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Endocrine Reviews Nov 2023Ovarian cancer (OC) represents a collection of rare but lethal gynecologic cancers where the difficulty of early detection due to an often-subtle range of abdominal...
Ovarian cancer (OC) represents a collection of rare but lethal gynecologic cancers where the difficulty of early detection due to an often-subtle range of abdominal symptoms contributes to high fatality rates. With the exception of BRCA1/2 mutation carriers, OC most often manifests as a post-menopausal disease, a time in which the ovaries regress and circulating reproductive hormones diminish. Progesterone is thought to be a "protective" hormone that counters the proliferative actions of estrogen, as can be observed in the uterus or breast. Like other steroid hormone receptor family members, the transcriptional activity of the nuclear progesterone receptor (nPR) may be ligand dependent or independent and is fully integrated with other ubiquitous cell signaling pathways often altered in cancers. Emerging evidence in OC models challenges the singular protective role of progesterone/nPR. Herein, we integrate the historical perspective of progesterone on OC development and progression with exciting new research findings and critical interpretations to help paint a broader picture of the role of progesterone and nPR signaling in OC. We hope to alleviate some of the controversy around the role of progesterone and give insight into the importance of nPR actions in disease progression. A new perspective on the role of progesterone and nPR signaling integration will raise awareness to the complexity of nPRs and nPR-driven gene regulation in OC, help to reveal novel biomarkers, and lend critical knowledge for the development of better therapeutic strategies.
Topics: Female; Humans; Progesterone; BRCA1 Protein; BRCA2 Protein; Receptors, Progesterone; Ovarian Neoplasms; Estrogens; Breast Neoplasms
PubMed: 37261958
DOI: 10.1210/endrev/bnad018 -
Prostaglandins & Other Lipid Mediators Oct 2023The antitumor agent cisplatin and steroid hormone progesterone separate and combined action on content of total phospholipids and their individual classes in nuclei from... (Review)
Review
The antitumor agent cisplatin and steroid hormone progesterone separate and combined action on content of total phospholipids and their individual classes in nuclei from rat brain cells were investigated. Cisplatin and progesterone exhibit their own characteristic properties, when used separately. Cisplatin reduces, and progesterone, on the contrary, increases the content of total phospholipids. When used together, the effects of these drugs are summed up. Cisplatin reduces the content of all 7 individual phospholipids found in rat brain nuclear preparations. Progesterone, on the other hand, increases the content of 5 classes of phospholipids. The combined use of cisplatin and progesterone restores 5 classes of nuclear phospholipids to the baseline level, and increases the quantity of 2 classes. The obtained results are discussed in terms of antagonistic effects of studied drugs, which can help in reducing undesirable side effects of cisplatin in case of combined use of antitumor drug and steroid.
Topics: Rats; Animals; Cisplatin; Progesterone; Phospholipids; Antineoplastic Agents; Steroids
PubMed: 37247723
DOI: 10.1016/j.prostaglandins.2023.106750 -
Seminars in Thrombosis and Hemostasis Feb 2024The development of oral contraceptives (OCs) began in 1921 and continued in the following years until the first regulatory approval from the Food and Drug Administration...
The development of oral contraceptives (OCs) began in 1921 and continued in the following years until the first regulatory approval from the Food and Drug Administration was granted in 1960. However, it took several years to realize that OCs presented an important but not frequent risk of venous thrombosis. Several reports ignored this dangerous effect and only in 1967 the Medical Research Council clearly stated this as an important risk. Later, research led to the formulation of second-generation OCs containing progestins, which nevertheless presented an increased thrombotic risk. In early 1980s, OCs containing third-generation progestins were introduced into the market. Only in 1995, it became clear that these new compounds induced a higher thrombotic risk than that related to the second-generation progestins. It appeared clear that the modulating action of progestins was against the procoagulant activity of estrogens. Lastly, at the end of the 2000s, OCs containing natural estrogens and a fourth-generation progestin (dienogest) became available. The prothrombotic effect of those natural products was not different from that of preparations containing second-generation progestins. Moreover, research over the years has produced much data on risk factors associated with OCs use such as age, obesity, cigarette smoking, and thrombophilia. These findings allowed us to better assess the individual thrombotic risk (both arterial and thrombotic) of each woman before offering an OC. Furthermore, research has shown that in high-risk people the use of single progestin is not dangerous as far as thrombosis is concerned. In conclusion, the OCs road has been long and difficult but has led to a great and unthinkable scientific and social enrichment since the 1960s.
