnRH-ant, is in my opinion a valuable addition to the armamentarium of OS protocols. It allows cycle programming, better follicular synchronization and offers successful outcome in a variety of challenging cases such as poor responders, Poseidon group 4 poor prognosis patients, those with elevated peak progesterone (P) serum levels, poor embryo quality or repeated IVF failures.
Topics: Pregnancy; Female; Humans; Fertilization in Vitro; Pregnancy Rate; Ovulation Induction; Gonadotropin-Releasing Hormone; Embryo Transfer; Hormone Antagonists; Retrospective Studies
PubMed: 36710334
DOI: 10.1186/s12958-023-01069-7 -
Frontiers in Endocrinology 2023To investigate the impact of the progesterone concentration on the human chorionic gonadotropin (hCG) trigger day on clinical outcomes with an antagonist protocol.
Impact of progesterone concentration on human chorionic gonadotropin trigger day on clinical outcomes with one top-quality cleavage-stage embryo or blastocyst transfer in fresh fertilization cycles.
OBJECTIVE
To investigate the impact of the progesterone concentration on the human chorionic gonadotropin (hCG) trigger day on clinical outcomes with an antagonist protocol.
METHODS
The retrospective cohort study included a total of 1,550 fresh autologous ART cycles with one top-quality embryo transfer. Multivariate regression analysis, curve fitting, and threshold effect analysis were performed.
RESULTS
A significant association was found between the progesterone concentration and clinical pregnancy rate (adjusted OR, 0.77; 95% CI, 0.62-0.97; P = 0.0234), especially in blastocyst transfer (adjusted OR, 0.56; 95% CI, 0.39-0.78; P = 0.0008). The association between the progesterone concentration and the ongoing pregnancy rate was insignificant. The clinical pregnancy rate showed a linear relationship with an increased progesterone concentration in cleavage-stage embryo transfer. In blastocyst transfer, as the progesterone concentration increased, the clinical and ongoing pregnancy rates showed a parabolic reverse-U curve; the curve initially increased before declining at high progesterone concentrations. The clinical pregnancy rate increased with a progesterone concentration up to 0.80 ng/mL rather than tended to be stable. The clinical pregnancy rate significantly decreased when the progesterone concentration was ≥0.80 ng/mL.
CONCLUSION
The progesterone concentration on the hCG trigger day exhibits a curvilinear relationship with pregnancy outcomes in blastocyst transfer cycles, and the optimal threshold of the progesterone concentration is 0.80 ng/mL.
Topics: Pregnancy; Female; Humans; Progesterone; Retrospective Studies; Fertilization in Vitro; Embryo Transfer; Chorionic Gonadotropin
PubMed: 37409225
DOI: 10.3389/fendo.2023.1085287 -
Endocrine Reviews Oct 2019Nuclear receptors (NRs) are transcription factors actively involved in many aspects of human physiology and pathology, serving as sensors of stimuli, master regulators... (Review)
Review
Nuclear receptors (NRs) are transcription factors actively involved in many aspects of human physiology and pathology, serving as sensors of stimuli, master regulators of downstream molecular events, and hubs governing complex gene regulatory networks. The importance of various members of the NR superfamily in cancer has led to substantial efforts to target them therapeutically. Notably, drugs that block the action of estrogen receptor (ER)α in patients with ERα+ breast cancer or the androgen receptor (AR) in patients with prostate cancer have provided remarkable improvements in survival. However, there is continuing need for novel drugs that target ERα or the AR owing to resistance to established drugs, and there are also promising opportunities for targeting other NRs in cancer. In this review, we provide an overview of NR-based drug discovery in cancer and related resistance mechanisms, focusing on novel strategies for targeting well-established NR targets, including ERα, the AR, the glucocorticoid receptor, and the progesterone receptor, as well as opportunities to target other NRs that are attracting interest in immuno-oncology, such as liver X receptors, retinoic acid-related orphan receptors, and farnesoid X receptors.
Topics: Animals; Breast Neoplasms; Cell Nucleus; Drug Discovery; Female; Humans; Male; Neoplasms; Prostatic Neoplasms; Receptors, Estrogen; Receptors, Glucocorticoid; Receptors, Progesterone; Receptors, Steroid
PubMed: 30869771
DOI: 10.1210/er.2018-00222 -
Pharmacological Research Feb 2020Endometriosis is a common gynecological disorder, which is treated surgically and/ or pharmacologically with an unmet clinical need for new therapeutics. A completed... (Review)
Review
Endometriosis is a common gynecological disorder, which is treated surgically and/ or pharmacologically with an unmet clinical need for new therapeutics. A completed phase I trial and a recent phase II trial that investigated the steroidal aldo-keto reductase 1C3 (AKR1C3) inhibitor BAY1128688 in endometriosis patients prompted this critical assessment on the role of AKR1C3 in endometriosis. This review includes an introduction to endometriosis with emphasis on the roles of prostaglandins and progesterone in its pathophysiology. This is followed by an overview of the major enzymatic activities and physiological functions of AKR1C3 and of the data published to date on the expression of AKR1C3 in endometriosis at the mRNA and protein levels. The review concludes with the rationale for using AKR1C3 inhibitors, a discussion of the effects of AKR1C3 inhibition on the pathophysiology of endometriosis and a brief overview of other drugs under clinical investigation for this indication.
