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Current Opinion in Endocrinology,... Aug 2022This review is intended to provide perspective on the history of selective progesterone receptor modulators (SPRMs) and progesterone antagonists, their current... (Review)
Review
PURPOSE OF REVIEW
This review is intended to provide perspective on the history of selective progesterone receptor modulators (SPRMs) and progesterone antagonists, their current availability, therapeutic promise and safety concerns.
RECENT FINDINGS
Despite keen interest in synthesis of these compounds, only a handful have had clinical test results allowing for commercialization. Mifepristone is well tolerated and effective for single dose first trimester at-home pregnancy termination and is available in much of the world. Ulipristal acetate, at single doses, is well tolerated and effective for emergency contraception, with less availability. Chronic use of these agents has been associated with abnormal liver enzymes, and rarely, with hepatic failure; causality is not understood.
SUMMARY
SPRMs and progesterone antagonists have great therapeutic promise for use in other reproductive disorders, including breast cancer, endometriosis, adenomyosis, estrogen-free contraception and cervical ripening but require additional study. Alternative formulations, whether local (topical breast or intrauterine) or extended-release may reduce the incidence of liver function abnormalities and should be explored.
Topics: Female; Hormone Antagonists; Humans; Mifepristone; Pregnancy; Progesterone; Receptors, Progesterone; Reproductive Health
PubMed: 35776850
DOI: 10.1097/MED.0000000000000753 -
Nature Medicine Nov 2021Blockade of the cyclin-dependent kinase 4 and 6 pathway has been shown to be effective in the treatment of hormone receptor-positive advanced breast cancer (ABC). We... (Randomized Controlled Trial)
Randomized Controlled Trial
Blockade of the cyclin-dependent kinase 4 and 6 pathway has been shown to be effective in the treatment of hormone receptor-positive advanced breast cancer (ABC). We report the interim results of DAWNA-1 ( NCT03927456 ), a double-blind, randomized, phase 3 trial of dalpiciclib (a new cyclin-dependent kinase 4 and 6 inhibitor) plus fulvestrant in hormone receptor-positive, HER2-negative ABC with disease progression after endocrine therapy. A total of 361 patients were randomized 2:1 to receive dalpiciclib plus fulvestrant or placebo plus fulvestrant. The study met the primary end point, showing significantly prolonged investigator-assessed progression-free survival with dalpiciclib plus fulvestrant versus placebo plus fulvestrant (median = 15.7, 95% confidence interval (CI) = 11.1-not reached versus 7.2, 95% CI = 5.6-9.2 months; hazard ratio = 0.42, 95% CI = 0.31-0.58; one-sided P < 0.0001 (boundary was P ≤ 0.008)). The most common grade 3 or 4 adverse events with dalpiciclib plus fulvestrant were neutropenia (84.2%) and leukopenia (62.1%). The incidence of serious adverse events was 5.8% with dalpiciclib plus fulvestrant versus 6.7% with placebo plus fulvestrant. Our findings support dalpiciclib plus fulvestrant as a new treatment option for pretreated hormone receptor-positive, HER2-negative ABC.
Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Cell Proliferation; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Disease Progression; Double-Blind Method; Female; Fulvestrant; Humans; Middle Aged; Piperidines; Placebos; Progression-Free Survival; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone
PubMed: 34737452
DOI: 10.1038/s41591-021-01562-9 -
Therapeutische Umschau. Revue... 2021Endometriosis and Menopause Endometriosis is supposed to affect only women in their reproductive years, but endometriotic lesions can reactivate in menopause and cause...