Topics: Female; Humans; Progestins; Contraceptives, Oral; Thrombosis; Risk Factors; Estrogens
PubMed: 36913971
DOI: 10.1055/s-0043-1764382 -
Frontiers in Endocrinology 2023To determine whether progestin-primed ovarian stimulation (PPOS) is more effective for women with diminished ovarian reserve (DOR) than clomiphene citrate (CC)/letrozole... (Meta-Analysis)
Meta-Analysis
BACKGROUND
To determine whether progestin-primed ovarian stimulation (PPOS) is more effective for women with diminished ovarian reserve (DOR) than clomiphene citrate (CC)/letrozole (LE) plus gonadotropin in IVF or ICSI treatment.
METHODS
Nine databases were searched until May 24, 2023, to identify relevant studies. Forest plots were used to present the results of this meta-analysis. Begg's and Egger's tests were applied to estimate publication bias. Subgroup and sensitivity analysis were performed to check the potential sources of heterogeneity and verify the robustness of the pooled results, respectively.
RESULTS
A total of 14 studies with 4182 participants were included for meta-analysis. There was evidence of a statistically notable increase in clinical pregnancy rate (OR = 1.39, 95%CI [1.01, 1.91], = 0.05), optimal embryos rate (OR = 1.50, 95%CI [1.20, 1.88], = 0.0004), and cumulative pregnancy rate (OR = 1.73, 95%CI [1.14, 2.60], = 0.009), the duration and the amount of gonadotropin required (MD = 1.56, 95%CI [0.47, 2.66], = 0.005; SMD = 1.51, 95%CI [0.90, 2.12], < 0.00001), along with decrease cycle cancellation rate (OR = 0.78, 95%CI [0.64, 0.95], = 0.02), luteinizing hormone (LH) level on the day of hCG (SMD = -0.81, 95%CI [-1.10, -0.53], < 0.00001), and premature LH surge rate (OR = 0.10, 95%CI [0.07, 0.15], < 0.00001) when PPOS was used. No evidence for publication bias within results was revealed.
CONCLUSIONS
Based on evidence-based results, PPOS protocol seems to improve IVF/ICSI outcomes for women with DOR. More research with larger sample sizes and rigorous designs are required to further explore the value of PPOS among women diagnosed with DOR.
SYSTEMATIC REVIEW REGISTRATION
www.crd.york.ac.uk, identifier CRD42023430202.
Topics: Female; Humans; Pregnancy; Ovarian Diseases; Ovarian Reserve; Ovulation Induction; Progestins; Sperm Injections, Intracytoplasmic; Steroids; Clinical Protocols
PubMed: 37670890
DOI: 10.3389/fendo.2023.1232935 -
Reproductive Health Aug 2023Previous studies have reported that after laparoscopic cystectomy of ovarial endometrioma, the ovarian response to gonadotropin (Gn) significantly decreased. However,...
Analysis of cumulative live birth rate outcomes of three ovarian stimulation protocols in patients after laparoscopic cystectomy of ovarial endometrioma: a retrospective cohort study.
BACKGROUND
Previous studies have reported that after laparoscopic cystectomy of ovarial endometrioma, the ovarian response to gonadotropin (Gn) significantly decreased. However, for patients with diminished ovarian reserve (DOR) after ovarian surgery, how to choose the most appropriate controlled ovarian hyperstimulation protocol has not been concluded. Compared with the traditional agonist regimen, the gonadotropin (Gn)-releasing hormone (GnRH) antagonist, microstimulation, and progestin-primed ovarian stimulation (PPOS) protocols are simple to operate and have a shorter cycle, which are often used in patients with DOR. So the purpose of our study is to compare the assisted reproductive outcomes of these three controlled ovarian hyperstimulation protocols in patients with DOR following laparoscopic cystectomy of ovarial endometrioma.
METHODS
In this retrospective cohort study, 89 patients with DOR who had undergone in vitro fertilisation/intracytoplasmic sperm injection at the Department of Reproductive Medicine at the Third Affiliated Hospital of Zhengzhou University from 1 to 2018 to 31 December 2020 were included. According to the controlled ovarian hyperstimulation protocols employed, the patients were divided into GnRH antagonist (38 patients), PPOS (27 patients), and microstimulation (24 patients) groups. The basic data and clinical outcomes of the three groups were compared. The main outcome measure was the cumulative live birth rate.
