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World Journal of Clinical Cases Mar 2023The prevalence of female infertility between the ages of 25 and 44 is 3.5% to 16.7% in developed countries and 6.9% to 9.3% in developing countries. This means that...
BACKGROUND
The prevalence of female infertility between the ages of 25 and 44 is 3.5% to 16.7% in developed countries and 6.9% to 9.3% in developing countries. This means that infertility affects one in six couples and is recognized by the World Health Organization as the fifth most serious global disability. The International Committee for Monitoring Assisted Reproductive Technology reported that the global total of babies born as a result of assisted reproductive technology procedures and other advanced fertility treatments is more than 8 million. Advancements in controlled ovarian hyperstimulation procedures led to crucial accomplishments in human fertility treatments. The European Society for Human Reproduction and Embryology guideline on ovarian stimulation gave us valuable evidence-based recommendations to optimize ovarian stimulation in assisted reproductive technology. Conventional ovarian stimulation protocols for fertilization (IVF)-embryo transfer are based upon the administration of gonadotropins combined with gonadotropin-releasing hormone (GnRH) analogues, either GnRH agonists (GnRHa) or antagonists. The development of ovarian cysts requires the combination of GnRHa and gonadotropins for controlled ovarian hyperstimulation. However, in rare cases patients may develop an ovarian hyper response after administration of GnRHa alone.
CASE SUMMARY
Here, two case studies were conducted. In the first case, a 33-year-old female diagnosed with polycystic ovary syndrome presented for her first IVF cycle at our reproductive center. Fourteen days after triptorelin acetate was administrated (day 18 of her menstrual cycle), bilateral ovaries presented polycystic manifestations. The patient was given 5000 IU of human chorionic gonadotropin. Twenty-two oocytes were obtained, and eight embryos formed. Two blastospheres were transferred in the frozen-thawed embryo transfer cycle, and the patient was impregnated. In the second case, a 37-year-old woman presented to the reproductive center for her first donor IVF cycle. Fourteen days after GnRHa administration, the transvaginal ultrasound revealed six follicles measuring 17-26 mm in the bilateral ovaries. The patient was given 10000 IU of human chorionic gonadotropin. Three oocytes were obtained, and three embryos formed. Two high-grade embryos were transferred in the frozen-thawed embryo transfer cycle, and the patient was impregnated.
CONCLUSION
These two special cases provide valuable knowledge through our experience. We hypothesize that oocyte retrieval can be an alternative to cycle cancellation in these conditions. Considering the high progesterone level in most cases of this situation, we advocate freezing embryos after oocyte retrieval rather than fresh embryo transfer.
PubMed: 36998947
DOI: 10.12998/wjcc.v11.i9.2067 -
Biomedicines Mar 2023The clinical use of mifepristone for medical abortions has been established in 1987 in France and since 2000 in the United States. Mifepristone has a limited medical...
The clinical use of mifepristone for medical abortions has been established in 1987 in France and since 2000 in the United States. Mifepristone has a limited medical period that lasts <9 weeks of gestation, and the incidence of mifepristone treatment failure increases with gestation time. Mifepristone functions as an antagonist for progesterone and glucocorticoid receptors. Studies have confirmed that mifepristone treatments can directly contribute to endometrium disability by interfering with the endometrial receptivity of the embryo, thus causing decidual endometrial degeneration. However, whether mifepristone efficacy directly affects embryo survival and growth is still an open question. Some women choose to continue their pregnancy after mifepristone treatment fails, and some women express regret and seek medically unapproved mifepristone antagonization with high doses of progesterone. These unapproved treatments raise the potential risk of embryonic fatality and developmental anomalies. Accordingly, in the present study, we collected mouse blastocysts ex vivo and treated implanted blastocysts with mifepristone for 24 h. The embryos were further cultured to day 8 in vitro to finish their growth in the early somite stage, and the embryos were then collected for RNA sequencing (control = 3, mifepristone = 3). When we performed a gene set enrichment analysis, our data indicated that mifepristone treatment considerably altered the cellular pathways of embryos in terms of viability, proliferation, and development. The data indicated that mifepristone was involved in hallmark gene sets of protein secretion, mTORC1, fatty acid metabolism, IL-2-STAT5 signaling, adipogenesis, peroxisome, glycolysis, E2F targets, and heme metabolism. The data further revealed that mifepristone interfered with normal embryonic development. In sum, our data suggest that continuing a pregnancy after mifepristone treatment fails is inappropriate and infeasible. The results of our study reveal a high risk of fetus fatality and developmental problems when pregnancies are continued after mifepristone treatment fails.
