Supplementation with vitamin D improves the embryo quality in in vitro fertilization (IVF) programs, independently of the patients' basal vitamin D status.

PURPOSE: The study aims to demonstrate the effects of Vitamin D (VD) supplementation, prior to oocyte pick-up within IVF protocols, in women with diverse VD status at the enrollment. METHODS: A total of 204 women eligible for intra-cytoplasmatic sperm injection (ICSI) cycles were included in the study and two homogeneous groups were selected from the database. Both group of patients with normal VD baseline level (> 40 ng/ml) and patients with low VD baseline level (< 20 ng/ml) were divided into control group and treatment group. The control group followed the standard procedure. The treatment group was supplemented with vitamin D3 as cholecalciferol in combination with Myo-Inositol, folic acid, and melatonin 3 months before standard procedure, once a day in the evening. RESULTS: VD levels significantly increased in the study group of low baseline VD, both in serum and in the follicular fluid compared to controls. The treatment induced a significant improvement of the embryo quality in both group of patients considered. CONCLUSION: Supplementation of VD in patients undergoing ICSI procedures significantly improved the number of top-quality embryos compared with the control group, either starting from VD normal baseline values or starting from low values. TRIAL REGISTRATION NUMBER: 07/2018.

Dietary supplementation of osthole and icariin improves the production performance of laying hens by promoting follicular development.

Osthole (Ost) and icariin (Ica) are extracted from traditional Chinese medicine Cnidium monnieri and Epimedii Folium, respectively, and both exhibit estrogen-like biological activity. This study aimed to determine the efficacy and safety of combining Ost with Ica on the production performance of laying hens and to explore their possible mechanisms. The production performance, egg quality, residues of Ost and Ica in eggs, serum reproductive hormone levels, expression of ovarian reproductive hormone receptor, proliferation of granulosa cells in small yellow follicles (SYF), and progesterone secretion in large yellow follicles (LYF) related genes and proteins expression were detected. The results showed that adding 2 mg/kg Ost + 2 mg/kg Ica to the feed increased the laying rate, average egg weight, Haugh unit, and protein height of laying hens. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and progesterone (P4) levels increased, and the expression of ovarian estrogen receptor (ER), follicle-stimulating hormone receptor (FSHR), and progesterone receptor (PGR) mRNA was up-regulated. Additionally, the mRNA and protein levels of steroidogenesis acute regulatory protein (StAR), cytochrome P450 side-chain cleavage (P450scc), and 3ß-hydroxysteroid dehydrogenase (3ß-HSD) increased in LYF. Furthermore, mRNA and protein levels of proliferating cell nuclear antigen (PCNA), cyclin E1, and cyclin A2 were up-regulated in SYF. The residues of Ost and Ica in egg samples were not detected by high-performance liquid chromatography (HPLC). In conclusion, dietary supplementation of Ost and Ica increased granulosa cells proliferation in SYF and increased P4 secretion in granulosa cells of LYF, ultimately improving the production performance of laying hens.

Ovarian response and embryo ploidy following oral micronized progesterone-primed ovarian stimulation versus GnRH antagonist protocol. A prospective study with repeated ovarian stimulation cycles.