RESULTS
No significant differences in the age of the female patients and their spouses and female patients' body mass index and basal endocrine levels (follicle-stimulating hormone and oestradiol) were noted among the three groups (P > 0.05). The GnRH antagonist group had higher antral follicle counts, greater endometrial thickness on the human chorionic Gn injection day, greater number of oocytes retrieved, and higher two pronuclear embryo counts than did the other two groups. However, the starting dosage of Gn was lower in the GnRH antagonist group than in the other two groups. The microstimulation group had a significantly higher oocyte output rate and high-quality embryo rate than did the other two groups (P < 0.05). No significant differences in the total dosage of Gn, cumulative pregnancy rate, cumulative live birth rate, viable embryo rate, and blastocyst formation rate were observed among the three groups (P > 0.05).
CONCLUSION
In conclusion, for patients aged under 40 years who experienced DOR after laparoscopic cystectomy of ovarial endometrioma, GnRH antagonist protocol and PPOS protocol can obtain better ovulation induction outcomes and cumulative live birth rate than microstimulation protocol, and are more suitable ovulation induction protocols.
Topics: Male; Pregnancy; Humans; Female; Aged; Endometriosis; Birth Rate; Cystectomy; Retrospective Studies; Semen; Ovulation Induction; Gonadotropin-Releasing Hormone; Progestins
PubMed: 37644567
DOI: 10.1186/s12978-023-01671-3 -
Reproductive Sciences (Thousand Oaks,... Nov 2023Recurrent spontaneous abortion (RSA) is one of the most common complications during pregnancy and seriously affects women's physical and mental health. About 50% of RSA...
Recurrent spontaneous abortion (RSA) is one of the most common complications during pregnancy and seriously affects women's physical and mental health. About 50% of RSA cases are of unknown etiology. Our previous study found that the decidual tissue of patients with unexplained recurrent spontaneous abortion (URSA) had low expression levels of serum and glucocorticoid-induced protein kinase (SGK) 1. Endometrial decidualization is a key link in the early stage of pregnancy and is crucial to the development and maintenance of pregnancy. Decidualization is the proliferation and differentiation of endometrial stromal cells into deciduals, which involves a complex physiological process such as ovarian steroid hormones (estrogen, progesterone, prolactin, etc.), growth factors, and intercellular signaling. The binding of estrogen and its receptor stimulates the synthesis of endometrial deciduating markers prolactin (PRL) and insulin-like growth factor binding protein 1 (IGFBP-1), which mediates the occurrence of decidualization. Among them, SGK1/ENaC is a signaling pathway closely related to decidualization. The purpose of this study was to further investigate the expression of SGK1 and decidualization-related molecules in the decidual tissue of URSA patients and to explore the potential mechanism of SGK1's protective effect in URSA patients and in mouse models. Decidual tissue samples from 30 URSA patients and 30 women who actively terminated pregnancy were collected, and a URSA mouse model was established and treated with dydrogesterone. Expression levels of SGK1 and its signaling pathway-related proteins (p-Nedd4-2, 14-3-3 protein and ENaC-a), estrogen and progesterone receptors (ERβ, PR), and decidualization markers (PRLR, IGFBP-1) were assessed. Our study found that SGK1, p-Nedd4-2, 14-3-3 proteins, and ENaC-a expression levels were reduced in the decidual tissue, the SGK1/ENaC signaling pathway was inhibited, and the expression levels of the decidualization markers PRLR and IGFBP-1 were downregulated in the URSA group compared with the controls. Additionally, the concentrations of E, P, and PRL in the serum of mice were decreased in the URSA group compared with the controls. However, SGK1/ENaC pathway-related proteins, estrogen and progesterone and their receptors, and decidualization-related molecules were upregulated by dydrogesterone. These data suggest that estrogen and progesterone can induce decidualization by activating the SGK1/ENaC signaling pathway; disruption of this pathway can lead to the development of URSA. Dydrogesterone can increase the expression level of SGK1 protein in decidual tissue.
Topics: Humans; Pregnancy; Female; Mice; Animals; Progesterone; Decidua; Insulin-Like Growth Factor Binding Protein 1; Abortion, Spontaneous; Prolactin; Dydrogesterone; Signal Transduction; Estrogens; Abortion, Habitual; Stromal Cells
PubMed: 37280474
DOI: 10.1007/s43032-023-01273-1 -
Gynecological Endocrinology : the... Dec 2023To compare the effects of progestin-primed ovarian stimulation (PPOS) protocol and GnRH-a long protocol in infertility patients with normal ovarian reserve function... (Review)
Review
OBJECTIVE
To compare the effects of progestin-primed ovarian stimulation (PPOS) protocol and GnRH-a long protocol in infertility patients with normal ovarian reserve function undergoing invitro fertilization and embryo transfer.