PubMed: 36979886
DOI: 10.3390/biomedicines11030907 -
F&S Reports Mar 2023Evidence strongly supports the use of mifepristone-misoprostol combination treatment for early pregnancy loss (EPL) among pregnancies conceived without assisted...
OBJECTIVE
Evidence strongly supports the use of mifepristone-misoprostol combination treatment for early pregnancy loss (EPL) among pregnancies conceived without assisted reproductive technologies. No literature exists, however, regarding the efficacy of this treatment in the medical management of EPL among pregnancies after in vitro fertilization and embryo transfer (IVF-ET). These patients differ as some use exogenous hormonal supplementation to provide pregnancy support. Thus, the management for EPL may differ between unassisted conceptions and those after ET. Mifepristone, a progesterone receptor antagonist, may demonstrate an altered treatment effect when used with misoprostol to manage EPL in assisted reproductive technologie-conceived pregnancies.
OBJECTIVE
To describe our institution's experience using mifepristone-misoprostol to manage EPL after in vitro fertilization with embryo transfer IVF-ET.
DESIGN
Retrospective case series.
SETTING
Single academic institution from 2020 to 2022.
PATIENTSS
Nine patients with ultrasound confirmed EPL after IVF-ET.
INTERVENTIONS
All 9 patients underwent in vitro fertilization followed by fresh or frozen embryo transfer. All 9 received 200 mg of mifepristone 24 hours before 800 μg of misoprostol.
MAIN OUTCOME MEASUREMENTS
Incomplete abortion, need for surgical management, number of days to negative serum human chorionic gonadotropin (hCG).
RESULTS
Of the 9 subjects included, one had a programmed frozen embryo transfer cycle, 6 had modified natural frozen embryo transfer cycles, and 2 underwent fresh ET. Eight subjects had successful expulsion of tissue with one dose of treatment, and one required uterine aspiration. No subjects required additional dosing of misoprostol. The mean number of days elapsed from mifepristone treatment to tissue expulsion was 4.89 ± 11.30 days and the mean days to negative-range serum hCG was 36.89 ± 18.59 days. At the initial ultrasound, all pregnancies had one gestational sac seen; 5/9 had a yolk sac; only 3 had fetal cardiac activity. The mean gestational age at the time of EPL diagnosis was 55.22 ± 8.77 days, with the majority (8/9) having completed 7 weeks gestation.
CONCLUSIONS
Mifepristone-misoprostol combination treatment appears to be a reasonable option for those with EPL after IVF-ET. Future, larger-scale studies are needed comparing combination treatment with misoprostol only among various ET protocols.
PubMed: 36959956
DOI: 10.1016/j.xfre.2023.01.003 -
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 -
Ginekologia Polska Mar 2023To investigate the effect of human chorionic gonadotropin day progesterone (hCG-P) level on pregnancy outcomes in in vitro fertilization (IVF) cycles.
OBJECTIVES
To investigate the effect of human chorionic gonadotropin day progesterone (hCG-P) level on pregnancy outcomes in in vitro fertilization (IVF) cycles.
MATERIAL AND METHODS
This study is an analysis of a cohort of 1318 fresh IVF- embryo transfer cycles, including 579 agonists and 739 antagonists, performed at a single IVF center between 2007 and 2018. For fresh cycles, we performed Receiver Operating Characteristic analysis (ROC) to calculate the threshold value of hCG-P, which affects pregnancy outcomes. We divided patients below and above the determined threshold value into two groups, then, correlation analysis and we performed logistic regression analysis.