STUDY QUESTION: Is there any difference in ovarian response and embryo ploidy following progesterone-primed ovarian stimulation (PPOS) using micronized progesterone or GnRH antagonist protocol? SUMMARY ANSWER: Pituitary downregulation with micronized progesterone as PPOS results in higher number of oocytes retrieved and a comparable number of euploid blastocysts to a GnRH antagonist protocol. WHAT IS KNOWN ALREADY: Although the GnRH antagonist is considered by most the gold standard protocol for controlling the LH surge during ovarian stimulation (OS) for IVF/ICSI, PPOS protocols are being increasingly used in freeze-all protocols. Still, despite the promising results of PPOS protocols, an early randomized trial reported potentially lower live births in recipients of oocytes resulting following downregulation with medroxyprogesterone acetate as compared with a GnRH antagonist protocol. The scope of the current prospective study was to investigate whether PPOS with micronized progesterone results in an equivalent yield of euploid blastocysts to a GnRH antagonist protocol. STUDY DESIGN, SIZE, DURATION: In this prospective study, performed between September 2019 to January 2022, 44 women underwent two consecutive OS protocols within a period of 6 months in a GnRH antagonist protocol or in a PPOS protocol with oral micronized progesterone. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 44 women underwent two OS cycles with an identical fixed dose of rFSH (225 or 300 IU) in both cycles. Downregulation in the first cycles was performed with the use of a flexible GnRH antagonist protocol (0.25 mg per day as soon as one follicle of 14 mm) and consecutively, after a washout period of 1 month, control of LH surge was performed with 200 mg of oral micronized progesterone from stimulation Day 1. After the completion of both cycles, all generated blastocysts underwent genetic analysis for aneuploidy screening (preimplantation genetic testing for aneuplody, PGT-A). MAIN RESULTS AND THE ROLE OF CHANCE: Comparisons between protocols did not reveal differences between the duration of OS. The hormonal profile on the day of trigger revealed statistically significant differences between protocols in all the tested hormones except for FSH: with significantly higher serum E2 levels, more elevated LH levels and higher progesterone levels in PPOS cycles as compared with antagonist cycles, respectively. Compared with the GnRH antagonist protocol, the PPOS protocol resulted in a significantly higher number of oocytes (12.7 ± 8.09 versus 10.3 ± 5.84; difference between means [DBM] -2.4 [95% CI -4.1 to -0.73]), metaphase II (9.1 ± 6.12 versus 7.3 ± 4.15; DBM -1.8 [95% CI -3.1 to -0.43]), and 2 pronuclei (7.1 ± 4.99 versus 5.7 ± 3.35; DBM -1.5 [95% CI -2.6.1 to -0.32]), respectively. Nevertheless, no differences were observed regarding the mean number of blastocysts between the PPOS and GnRH antagonist protocols (2.9 ± 2.11 versus 2.8 ± 2.12; DBM -0.07 [95% CI -0.67 to 0.53]) and the mean number of biopsied blastocysts (2.9 ± 2.16 versus 2.9 ± 2.15; DBM -0.07 [95% CI -0.70 to 0.56]), respectively. Concerning the euploidy rates per biopsied embryo, a 29% [95% CI 21.8-38.1%] and a 35% [95% CI 26.6-43.9%] were noticed in the PPOS and antagonist groups, respectively. Finally, no difference was observed for the primary outcome, with a mean number of euploid embryos of 0.86 ± 0.90 versus 1.00 ± 1.12 for the comparison of PPOS versus GnRh antagonist. LIMITATIONS, REASONS FOR CAUTION: The study was powered to detect differences in the mean number of euploid embryos and not in terms of pregnancy outcomes. Additionally, per protocol, there was no randomization, the first cycle was always a GnRH antagonist cycle and the second a PPOS with 1 month of washout period in between. WIDER IMPLICATIONS OF THE FINDINGS: In case of a freeze-all protocol, clinicians may safely consider oral micronized progesterone to control the LH surge and patients could benefit from the advantages of a medication of oral administration, with a potentially higher number of oocytes retrieved at a lower cost, without any compromise in embryo ploidy rates. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by an unrestricted grant from Theramex. N.P.P. has received Research grants from Merck Serono, Organon, Ferring Pharmaceutical, Roche, Theramex, IBSA, Gedeon Richter, and Besins Healthcare; honoraria for lectures from: Merck Serono, Organon, Ferring Pharmaceuticals, Besins International, Roche Diagnostics, IBSA, Theramex, and Gedeon Richter; consulting fees from Merck Serono, Organon, Besins Healthcare, and IBSA. M.d.M.V., F.M., and I.R. declared no conflicts of interest. TRIAL REGISTRATION NUMBER: The study was registered at Clinical Trials Gov. (NCT04108039).

Multi-faceted Anti-obesity Effects of N-Methyl-D-Aspartate (NMDA) Receptor Modulators: Central-Peripheral Crosstalk.