Topics: Aldo-Keto Reductase Family 1 Member C3; Animals; Endometriosis; Endometrium; Female; Humans
PubMed: 31546014
DOI: 10.1016/j.phrs.2019.104446 -
International Journal of Molecular... Mar 2023NOD-like receptor protein 3 (NLRP3) may contribute to the growth and propagation of breast cancer (BC). The effect of estrogen receptor-α (ER-α), progesterone receptor...
NOD-like receptor protein 3 (NLRP3) may contribute to the growth and propagation of breast cancer (BC). The effect of estrogen receptor-α (ER-α), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) on NLRP3 activation in BC remains unknown. Additionally, our knowledge of the effect of blocking these receptors on NLRP3 expression is limited. We used GEPIA, UALCAN, and the Human Protein Atlas for transcriptomic profiling of NLRP3 in BC. Lipopolysaccharide (LPS) and adenosine 5'-triphosphate (ATP) were used to activate NLRP3 in luminal A MCF-7 and in TNBC MDA-MB-231 and HCC1806 cells. Tamoxifen (Tx), mifepristone (mife), and trastuzumab (Tmab) were used to block ER-α, PR, and HER2, respectively, on inflammasome activation in LPS-primed MCF7 cells. The transcript level of was correlated with ER-ɑ encoding gene in luminal A (ER-α, PR) and TNBC tumors. NLRP3 protein expression was higher in untreated and LPS/ATP-treated MDA-MB-231 cells than in MCF7 cells. LPS/ATP-mediated NLRP3 activation reduced cell proliferation and recovery of wound healing in both BC cell lines. LPS/ATP treatment prevented spheroid formation in MDA-MB-231 cells but did not affect MCF7. HGF, IL-3, IL-8, M-CSF, MCP-1, and SCGF-b cytokines were secreted in both MDA-MB-231 and MCF7 cells in response to LPS/ATP treatment. Tx (ER-α inhibition) promoted NLRP3 activation and increased migration and sphere formation after LPS treatment of MCF7 cells. Tx-mediated activation of NLRP3 was associated with increased secretion of IL-8 and SCGF-b compared to LPS-only-treated MCF7 cells. In contrast, Tmab (Her2 inhibition) had a limited effect on NLRP3 activation in LPS-treated MCF7 cells. Mife (PR inhibition) opposed NLRP3 activation in LPS-primed MCF7 cells. We have found that Tx increased the expression of NLRP3 in LPS-primed MCF7. These data suggest a link between blocking ER-α and activation of NLRP3, which was associated with increased aggressiveness of the ER-α BC cells.
Topics: Female; Humans; Adenosine Triphosphate; Breast Neoplasms; Interleukin-8; Lipopolysaccharides; MCF-7 Cells; NLR Family, Pyrin Domain-Containing 3 Protein; Tamoxifen; Estrogen Receptor alpha; Receptors, Progesterone; Receptor, ErbB-2; Estrogen Antagonists
PubMed: 36902278
DOI: 10.3390/ijms24054846 -
Journal of Nuclear Medicine : Official... Feb 2020Estrogen receptor (ER) and progesterone receptor (PR) are important prognostic and predictive biomarkers in breast cancer. PET using ER- and PR-specific radioligands... (Review)
Review
Estrogen receptor (ER) and progesterone receptor (PR) are important prognostic and predictive biomarkers in breast cancer. PET using ER- and PR-specific radioligands enables a whole-body, noninvasive assessment of receptor expression. Recent investigations of ER imaging with F-fluoroestradiol have focused on diagnosing ER-positive metastatic disease, optimizing ER-targeted drug dosage, and predicting endocrine therapy benefit. Studies of PR imaging with F-fluorofuranyl norprogesterone have investigated how imaging changes in PR expression as a downstream target of ER activation may reflect an early response to ER-targeted therapy. This focused review highlights recent achievements in preclinical and clinical imaging of ER and PR in breast cancer.
Topics: Breast Neoplasms; Diagnostic Imaging; Humans; Prognosis; Receptors, Estrogen; Receptors, Progesterone
PubMed: 31732674
DOI: 10.2967/jnumed.119.228858 -
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