RESULTS
According to ROC curve analysis of hCG-P,AUC was 0.537 (95% CI: 0.510-0.564, p < 0.05) for LBR, and the threshold value for P was 0.78. The hCG-P threshold value of 0.78 proved to be significant in relation to BMI, type of drug used during induction, the hCG day E2, the total number of oocytes, the number of oocytes and the subsequent pregnancy outcome between the two groups (p < 0.05). However, the model we built, which accounted for hCG-P, total number of oocytes, age, BMI, induction protocol, total dose of gonadotropin used in induction did not prove significant in terms of its effect on LBR.
CONCLUSIONS
The threshold value of hCG-P that we found to have an effect on LBR was quite low compared with the P-value generally recommended in the literature. Therefore, further studies are needed to determine an accurate P-value that reduces success in managing fresh cycles.
PubMed: 36861902
DOI: 10.5603/GP.a2022.0114 -
Drug Design, Development and Therapy 2023Estrogens play a critical role in the pathogenesis of endometriosis and it is logical to assume that lowering estradiol levels with oral gonadotropin-releasing hormone... (Review)
Review
Estrogens play a critical role in the pathogenesis of endometriosis and it is logical to assume that lowering estradiol levels with oral gonadotropin-releasing hormone (GnRH) antagonists may prove effective, especially in women who fail to respond to progestogens. Indeed, due to progesterone resistance, oral contraceptives and progestogens work well in two-thirds of women suffering from endometriosis, but are ineffective in 33% of women. Oral GnRH antagonists have therefore been evaluated for management of premenopausal women with endometriosis-associated pelvic pain. The first publication on these drugs reported the efficacy of elagolix. The present paper is a narrative review of linzagolix, which is an orally administered GnRH receptor antagonist with low pharmacokinetic/pharmacodynamic variability. It binds to and blocks the GnRH receptor in the pituitary gland, resulting in a dose-dependent drop in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) production. This reduction in LH and FSH levels in turn leads to a dose-dependent decline in estrogen. Phase 2 and 3 trials are reviewed and discussed here. There is a place for GnRH antagonists in the management of symptomatic endometriosis, and linzagolix with or without add-back therapy (ABT) is one option that can be used at low doses, avoiding the need for ABT, which is contraindicated in some patients.
Topics: Humans; Female; Gonadotropin-Releasing Hormone; Endometriosis; Receptors, LHRH; Progestins; Estradiol; Follicle Stimulating Hormone; Luteinizing Hormone; Hormone Antagonists; Estrogens
PubMed: 36789095
DOI: 10.2147/DDDT.S269976 -
Kidney Diseases (Basel, Switzerland) Jan 2023Mineralocorticoid receptor antagonists (MRAs) protect cardiorenal function by robust anti-inflammatory and antifibrotic functions beyond classical functions of... (Review)
Review
BACKGROUND
Mineralocorticoid receptor antagonists (MRAs) protect cardiorenal function by robust anti-inflammatory and antifibrotic functions beyond classical functions of maintaining fluid and electrolyte homeostasis. The application of traditional steroidal MRAs to chronic kidney disease (CKD) has been limited by adverse events, especially when combined with renin-angiotensin system inhibitors, guideline-recommend drugs for CKD patients. Recently, the development of nonsteroidal MRAs gives patients with CKD a promising option.
SUMMARY
The discovery of nonsteroidal MRAs is based on the molecular structure of the mineralocorticoid receptor (MR) and differs in structure from spironolactone, a progesterone derivative. The structure of nonsteroidal MRAs determines their more effective and selective inhibition of MR providing patients more benefits with fewer adverse effects than MRAs. Recently, two types of nonsteroidal MRAs, finerenone and esaxerenone, have been authorized for clinical use. We elaborate on the physiological and pathophysiological mechanisms of MR, review the history of MRAs, compare two generations of MRAs, and introduce the forward clinical trials of finerenone and esaxerenone.