Hypothalamus is central to food intake and satiety. Recent data unveiled the expression of N-methyl-D-aspartate receptors (NMDAR) on hypothalamic neurons and their interaction with GABAA and serotoninergic neuronal circuits. However, the precise mechanisms governing energy homeostasis remain elusive. Notably, in females, the consumption of progesterone-containing preparations, such as hormonal replacement therapy and birth control pills, has been associated with hyperphagia and obesity-effects mediated through the hypothalamus. To elucidate this phenomenon, we employed the progesterone-induced obesity model in female Swiss albino mice. Four NMDAR modulators were selected viz. dextromethorphan (Dxt), minocycline, d-aspartate, and cycloserine. Obesity was induced in female mice by progesterone administration for 4 weeks. Mice were allocated into 7 groups, group-1 as vehicle control (arachis oil), group-2 (progesterone + arachis oil), and group-3 as positive-control (progesterone + sibutramine); other groups were treated with test drugs + progesterone. Various parameters were recorded like food intake, thermogenesis, serum lipids, insulin, AST and ALT levels, organ-to-body weight ratio, total body fat, adiposity index, brain serotonin levels, histology of liver, kidney, and sizing of fat cells. Dxt-treated group has shown a significant downturn in body weight (p < 0.05) by a decline in food intake (p < 0.01), organ-to-liver ratio (p < 0.001), adiposity index (p < 0.01), and a rise in body temperature and brain serotonin level (p < 0.001). Dxt demonstrated anti-obesity effects by multiple mechanisms including interaction with hypothalamic GABAA channels and anti-inflammatory and free radical scavenging effects, improving the brain serotonin levels, and increasing insulin release from the pancreatic ß-cells.

Progesterone treatment reduces food intake and body weight in ovariectomized female rats.

While the effects of progesterone on body weight and appetite in pre-menopausal conditions have been well elucidated, its effects in post-menopausal conditions have not been clarified. On the contrary, the effects of estrogen on body weight and appetite in post-menopausal conditions have been well established. In this study, the effects of progesterone treatment on body weight, appetite, and fat mass in ovariectomized rats were evaluated. In addition, the central and/or peripheral levels of oxytocin (OT), leptin, and their receptors, which are potent anorectic factors, were examined. Female rats were ovariectomized and divided into control, progesterone-treated, and estrogen-treated groups. Body weight, food intake, and subcutaneous fat mass were lower in both the progesterone and estrogen groups than in the control group. The estrogen group exhibited higher serum OT levels than the control group, whereas the OT levels of the progesterone and control groups did not differ. The serum leptin levels of both the progesterone and estrogen groups were lower than those of the control group. Gene expression analysis of OT, leptin, and their receptors in the hypothalamus and adipose tissue found few significant differences among the groups. Hypothalamic neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) mRNA levels involved in appetite regulation were slightly altered in the progesterone and estrogen groups. These findings suggest that progesterone treatment may have favorable effects on body weight, appetite, and fat mass regulation in post-menopausal conditions and that the mechanisms underlying these effects of progesterone differ from those underlying the effects of estrogen.

Lavender and metformin effectively propagate progesterone levels in patients with polycystic ovary syndrome: A randomized, double-blind clinical trial.

BACKGROUND: The present study aimed to evaluate the impacts of lavender and metformin on polycystic ovary syndrome (PCOS) patients. METHODS: We performed a randomized, double-blind clinical trial including 68 females aged 18 to 45, fulfilling the Rotterdam criteria for PCOS. The patients were randomized to receive lavender (250 mg twice daily) or metformin (500 mg three times a day) for 90 days. The serum progesterone was measured at baseline and after 90 days, one week before their expected menstruation. Moreover, the length of the menstrual cycle was documented. RESULTS: Our results showed that lavender and metformin treatment notably increased the progesterone levels in PCOS patients (increasing from 0.35 (0.66) and 0.8 (0.69) to 2.5 (6.2) and 2.74 (6.27) ng/mL, respectively, P < 0.001). However, we found no significant differences between the increasing effects of both treatments on progesterone levels. In addition, all patients in the lavender or metformin groups had baseline progesterone levels <3 ng/mL, reaching 14 (45.2%) patients >3 ng/mL. Lavender and metformin remarkably attenuated the menstrual cycle length in PCOS patients (decreasing from 56.0 (20.0) and 60 (12.0) to 42.0 (5.0) and 50.0 (14.0) days, respectively, P < 0.001). Furthermore, the decreasing effects of lavender on the menstrual cycle length were greater than the metformin group; however, it was not statistically significant (P = 0.06). CONCLUSION: Lavender effectively increased progesterone levels and regulated the menstrual cycles in PCOS patients, similar to metformin. Therefore, lavender may be a promising candidate for the treatment of PCOS.