METHODS
A retrospective cohort study was conducted to analyze the clinical data of 2013 cycles of patients with normal ovarian reserve function who underwent invitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) in the Department of Human Reproductive Center, Renmin Hospital, Hubei University of Medicine from January 2018 and June 2020. The PPOS protocol group included 679 cycles and GnRH-along protocol group included 1334 cycles, the pregnancy outcomes were compared between the two groups.
RESULTS
The duration of Gn used and total Gn used dosage in the PPOS protocol group were less than those in the GnRH-along protocol group (Duration of Gn used: 10.05 ± 1.48 vs 11.90 ± 1.85 d, < 0.001; Total Gn used dosage: 1944.49 ± 533.61 vs 2661.34 ± 987.97 IU, < 0.001); The LH levels were significantly higher on HCG trigger day in PPOS protocol compared to GnRH-a long protocol (2.8 ± 1 ± 1.07 vs 1.01 ± 0.62 IU/L, < 0.001), the E2 levels on HCG trigger day in PPOS protocol group was lower than that in the GnRH-a long protocol group (2135.92 ± 1387.00 vs 2417.01 ± 1010.70 pg/mL, < 0. 001). The number of oocytes retrieved in the PPOS protocol group was lower than that in the GnRH-along protocol group (8.03 ± 2.86 vs 9.47 ± 2.64, < 0.001). No significant differences were found in pregnancy outcome including clinical pregnancy rate, early miscarriage rate and ectopic pregnancy rate between the two group ( > 0.05); In addition, no severe OHSS occurred in the PPOS protocol group during ovulation induction, while 11 patients of severe ovarian hyperstimulation syndrome (OHSS) occurred in GnRH-a long protocol group ( < 0.001).
CONCLUSION
The clinical efficacy of PPOS protocol combining embryo cryopreservation is comparable to that of GnRH-a long protocol in patients with normal ovarian reserve function, and the PPOS protocol is able to reduce the incidence of severe OHSS significantly.
Topics: Female; Pregnancy; Humans; Male; Progestins; Gonadotropin-Releasing Hormone; Fertilization in Vitro; Retrospective Studies; Ovarian Reserve; Semen; Ovulation Induction; Ovarian Hyperstimulation Syndrome; Pregnancy Rate; Steroids
PubMed: 37236243
DOI: 10.1080/09513590.2023.2217263 -
Frontiers in Neuroendocrinology Oct 2023Cyclic variations in hormones during the normal menstrual cycle underlie multiple central nervous system (CNS)-linked disorders, including premenstrual mood disorder... (Meta-Analysis)
Meta-Analysis Review
A scoping review of hormonal clinical trials in menstrual cycle-related brain disorders: Studies in premenstrual mood disorder, menstrual migraine, and catamenial epilepsy.
UNLABELLED
Cyclic variations in hormones during the normal menstrual cycle underlie multiple central nervous system (CNS)-linked disorders, including premenstrual mood disorder (PMD), menstrual migraine (MM), and catamenial epilepsy (CE). Despite this foundational mechanistic link, these three fields operate independently of each other. In this scoping review (N = 85 studies), we survey existing human research studies in PMD, MM, and CE to outline the exogenous experimental hormone manipulation trials conducted in these fields. We examine a broad range of literature across these disorders in order to summarize existing diagnostic practices and research methods, highlight gaps in the experimental human literature, and elucidate future research opportunities within each field. While no individual treatment or study design can fit every disease, there is immense overlap in study design and established neuroendocrine-based hormone sensitivity among the menstrual cycle-related disorders PMD, MM, and CE.
SCOPING REVIEW STRUCTURED SUMMARY
Background. The menstrual cycle can be a biological trigger of symptoms in certain brain disorders, leading to specific, menstrual cycle-linked phenomena such as premenstrual mood disorders (PMD), menstrual migraine (MM), and catamenial epilepsy (CE). Despite the overlap in chronicity and hormonal provocation, these fields have historically operated independently, without any systematic communication about methods or mechanisms.
OBJECTIVE
Online databases were used to identify articles published between 1950 and 2021 that studied hormonal manipulations in reproductive-aged females with either PMD, MM, or CE. We selected N = 85 studies that met the following criteria: 1) included a study population of females with natural menstrual cycles (e.g., not perimenopausal, pregnant, or using hormonal medications that were not the primary study variable); 2) involved an exogenous hormone manipulation; 3) involved a repeated measurement across at least two cycle phases as the primary outcome variable.
CHARTING METHODS
After exporting online database query results, authors extracted sample size, clinical diagnosis of sample population, study design, experimental hormone manipulation, cyclical outcome measure, and results from each trial. Charting was completed manually, with two authors reviewing each trial.