KEY MESSAGES
Finerenone reduces the cardiovascular and kidney composite outcomes in diabetic patients with CKD eliciting a cardiorenal protection effect. Esaxerenone can effectively reduce blood pressure in hypertensive patients and albuminuria in diabetic patients with CKD. The risk of hyperkalemia is controllable and acceptable through the serum potassium-based dose titrate. Combination therapy with sodium-glucose cotransport-2 inhibition or a new potassium binder may be a safer and more efficient approach.
PubMed: 36756081
DOI: 10.1159/000528066 -
Human Reproduction (Oxford, England) Apr 2023Do cortisol/glucocorticoid receptors play an active role in the human ovary during ovulation and early luteinization?
STUDY QUESTION
Do cortisol/glucocorticoid receptors play an active role in the human ovary during ovulation and early luteinization?
SUMMARY ANSWER
The ovulatory hCG stimulation-induced glucocorticoid receptor signaling plays a crucial role in regulating steroidogenesis and ovulatory cascade in human periovulatory follicles.
WHAT IS KNOWN ALREADY
Previous studies reported an increase in cortisol levels in the human follicular fluid after the LH surge or ovulatory hCG administration. However, little is known about the role of cortisol/glucocorticoid receptors in the ovulatory process and luteinization in humans.
STUDY DESIGN, SIZE, DURATION
This study was an experimental prospective clinical and laboratory-based study. An in vivo experimental study was accomplished utilizing the dominant ovarian follicles from 38 premenopausal women undergoing laparoscopic sterilization. An in vitro experimental study was completed using the primary human granulosa/lutein cells (hGLC) from 26 premenopausal women undergoing IVF.
PARTICIPANTS/MATERIALS, SETTING, METHODS
This study was conducted in a private fertility clinic and academic medical centers. Dominant ovarian follicles were collected before the LH surge and at defined times after hCG administration from women undergoing laparoscopic sterilization. Primary hGLC were collected from women undergoing IVF. hGLC were treated without or with hCG in the absence or presence of RU486 (20 µM; dual antagonist for progesterone receptor and glucocorticoid receptor) or CORT125281 (50 µM; selective glucocorticoid receptor antagonist) for 12 or 36 h. The expression of genes involved in glucocorticoid receptor signaling, steroidogenesis, and ovulatory cascade was studied with RT-quantitative PCR and western blotting. The production of cortisol, corticosterone, and progesterone was assessed by hormone assay kits.
MAIN RESULTS AND THE ROLE OF CHANCE
hCG administration upregulated the expression of hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1), nuclear receptor subfamily 3 group C member 1 (NR3C1), FKBP prolyl isomerase 5 (FKBP5), and FKBP prolyl isomerase 4 (FKBP4) in human ovulatory follicles and in hGLC (P < 0.05). RU486 and CORT125281 reduced hCG-induced increases in progesterone and cortisol production in hGLC. The expression of genes involved in glucocorticoid receptor signaling, steroidogenesis, and the key ovulatory process was reduced by RU486 and/or CORT125281 in hGLC.
LARGE SCALE DATA
N/A.
LIMITATIONS, REASONS FOR CAUTION
The role of cortisol/glucocorticoid receptors demonstrated using the hGLC model may not fully reflect their physiological roles in vivo.
WIDER IMPLICATIONS OF THE FINDINGS
Successful ovulation and luteinization are essential for female fertility. Women with dysregulated cortisol levels often suffer from anovulatory infertility. Deciphering the functional role of glucocorticoid receptor signaling in human periovulatory follicles enhances our knowledge of basic ovarian physiology and may provide therapeutic insights into treating infertility in women.
STUDY FUNDING/COMPETING INTEREST(S)
This study was supported by P01HD71875 (to M.J., T.E.C., and M.B.) and R01HD096077 (to M.J.) from the Foundation for the National Institutes of Health and the BTPSRF of the University of Kentucky Markey Cancer Center (P30CA177558). The authors report no competing interests.
TRIAL REGISTRATION NUMBER
N/A.