Effect of Selenium and Zinc Supplementation on Reproductive Organs Following Postnatal Protein Malnutrition.

Protein diets are required for the normal development of the reproductive system and their inadequacy or deficiency might have hazardous functional complications during maturational and developmental stages. The study was carried out to evaluate the effect of selenium (Se) and zinc (Zn) supplementation on the male and female reproductive organs of rats with postnatal protein malnutrition. Male and female weanling rats were randomly assigned to six groups respectively. The adequate protein diet rats were fed with 16% casein diet while the protein malnourished diet (PMD) rats were fed with 5% casein diet. After the 8th week of feeding, Se (sodium selenite; Na2SeO3) and Zn (zinc sulfate; ZnSO4·7H2O) were supplemented for 3 weeks. The growth curve of body weights, lipid profile, testosterone and progesterone level, Na+-K+-ATPase activity, oxidative stress, and antioxidant status were evaluated. The results showed that PMD reduced the body weights of male and female rats. It also reduced the activities of catalase and glutathione peroxidase in the testes, but reductions in superoxide dismutase and glutathione-S-transferase activities, glutathione, vitamins C and E, testosterone, and progesterone levels were observed in both the testes and ovaries. Furthermore, PMD increased the nitric oxide level in both organs and altered the plasma lipid profiles in both sexes. Se and Zn supplementation, however, restored almost all the alterations observed in all the parameters analyzed. In conclusion, Se and Zn supplementation protects the male and female reproductive organs of rats against postnatal protein malnutrition.

Oral dydrogesterone versus micronized vaginal progesterone for luteal phase support: a double-blind crossover study investigating pharmacokinetics and impact on the endometrium.