RESULTS
Exogenous hormone manipulations have been tested as treatment options for PMD (N = 56 trials) more frequently than MM (N = 21) or CE (N = 8). Combined oral contraceptive (COC) trials, specifically those containing drospirenone as the progestin, are a well-studied area with promising results for treating both PMDD and MM. We found no trials of COCs in CE. Many trials test ovulation suppression using gonadotropin-releasing hormone agonists (GnRHa), and a meta-analysis supports their efficacy in PMD; GnRHa have been tested in two MM-related trials, and one CE open-label case series. Finally, we found that non-contraceptive hormone manipulations, including but not limited to short-term transdermal estradiol, progesterone supplementation, and progesterone antagonism, have been used across all three disorders.
CONCLUSIONS
Research in PMD, MM, and CE commonly have overlapping study design and research methods, and similar effects of some interventions suggest the possibility of overlapping mechanisms contributing to their cyclical symptom presentation. Our scoping review is the first to summarize existing clinical trials in these three brain disorders, specifically focusing on hormonal treatment trials. We find that PMD has a stronger body of literature for ovulation-suppressing COC and GnRHa trials; the field of MM consists of extensive estrogen-based studies; and current consensus in CE focuses on progesterone supplementation during the luteal phase, with limited estrogen manipulations due to concerns about seizure provocation. We argue that researchers in any of these respective disciplines would benefit from greater communication regarding methods for assessment, diagnosis, subtyping, and experimental manipulation. With this scoping review, we hope to increase collaboration and communication among researchers to ultimately improve diagnosis and treatment for menstrual-cycle-linked brain disorders.
Topics: Female; Humans; Pregnancy; Adult; Progesterone; Premenstrual Syndrome; Menstrual Cycle; Migraine Disorders; Estradiol; Estrogens; Mood Disorders; Epilepsy
PubMed: 37619655
DOI: 10.1016/j.yfrne.2023.101098 -
The Journal of Headache and Pain Nov 2023Women are disproportionately affected by migraine, representing up to 75% of all migraine cases. This discrepancy has been proposed to be influenced by differences in...
BACKGROUND
Women are disproportionately affected by migraine, representing up to 75% of all migraine cases. This discrepancy has been proposed to be influenced by differences in hormone levels between the sexes. One such hormone is progesterone. Calcitonin gene-related peptide (CGRP) system is an important factor in migraine pathophysiology and could be influenced by circulating hormones. The purpose of this study was to investigate the distribution of progesterone and its receptor (PR) in the trigeminovascular system, and to examine the role of progesterone to modulate sensory neurotransmission.
METHODS
Trigeminal ganglion (TG), hypothalamus, dura mater, and the basilar artery from male and female rats were carefully dissected. Expression of progesterone and PR proteins, and mRNA levels from TG and hypothalamus were analyzed by immunohistochemistry and real-time quantitative PCR. CGRP release from TG and dura mater were measured using an enzyme-linked immunosorbent assay. In addition, the vasomotor effect of progesterone on male and female basilar artery segments was investigated with myography.
RESULTS
Progesterone and progesterone receptor -A (PR-A) immunoreactivity were found in TG. Progesterone was located predominantly in cell membranes and in Aδ-fibers, and PR-A was found in neuronal cytoplasm and nucleus, and in satellite glial cells. The number of positive progesterone immunoreactive cells in the TG was higher in female compared to male rats. The PR mRNA was expressed in both hypothalamus and TG; however, the PR expression level was significantly higher in the hypothalamus. Progesterone did not induce a significant change neither in basal level nor upon stimulated release of CGRP from dura mater or TG in male or female rats when compared to the vehicle control. However, pre-treated with 10 µM progesterone weakly enhanced capsaicin induced CGRP release observed in the dura mater of male rats. Similarly, in male basilar arteries, progesterone significantly amplified the dilation in response to capsaicin.
CONCLUSIONS
In conclusion, these results highlight the potential for progesterone to modulate sensory neurotransmission and vascular responses in a complex manner, with effects varying by sex, tissue type, and the nature of the stimulus. Further investigations are needed to elucidate the underlying mechanisms and physiological implications of these findings.
Topics: Humans; Rats; Male; Female; Animals; Calcitonin Gene-Related Peptide; Rats, Sprague-Dawley; Progesterone; Capsaicin; Trigeminal Ganglion; Migraine Disorders; RNA, Messenger
PubMed: 37957603
DOI: 10.1186/s10194-023-01687-x -
Human Reproduction (Oxford, England) May 2024
Topics: Humans; Female; Ovulation Induction; Aneuploidy; Progestins; Pregnancy
PubMed: 38498840
DOI: 10.1093/humrep/deae051