Endometriosis and Menopause Endometriosis is supposed to affect only women in their reproductive years, but endometriotic lesions can reactivate in menopause and cause significant complaints in these patients. Altered needs and co-morbidities of the women request a different approach in therapy than in the younger ages. Reduction in chronic pain on the one hand and alleviation of climacteric symptoms, like hot-flushes and vaginal dryness, on the other hand, are main concerns to the physician in charge. Consequently, keeping the balance between the hypoestrogenic state, which is necessary to reduce activity and size of endometriotic lesions, and hormone replacement therapy (HRT) to relief menopausal complaints, depicts the key in treating these women. Progesterons, GnRH-analoga (with addback) and intrauterine devices depict the basic therapeutic strategy in perimenopausal women. In case of uncertain sonographic findings or intractable symptoms, a surgical approach (and histology) should be performed. Aromatase inhibitors, melatonin, oral GnRH-antagonists and ablation of the endometrium (in bare dysmenorrhea) represent promising alternatives to the established therapy. Requesting an HRT, it is important to add progesterone for at least two years, even in the patients with a prior hysterectomy to avoid a recurrence of residual lesions.
Topics: Endometriosis; Female; Humans; Menopause
PubMed: 34555977
DOI: 10.1024/0040-5930/a001295 -
Psychopharmacology Jan 2023The female menstrual or estrous cycle and its associated fluctuations in circulating estradiol (E2), progesterone, and other gonadal hormones alter orexin or hypocretin... (Review)
Review
RATIONALE
The female menstrual or estrous cycle and its associated fluctuations in circulating estradiol (E2), progesterone, and other gonadal hormones alter orexin or hypocretin peptide production and receptor activity. Depending on the estrous cycle phase, the transcription of prepro-orexin mRNA, post-translational modification of orexin peptide, and abundance of orexin receptors change in a brain region-specific manner. The most dramatic changes occur in the hypothalamus, which is considered the starting point of the hypothalamic-pituitary-gonadal axis as well as the hub of orexin-producing neurons. Thus, hypothalamus-regulated behaviors, including arousal, feeding, reward processing, and the stress response depend on coordinated efforts between E2, progesterone, and the orexin system. Given the rise of orexin therapeutics for various neuropsychiatric conditions including insomnia and affective disorders, it is important to delineate the behavioral outcomes of this drug class in both sexes, as well as within different time points of the female reproductive cycle.
OBJECTIVES
Summarize how the menstrual or estrous cycle affects orexin system functionality in animal models in order to predict how orexin pharmacotherapies exert varying degrees of behavioral effects across the dynamic hormonal milieu.
Topics: Male; Animals; Female; Orexins; Estradiol; Progesterone; Orexin Receptors; Peptides; Estrous Cycle
PubMed: 36571628
DOI: 10.1007/s00213-022-06296-1 -
Breast Cancer (Tokyo, Japan) Jul 2020Quadruple negative breast cancer (QNBC), lacking the expression of ER (estrogen receptor), PR (progesterone receptor), HER2 (human epidermal growth factor receptor-2)... (Review)
Review
Quadruple negative breast cancer (QNBC), lacking the expression of ER (estrogen receptor), PR (progesterone receptor), HER2 (human epidermal growth factor receptor-2) and AR (androgen receptor), was regarded as one breast cancer subtype with the worst prognosis. Recently, the molecular features of QNBC are not well understood. Different from AR-positive triple-negative breast cancer, QNBC is insensitive to conventional chemotherapeutic agents and has no efficient treatment targets. However, QNBC has been shown to express unique proteins that may be amenable to use in the development of targeted therapies. Here we reviewed the features of QNBC and proteins that may serve as effective targets for QNBC treatment, such as ACSL4, SKP2, immune checkpoint inhibitors, EGFR, MicroRNA signatures and Engrailed 1.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Coenzyme A Ligases; ErbB Receptors; Female; Gene Expression Regulation, Neoplastic; Homeodomain Proteins; Humans; MicroRNAs; Prognosis; Receptor, ErbB-2; Receptors, Androgen; Receptors, Estrogen; Receptors, Progesterone; S-Phase Kinase-Associated Proteins
PubMed: 31939077
DOI: 10.1007/s12282-020-01047-6 -
International Journal of Molecular... Oct 2021To evaluate the effectiveness of a new class of medical drugs, namely oral gonadotropin-releasing hormone (GnRH) antagonists, in the management of premenopausal women... (Review)
Review
To evaluate the effectiveness of a new class of medical drugs, namely oral gonadotropin-releasing hormone (GnRH) antagonists, in the management of premenopausal women with endometriosis-associated pelvic pain. We reviewed the most relevant papers ( = 27) on the efficacy of new medical alternatives (oral GnRH antagonists) as therapy for endometriosis. We first briefly summarized the concept of progesterone resistance and established that oral contraceptives and progestogens work well in two-thirds of women suffering from endometriosis. Since clinical evidence shows that estrogens play a critical role in the pathogenesis of the disease, lowering their levels with oral GnRH antagonists may well prove effective, especially in women who fail to respond to progestogens. There is a need for reliable long-term oral treatment capable of managing endometriosis symptoms, taking into consideration both the main symptoms and phenotype of the disease. Published studies reviewed and discussed here confirm the efficacy of GnRH antagonists. There is a place for GnRH antagonists in the management of symptomatic endometriosis. Novel algorithms that take into account the different phenotypes are proposed.