STUDY QUESTION: How do plasma progesterone (P) and dydrogesterone (D) concentrations together with endometrial histology, transcriptomic signatures, and immune cell composition differ when oral dydrogesterone (O-DYD) or micronized vaginal progesterone (MVP) is used for luteal phase support (LPS)? SUMMARY ANSWER: Although after O-DYD intake, even at steady-state, plasma D and 20αdihydrodydrogesterone (DHD) concentrations spiked in comparison to P concentrations, a similar endometrial signature was observed by histological and transcriptomic analysis of the endometrium. WHAT IS KNOWN ALREADY: O-DYD for LPS has been proven to be noninferior compared to MVP in two phase III randomized controlled trials. Additionally, a combined individual participant data and aggregate data meta-analysis indicated that a higher pregnancy rate and live birth rate may be obtained in women receiving O-DYD versus MVP for LPS in fresh IVF/ICSI cycles. Little data are available on the pharmacokinetic (PK) profiles of O-DYD versus MVP and their potential molecular differences at the level of the reproductive organs, particularly at the endometrial level. STUDY DESIGN, SIZE, DURATION: Thirty oocyte donors were planned to undergo two ovarian stimulation (OS) cycles with dual triggering (1.000 IU hCG + 0.2 mg triptorelin), each followed by 1 week of LPS: O-DYD or MVP, in a randomized, cross-over, double-blind, double-dummy fashion. On both the first and eighth days of LPS, serial blood samples upon first dosing were harvested for plasma D, DHD, and P concentration analyses. On Day 8 of LPS, an endometrial biopsy was collected for histologic examination, transcriptomics, and immune cell analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: All oocyte donors were <35 years old, had regular menstrual cycles, no intrauterine contraceptive device, anti-Müllerian hormone within normal range and a BMI ≤29 kg/m2. OS was performed on a GnRH antagonist protocol followed by dual triggering (1.000 IU hCG + 0.2 mg triptorelin) as soon as ≥3 follicles of 20 mm were present. Following oocyte retrieval, subjects initiated LPS consisting of MVP 200 mg or O-DYD 10 mg, both three times daily. D, DHD, and P plasma levels were measured using liquid chromatography-tandem mass spectrometry. Histological assessment was carried out using the Noyes criteria. Endometrial RNA-sequencing was performed for individual biopsies and differential gene expression was analyzed. Endometrial single-cell suspensions were created followed by flow cytometry for immune cell typing. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 21 women completed the entire study protocol. Subjects and stimulation characteristics were found to be similar between groups. Following the first dose of O-DYD, the average observed maximal plasma concentrations (Cmax) for D and DHD were 2.9 and 77 ng/ml, respectively. The Cmax for D and DHD was reached after 1.5 and 1.6 h (=Tmax), respectively. On the eighth day of LPS, the first administration of that day gave rise to a Cmax of 3.6 and 88 ng/ml for D and DHD, respectively. For both, the observed Tmax was 1.5 h. Following the first dose of MVP, the Cmax for P was 16 ng/ml with a Tmax of 4.2 h. On the eighth day of LPS, the first administration of that day showed a Cmax for P of 21 ng/ml with a Tmax of 7.3 h. All 42 biopsies showed endometrium in the secretory phase. The mean cycle day was 23.9 (±1.2) in the O-DYD group versus 24.0 (±1.3) in the MVP group. RNA-sequencing did not reveal significantly differentially expressed genes between samples of both study groups. The average Euclidean distance between samples following O-DYD was significantly lower than following MVP (respectively 12.1 versus 18.8, Mann-Whitney P = 6.98e-14). Immune cell profiling showed a decrease of CD3 T-cell, γδ T-cell, and B-cell frequencies after MVP treatment compared to O-DYD, while the frequency of natural killer (NK) cells was significantly increased. LIMITATIONS, REASONS FOR CAUTION: The main reason for caution is the small sample size, given the basic research nature of the project. The plasma concentrations are best estimates as this was not a formal PK study. Whole tissue bulk RNA-sequencing has been performed not correcting for bias caused by different tissue compositions across biopsies. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study comparing O-DYD/MVP, head-to-head, in a randomized design on a molecular level in IVF/ICSI. Plasma serum concentrations suggest that administration frequency is important, in addition to dose, specifically for O-DYD showing a rapid clearance. The molecular endometrial data are overall comparable and thus support the previously reported noninferior reproductive outcomes for O-DYD as compared to MVP. Further research is needed to explore the smaller intersample distance following O-DYD and the subtle changes detected in endometrial immune cells. STUDY FUNDING/COMPETING INTEREST(S): Not related to this work, C.Bl. has received honoraria for lectures, presentations, manuscript writing, educational events, or scientific advice from Abbott, Ferring, Organon, Cooper Surgical, Gedeon-Richter, IBSA, and Merck. H.T. has received honoraria for lectures, presentations, manuscript writing, educational events, or scientific advice from Abbott, Ferring, Cooper Surgical, Gedeon-Richter, Cook, and Goodlife. S.M. has received honoraria for lectures, presentations, educational events, or scientific advice from Abbott, Cooper Surgical, Gedeon-Richter, IBSA, and Merck and Oxolife. G.G. has received honoraria for lectures, presentations, educational events, or scientific advice from Merck, MSD, Organon, Ferring, Theramex, Gedeon-Richter, Abbott, Biosilu, ReprodWissen, Obseva, PregLem, Guerbet, Cooper, Igyxos, and OxoLife. S.V.-S. is listed as inventor on two patents (WO2019115755A1 and WO2022073973A1), which are not related to this work. TRIAL REGISTRATION NUMBER: EUDRACT 2018-000105-23.

Structure-activity relationship and docking analysis of nature flavonoids as inhibitors of human and rat gonadal 3ß-hydroxysteroid dehydrogenases for therapeutic purposes.