Topics: Female; Humans; Progesterone; Receptors, Glucocorticoid; Hydrocortisone; Glucocorticoids; Prospective Studies; Mifepristone; Infertility, Female; Receptors, LH; Luteinization; Peptidylprolyl Isomerase
PubMed: 36752644
DOI: 10.1093/humrep/dead017 -
JBRA Assisted Reproduction Mar 2023The aim of this study is to determine whether the serum concentrations of progesterone and/or prolactin after fresh embryo transfer are associated with pregnancy rates...
OBJECTIVE
The aim of this study is to determine whether the serum concentrations of progesterone and/or prolactin after fresh embryo transfer are associated with pregnancy rates in in vitro fertilization treatment.
METHODS
This retrospective cohort study evaluated in vitro fertilization treatments with fresh embryo transfer, which were performed between 2013 and 2019 in a private clinic in Curitiba, Brazil. The serum concentrations of progesterone and prolactin were evaluated by chemiluminescence nine days after oocyte retrieval. The type of progesterone supplementation and pituitary blockage during the cycle of oocyte stimulation were evaluated.
RESULTS
330 fertilization cycles were performed in the 293 studied patients. The mean age of patients was 35.5±4.1years. The most seen isolated infertility factor was endometriosis (24.2% of the cases), while progesterone supplementation was performed intramuscularly in 73.9% of the cases. The progesterone values above 32.1ng/ml at day 9 (D9) were associated with better pregnancy rates. In cycles using antagonist and intramuscular luteal phase supplementation, higher pregnancy rates with progesterone values above 37.83ng/ml were observed. Moreover, prolactin showed no significant association with any of the studied variables.
CONCLUSIONS
The serum progesterone concentrations above 32.1ng/ml at D9 that were taken one week before pregnancy testing were associated with successful in vitro fertilization treatment. Furthermore, prolactin showed no significant association with any of the studied variables.
Topics: Pregnancy; Female; Humans; Progesterone; Prolactin; Retrospective Studies; Fertilization in Vitro; Embryo Transfer; Luteal Phase
PubMed: 36749817
DOI: 10.5935/1518-0557.20220071 -
Reproduction & Fertility Feb 2023Kisspeptin, a hypothalamic neuropeptide encoded by the KISS1 gene, has a pivotal role in promoting GnRH secretion in mammals. Kisspeptin and its receptor (KISS1R) are...
Kisspeptin, a hypothalamic neuropeptide encoded by the KISS1 gene, has a pivotal role in promoting GnRH secretion in mammals. Kisspeptin and its receptor (KISS1R) are also expressed in certain peripheral tissues including gonads, suggesting intra-gonadal roles. Such actions at the level of the bovine ovary have not been explored previously. The current aims were to determine whether KISS1 and its receptor (KISS1R) are expressed in the bovine ovary and whether kisspeptin or a kisspeptin antagonist can modulate ovarian steroid production by cultured ovarian cells. Granulosa (GC) and theca interna (TC) were collected from antral follicles (3-18 mm) categorized into five class sizes. Early, mid and regressing corpora lutea (CL) were also collected for RT-qPCR analysis of KISS1 and KISS1R expression. Bovine TC and GC cultured under both non-luteinizing (serum-free) and luteinizing (serum-supplemented) conditions were treated for 4 days with kisspeptin-10 (10-10-10-6M) or kisspeptin antagonist (p234; 10-10-10-6M), alone and in combination with either FSH (GC), LH (TC) or forskolin (luteinized GC/TC). Steroid secretion (GC: oestradiol, progesterone; TC: androstenedione, progesterone; luteinized GC/TC: progesterone) was measured by ELISA and viable cell number determined by neutral red uptake assay. KISS1 and KISS1R transcripts were detected in TC, GC and CL with significant differences between follicle categories and CL stages. However, neither kisspeptin-10 nor kisspeptin antagonist affected steroid secretion or viable cell number in any of the four ovarian cell culture models. As such, the hypothesis that kisspeptin has a direct intra-ovarian role to modulate follicular or luteal steroidogenesis, or cell proliferation/survival, is not supported.
PubMed: 36745024
DOI: 10.1530/RAF-22-0088