Topics: Endometriosis; Estradiol; Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Hormone Replacement Therapy; Humans; Infertility; Pain; Progestins
PubMed: 34768770
DOI: 10.3390/ijms222111342 -
Genome Medicine Jun 2022Breast cancer is a leading cause of death in premenopausal women. Progesterone drives expansion of luminal progenitor cells, leading to the development of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Breast cancer is a leading cause of death in premenopausal women. Progesterone drives expansion of luminal progenitor cells, leading to the development of poor-prognostic breast cancers. However, it is not known if antagonising progesterone can prevent breast cancers in humans. We suggest that targeting progesterone signalling could be a means of reducing features which are known to promote breast cancer formation.
METHODS
In healthy premenopausal women with and without a BRCA mutation we studied (i) estrogen and progesterone levels in saliva over an entire menstrual cycle (n = 20); (ii) cancer-free normal breast-tissue from a control population who had no family or personal history of breast cancer and equivalently from BRCA1/2 mutation carriers (n = 28); triple negative breast cancer (TNBC) biopsies and healthy breast tissue taken from sites surrounding the TNBC in the same individuals (n = 14); and biopsies of ER+ve/PR+ve stage T1-T2 cancers and healthy breast tissue taken from sites surrounding the cancer in the same individuals (n = 31); and (iii) DNA methylation and DNA mutations in normal breast tissue (before and after treatment) from clinical trials that assessed the potential preventative effects of vitamins and antiprogestins (mifepristone and ulipristal acetate; n = 44).
RESULTS
Daily levels of progesterone were higher throughout the menstrual cycle of BRCA1/2 mutation carriers, raising the prospect of targeting progesterone signalling as a means of cancer risk reduction in this population. Furthermore, breast field cancerization DNA methylation signatures reflective of (i) the mitotic age of normal breast epithelium and (ii) the proportion of luminal progenitor cells were increased in breast cancers, indicating that luminal progenitor cells with elevated replicative age are more prone to malignant transformation. The progesterone receptor antagonist mifepristone reduced both the mitotic age and the proportion of luminal progenitor cells in normal breast tissue of all control women and in 64% of BRCA1/2 mutation carriers. These findings were validated by an alternate progesterone receptor antagonist, ulipristal acetate, which yielded similar results. Importantly, mifepristone reduced both the TP53 mutation frequency as well as the number of TP53 mutations in mitotic-age-responders.
CONCLUSIONS
These data support the potential usage of antiprogestins for primary prevention of poor-prognostic breast cancers.
TRIAL REGISTRATION
Clinical trial 1 Mifepristone treatment prior to insertion of a levonorgestrel releasing intrauterine system for improved bleeding control - a randomized controlled trial, clinicaltrialsregister.eu, 2009-009014-40 ; registered on 20 July 2009. Clinical trial 2 The effect of a progesterone receptor modulator on breast tissue in women with BRCA1 and 2 mutations, clinicaltrials.gov, NCT01898312 ; registered on 07 May 2013. Clinical trial 3 A pilot prevention study of the effects of the anti- progestin Ulipristal Acetate (UA) on surrogate markers of breast cancer risk, clinicaltrialsregister.eu, 2015-001587-19 ; registered on 15 July 2015.