The potential inhibitory effects of flavonoids on gonadal steroid biosynthesis have gained attention due to their widespread presence in natural plant sources. Specifically, our study focused on evaluating the inhibitory efficacy of these compounds on human 3ß-hydroxysteroid dehydrogenase 2 (h3ß-HSD2) and rat homolog r3ß-HSD1, enzymes responsible for the conversion of pregnenolone to progesterone. Through our investigations, we observed that the potency of flavonoids was silymarin (IC50, 1.31 µM) > luteolin (4.63 µM) > tectorigenin > (5.86 µM), and rutin (44.12 µM) in inhibiting human KGN cell microsomal h3ß-HSD2. Similarly, the potency of flavonoids was silymarin (9.50 µM) > luteolin (11.49 µM) > tectorigenin (14.06 µM), and rutin (145.71 µM) in inhibiting rat testicular r3ß-HSD1. Silymarin, luteolin, and tectorigenin acted as mixed inhibitors of both human and rat 3ß-HSDs. Luteolin and tectorigenin were able to penetrate human KGN cells to inhibit progesterone secretion. Furthermore, docking analysis and structure-activity relationship analysis highlighted the importance of hydrogen bond formation for the inhibitory efficacy of these compounds against h3ß-HSD2 and r3ß-HSD1. Overall, this study demonstrates that silymarin exhibits the most potent inhibition of human and rat gonadal 3ß-HSDs, and significant SAR differences exist among the tested compounds.

Sphingomyelin Metabolism Modifies Luminal A Breast Cancer Cell Line under a High Dose of Vitamin C.

The role of sphingomyelin metabolism and vitamin C in cancer has been widely described with conflicting results ranging from a total absence of effect to possible preventive and/or protective effects. The aim of this study was to establish the possible involvement of sphingomyelin metabolism in the changes induced by vitamin C in breast cancer cells. The MCF7 cell line reproducing luminal A breast cancer and the MDA-MB-231 cell line reproducing triple-negative breast cancer were used. Cell phenotype was tested by estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 expression, and proliferation index percentage. Sphingomyelin was localized by an EGFP-NT-Lys fluorescent probe. Sphingomyelin metabolism was analyzed by RT-PCR, Western blotting and UFLC-MS/MS. The results showed that a high dose of vitamin C produced reduced cell viability, modulated cell cycle related genes, and changed the cell phenotype with estrogen receptor downregulation in MCF7 cell. In these cells, the catabolism of sphingomyelin was promoted with a large increase in ceramide content. No changes in viability and molecular expression were observed in MB231 cells. In conclusion, a high dose of vitamin C induces changes in the luminal A cell line involving sphingomyelin metabolism.

Navigating a plethora of progesterone receptors: Comments on the safety/risk of progesterone supplementation in women with a history of breast cancer or at high-risk for developing breast cancer.

Progesterone and progestin agonists are potent steroid hormones. There are at least three major types of progesterone receptor (PR) families that interact with and respond to progesterone or progestin ligands. These receptors include ligand-activated transcription factor isoforms (PR-A and PR-B) encoded by the PGR gene, often termed classical or nuclear progesterone receptor (nPR), membrane-spanning progesterone receptor membrane component proteins known as PGRMC1/2, and a large family of progestin/adipoQreceptors or PAQRs (also called membrane PRs or mPRs). Cross-talk between mPRs and nPRs has also been reported. The complexity of progesterone actions via a plethora of diverse receptors warrants careful consideration of the clinical applications of progesterone, which primarily include birth control formulations in young women and hormone replacement therapy following menopause. Herein, we focus on the benefits and risk of progesterone/progestin supplementation. We conclude that progesterone-only supplementation is considered safe for most reproductive-age women. However, women who currently have ER + breast cancer or have had such cancer in the past should not take sex hormones, including progesterone. Women at high-risk for developing breast or ovarian cancer, either due to their family history or known genetic factors (such as BRCA1/2 mutation) or hormonal conditions, should avoid exogenous sex hormones and proceed with caution when considering using natural hormones to mitigate menopausal symptoms and/or improve quality of life after menopause. These individuals are urged to consult with a qualified OB-GYN physician to thoroughly assess the risks and benefits of sex hormone supplementation. As new insights into the homeostatic roles and specificity of highly integrated rapid signaling and nPR actions are revealed, we are hopeful that the benefits of using progesterone use may be fully realized without an increased risk of women's cancer.

The effect of progesterone supplementation in women with threatened miscarriage on fetal fraction in non-invasive prenatal testing: A matched case-control study.

AIM: To evaluate the effect of progesterone use on fetal fraction (FF) in non-invasive prenatal testing (NIPT) due to the threat of first trimester miscarriage. METHODS: This case control study included the pregnant who were referred to our clinic for non-invasive prenatal testing. The patients were categorized into three groups: Pregnant women with vaginal bleeding and using progesterone, pregnant women with vaginal bleeding and not using progesterone, and pregnant women without bleeding. The groups were formed by matching gestational week. Women with multiple pregnancy, BMI (body mass index) ≥25, abnormal fetal karyotype, and chronic disease were excluded from the study. Maternal characteristics, FF of the NIPT were recruited from the computer based medical records. RESULTS: A total of 10,275 NIPT tests were performed during the study period. 3% of the patients (n = 308) were found at risk of miscarriage. 100 patients with a vaginal bleeding and 50 control patients were matched. The median value of the fetal fraction ratio was found to be 6.55 in pregnant women without vaginal bleeding, 7.05 in pregnant women who had vaginal bleeding and using progesterone, and 7.3 in pregnant women who had vaginal bleeding and did not use progesterone. Although the fetal fraction ratio was found to be higher in pregnant women with vaginal bleeding and lower in progesterone users, this situation could not reach the level of statistical significance (p = 0.351). CONCLUSIONS: The fetal fraction rate in maternal blood is not affected in pregnant women who use progesterone due to vaginal bleeding in early gestational weeks.

Fennel affects porcine ovarian cell functions: The interrelationships with the environmental contaminant benzene.

The objective of this study was to examine the direct effects of the medicinal plant fennel on basic functions of ovarian cells, including proliferation, apoptosis, and release of progesterone and insulin-like growth factor I (IGFI), as well as to prevent the influence of the environmental contaminant benzene on these cells. Porcine ovarian granulosa cells were cultured with or without fennel extract alone or in combination with benzene. The expression of the proliferation marker PCNA and the apoptosis marker bax was analyzed by quantitative immunocytochemistry and enzyme-linked immunosorbent assay (ELISA). Fennel was able to promote proliferation and IGF-I release, but to suppress apoptosis and progesterone release. Benzene promoted the accumulation of both the proliferation and apoptosis markers, as well as IGF-I release, but it inhibited progesterone secretion. The presence of fennel did not prevent the effects of benzene on any of the measured parameters, while benzene prevented the effects of fennel on cell proliferation, apoptosis, and IGF-I but not progesterone output. These observations demonstrate the direct influence of fennel and benzene on basic ovarian cell functions. Furthermore, they show the inability of fennel to prevent the effects of benzene on these cells. On the other hand, the environmental contaminant benzene can block the response of ovarian cells to the medicinal plant fennel.

Effectiveness of Zhenqi Buxue Oral Liquid Combined with Progesterone for Treatment of Oligomenorrhea and Hypomenorrhea with Qi-Blood and Kidney (Shen) Essence Deficiency: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the effectiveness and safety of Zhenqi Buxue Oral Liquid (ZQ), progesterone capsules, and their combination in treating oligomenorrhea and hypomenorrhea with qi-blood and Kidney (Shen) essence deficiency. METHODS: This was a prospective, randomized, multi-center controlled trial between June 2022 to December 2022. Ninety-six oligomenorrhea and hypomenorrhea patients with qi-blood and Shen essence deficiency were randomly assigned to receive ZQ (ZQ group, 29 cases), progesterone capsules (PG group, 32 cases), or the combined Chinese and Western medicine (COM group, 31 cases) at a ratio of 1:1:1. Patients in the ZQ or PG group took daily 10 mL twice a day of ZQ or 200 mg once a day of progesterone capsules for 10 consecutive days on day 15 of the menstrual cycle respectively, and patients in the COM group received the same ZQ combined with progesterone capsules. The treatment course lasted for 3 months and follow-up was performed at 1 and 3 months after the end of treatment. Primary endpoint was the menstrual Traditional Chinese Medicine Syndrome Scale (TCMSS) scores. Secondary endpoints included pictorial blood loss assessment chart (PBAC) scores, clinical efficacy rate, 36-item Short Form Health Survey (SF-36) scores, sex hormones and thickness of endometrium. Adverse events (AEs) were recorded. RESULTS: TCMSS scores after 1- and 3-month treatment in all groups were significantly lower than those at baseline (P<0.05). Only TCMSS scores after 3-month treatment in the ZQ and COM groups continuously decreased compared with those after 1-month treatment in the same group (P<0.01). TCMSS scores after 3-month treatment in the ZQ and COM groups were significantly lower than those in the PG group (P<0.05, P<0.01). Compared with baseline, PBAC scores in the ZQ and COM groups after 3 months of treatment were also significantly higher (both P<0.01). The total effective rates of TCM syndrome of 3-month treatment were significantly improved in all groups compared with that after 1 month of treatment (P<0.05). The total effective rate of the COM group was the highest in the 3rd month of treatment and significantly higher than that of PG group alone (P<0.05). Compared with baseline, only the SF-36 scores of COM group were significantly improved after 3 months of treatment (P<0.05). No serious adverse reactions were observed after treatment. CONCLUSIONS: The combination of ZQ and PG, or ZQ only had better effects on reducing TCMSS scores compared with PG, and COM showed the higher total effective rate compared with monotherapy. Besides, COM could effectively improve menstrual blood loss and quality of life. ZQ combined with PG may be an effective and safe option for oligomenorrhea and hypomenorrhea patients with qi-blood and Shen essence deficiency.