Topics: Breast Neoplasms; Epigenesis, Genetic; Female; Humans; Mifepristone; Mutation; Progesterone; Receptors, Estrogen; Receptors, Progesterone; Triple Negative Breast Neoplasms
PubMed: 35701800
DOI: 10.1186/s13073-022-01063-5 -
The Cochrane Database of Systematic... Oct 2020A frozen embryo transfer (FET) cycle is when one or more embryos (frozen during a previous treatment cycle) are thawed and transferred to the uterus. Some women undergo... (Meta-Analysis)
Meta-Analysis
BACKGROUND
A frozen embryo transfer (FET) cycle is when one or more embryos (frozen during a previous treatment cycle) are thawed and transferred to the uterus. Some women undergo fresh embryo transfer (ET) cycles with embryos derived from donated oocytes. In both situations, the endometrium is primed with oestrogen and progestogen in different doses and routes of administration.
OBJECTIVES
To evaluate the most effective endometrial preparation for women undergoing transfer with frozen embryos or embryos from donor oocytes with regard to the subsequent live birth rate (LBR).
SEARCH METHODS
The Cochrane Gynaecology and Fertility Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, LILACS, trials registers and abstracts of reproductive societies' meetings were searched in June 2020 together with reference checking and contact with study authors and experts in the field to identify additional studies.
SELECTION CRITERIA
Randomised controlled trials (RCTs) evaluating endometrial preparation in women undergoing fresh donor cycles and frozen embryo transfers.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures recommended by Cochrane. We analysed all available interventions versus placebo, no treatment, or between each other. The primary review outcome was live birth rate. Secondary outcomes were clinical and multiple pregnancy, miscarriage, cycle cancellation, endometrial thickness and adverse effects.
MAIN RESULTS
Thirty-one RCTs (5426 women) were included. Evidence was moderate to very low-quality: the main limitations were serious risk of bias due to poor reporting of methods, and serious imprecision. Stimulated versus programmed cycle We are uncertain whether a letrozole-stimulated cycle compared to a programmed cycle, for endometrial preparation, improves LBR (odds ratio (OR) 1.26, 95% confidence interval (CI) 0.49 to 3.26; 100 participants; one study; very low-quality evidence). Stimulating with follicle stimulating hormone (FSH), letrozole or clomiphene citrate may improve clinical pregnancy rate (CPR) (OR 1.63, 95% CI 1.12 to 2.38; 656 participants; five studies; I = 11%; low-quality evidence). We are uncertain if they reduce miscarriage rate (MR) (OR 0.79, 95% CI 0.36 to 1.71; 355 participants; three studies; I = 0%; very low-quality evidence). Endometrial thickness (ET) may be reduced with clomiphene citrate (mean difference(MD) -1.04, 95% CI -1.59 to -0.49; 92 participants; one study; low-quality evidence). Other outcomes were not reported. Natural versus programmed cycle We are uncertain of the effect from a natural versus programmed cycle for LBR (OR 0.97, 95% CI 0.74 to 1.28; 1285 participants; four studies; I = 0%; very low-quality evidence) and CPR (OR 0.79, 95% CI 0.62 to 1.01; 1249 participants; five studies; I = 60%; very low-quality evidence), while a natural cycle probably reduces the cycle cancellation rate (CCR) (OR 0.60, 95% CI 0.44 to 0.82; 734 participants; one study; moderate-quality evidence). We are uncertain of the effect on MR and ET. No study reported other outcomes. Transdermal versus oral oestrogens From low-quality evidence we are uncertain of the effect transdermal compared to oral oestrogens has on CPR (OR 0.86, 95% CI 0.59 to 1.25; 504 participants; three studies; I = 58%) or MR (OR 0.55, 95% CI 0.27 to 1.09; 414 participants; two studies; I = 0%). Other outcomes were not reported. Day of starting administration of progestogen When doing a fresh ET using donated oocytes in a synchronised cycle starting progestogen on the day of oocyte pick-up (OPU) or the day after OPU, in comparison with recipients that start progestogen the day prior to OPU, probably increases the CPR (OR 1.87, 95% CI 1.13 to 3.08; 282 participants; one study, moderate-quality evidence). We are uncertain of the effect on multiple pregnancy rate (MPR) or MR. It probably reduces the CCR (OR 0.28, 95% CI 0.11 to 0.74; 282 participants; one study; moderate-quality evidence). No study reported other outcomes. Gonadotropin-releasing hormone (GnRH) agonist versus control A cycle with GnRH agonist compared to without may improve LBR (OR 2.62, 95% CI 1.19 to 5.78; 234 participants; one study; low-quality evidence). From low-quality evidence we are uncertain of the effect on CPR (OR 1.08, 95% CI 0.82 to 1.43; 1289 participants; eight studies; I = 20%), MR (OR 0.85, 95% CI 0.36 to 2.00; 828 participants; four studies; I = 0%), CCR (OR 0.49, 95% CI 0.21 to 1.17; 530 participants; two studies; I = 0%) and ET (MD -0.08, 95% CI -0.33 to 0.16; 697 participants; four studies; I = 4%). No study reported other outcomes. Among different GnRH agonists From very low-quality evidence we are uncertain if cycles among different GnRH agonists improves CPR or MR. No study reported other outcomes. GnRH agonists versus GnRH antagonists GnRH antagonists compared to agonists probably improves CPR (OR 0.62, 95% CI 0.42 to 0.90; 473 participants; one study; moderate-quality evidence). We are uncertain of the effect on MR and MPR. No study reported other outcomes. Aspirin versus control From very low-quality evidence we are uncertain whether a cycle with aspirin versus without improves LBR, CPR, or ET. Steroids versus control From very low-quality evidence we are uncertain whether a cycle with steroids compared to without improves LBR, CPR or MR. No study reported other outcomes.
AUTHORS' CONCLUSIONS
There is insufficient evidence on the use of any particular intervention for endometrial preparation in women undergoing fresh donor cycles and frozen embryo transfers. In frozen embryo transfers, low-quality evidence showed that clinical pregnancy rates may be improved in a stimulated cycle compared to a programmed one, and we are uncertain of the effect when comparing a programmed cycle to a natural cycle. Cycle cancellation rates are probably reduced in a natural cycle. Although administering a GnRH agonist, compared to without, may improve live birth rates, clinical pregnancy rates will probably be improved in a GnRH antagonist cycle over an agonist cycle. In fresh synchronised oocyte donor cycles, the clinical pregnancy rate is probably improved and cycle cancellation rates are probably reduced when starting progestogen the day of or day after donor oocyte retrieval. Adequately powered studies are needed to evaluate each treatment more accurately.
Topics: Abortion, Spontaneous; Bias; Clomiphene; Cryopreservation; Drug Administration Schedule; Embryo Implantation; Embryo Transfer; Embryo, Mammalian; Endometrium; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Letrozole; Live Birth; Oocyte Donation; Pregnancy; Pregnancy Rate; Progesterone; Progestins; Randomized Controlled Trials as Topic
PubMed: 33112418
DOI: 10.1002/14651858.CD006359.pub3 -
The Journal of Clinical Endocrinology... Feb 2022Progesterone resistance, a known pathologic condition associated with a reduced cellular response to progesterone and heightened estrogen responses, appears to have a... (Observational Study)
Observational Study
CONTEXT
Progesterone resistance, a known pathologic condition associated with a reduced cellular response to progesterone and heightened estrogen responses, appears to have a normal physiologic role in mammalian reproduction. The molecular mechanism responsible for progesterone resistance in normal and abnormal endometrium remains unclear.
OBJECTIVE
To examine the roles of sirtuin-1 (SIRT1) in normal endometrium as well as endometrium associated with infertility and endometriosis, as an epigenetic modulator associated with progesterone resistance.
METHODS
SIRT1 expression was examined by Western blot, quantitative real-time polymerase chain reaction, and immunohistochemistry in mouse uterus and human endometrium. Mice with uterine specific Sirt1 overexpression were developed to examine SIRT1's role in endometrial function and endometriosis development. EX-527, a SIRT1 inhibitor, and SRT1720, a SIRT1 agonist, were also used to evaluate SIRT1 effect on endometriosis.
RESULTS
In normal healthy women, endometrial SIRT1 is expressed only during menses. SIRT1 was dramatically overexpressed in the endometrium from women with endometriosis in both the epithelium and stroma. In mice, SIRT1 is expressed at the time of implantation between day 4.5 and 5.5 of pregnancy. Overexpression of SIRT1 in the mouse uterus leads to subfertility due to implantation failure, decidualization defects and progesterone resistance. SIRT1 overexpression in endometriotic lesions promotes worsening endometriosis development. EX-527 significantly reduced the number of endometriotic lesions in the mouse endometriosis model.
CONCLUSIONS
SIRT1 expression and progesterone resistance appears to play roles in normal endometrial functions. Aberrant SIRT1 expression contributes to progesterone resistance and may participate in the pathophysiology of endometriosis. SIRT1 is a novel and targetable protein for the diagnosis as well as treatment of endometriosis and the associated infertility seen in this disease.
Topics: Adult; Animals; Carbazoles; Case-Control Studies; Disease Models, Animal; Embryo Implantation; Endometriosis; Endometrium; Epigenesis, Genetic; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Infertility, Female; Menstruation; Mice; Mice, Transgenic; Middle Aged; Progesterone; Sirtuin 1; Uterine Diseases; Young Adult
PubMed: 34665857
DOI: 10.1210/clinem/dgab753 -
Biochemical Pharmacology Jul 2020The progesterone receptor (PR) mediates progesterone regulation of female reproductive physiology, as well as gene transcription in non-reproductive tissues, such as... (Review)
Review
The progesterone receptor (PR) mediates progesterone regulation of female reproductive physiology, as well as gene transcription in non-reproductive tissues, such as brain, bone, lung and vasculature, in both women and men. An unusual property of progesterone is its high affinity for the mineralocorticoid receptor (MR), which regulates electrolyte transport in the kidney in humans and other terrestrial vertebrates. In humans, rats, alligators and frogs, progesterone antagonizes activation of the MR by aldosterone, the physiological mineralocorticoid in terrestrial vertebrates. In contrast, in elephant shark, ray-finned fishes and chickens, progesterone activates the MR. Interestingly, cartilaginous fishes and ray-finned fishes do not synthesize aldosterone, raising the question of which steroid(s) activate the MR in cartilaginous fishes and ray-finned fishes. The simpler synthesis of progesterone, compared to cortisol and other corticosteroids, makes progesterone a candidate physiological activator of the MR in elephant sharks and ray-finned fishes. Elephant shark and ray-finned fish MRs are expressed in diverse tissues, including heart, brain and lung, as well as, ovary and testis, two reproductive tissues that are targets for progesterone, which together suggests a multi-faceted physiological role for progesterone activation of the MR in elephant shark and ray-finned fish. The functional consequences of progesterone as an antagonist of some terrestrial vertebrate MRs and as an agonist of fish and chicken MRs are not fully understood. The physiological activities of progesterone through binding to vertebrate MRs merits further investigation.
Topics: Aldosterone; Alligators and Crocodiles; Amino Acid Sequence; Animals; Anura; Brain; Chickens; Female; Gene Expression Regulation; Humans; Hydrocortisone; Kidney; Ligands; Lung; Ovary; Phylogeny; Progesterone; Rats; Receptors, Mineralocorticoid; Sharks; Signal Transduction; Species Specificity
PubMed: 32305433
DOI: 10.1016/j.bcp.2020.113976