New medicines for spontaneous preterm birth prevention and preterm labour management: landscape analysis of the medicine development pipeline.

BACKGROUND: There are few medicines in clinical use for managing preterm labor or preventing spontaneous preterm birth from occurring. We previously developed two target product profiles (TPPs) for medicines to prevent spontaneous preterm birth and manage preterm labor. The objectives of this study were to 1) analyse the research and development pipeline of medicines for preterm birth and 2) compare these medicines to target product profiles for spontaneous preterm birth to identify the most promising candidates. METHODS: Adis Insight, Pharmaprojects, WHO international clinical trials registry platform (ICTRP), PubMed and grant databases were searched to identify candidate medicines (including drugs, dietary supplements and biologics) and populate the Accelerating Innovations for Mothers (AIM) database. This database was screened for all candidates that have been investigated for preterm birth. Candidates in clinical development were ranked against criteria from TPPs, and classified as high, medium or low potential. Preclinical candidates were categorised by product type, archetype and medicine subclass. RESULTS: The AIM database identified 178 candidates. Of the 71 candidates in clinical development, ten were deemed high potential (Prevention: Omega-3 fatty acid, aspirin, vaginal progesterone, oral progesterone, L-arginine, and selenium; Treatment: nicorandil, isosorbide dinitrate, nicardipine and celecoxib) and seven were medium potential (Prevention: pravastatin and lactoferrin; Treatment: glyceryl trinitrate, retosiban, relcovaptan, human chorionic gonadotropin and Bryophyllum pinnatum extract). 107 candidates were in preclinical development. CONCLUSIONS: This analysis provides a drug-agnostic approach to assessing the potential of candidate medicines for spontaneous preterm birth. Research should be prioritised for high-potential candidates that are most likely to meet the real world needs of women, babies, and health care professionals.

Kisspeptin promotes follicular development through its effects on modulation of P450 aromatase expression and steroidogenesis in sheep ovarian follicles.

The present study was conducted to ascertain whether the role of kisspeptin in promoting in vitro development of preantral follicles was through the regulation of P450 aromatase gene expression and steroidogenesis in sheep. Accordingly, the cumulus cells and oocytes were collected from different development stages of preantral follicles grown in vivo and cultured in vitro in TCM199B (Group I), TCM199B + KP (10 µg/mL) (Group II) and Standard medium + KP (10 µg/mL). To measure the steroid (Estradiol-17ß; E2 and Progesterone; P4 ) synthesis through ELISA, spent culture medium was collected separately from the same in vitro groups. E2 synthesis in the spent medium collected from all the three groups showed an increasing trend from PFs' exposed to respective culture media for 3 min to 2-day culture stage but decreased thereafter till 6-day culture stage. This is followed by a sharp increase in E2 concentration in the spent medium collected after in vitro maturation. However, P4 synthesis in group III followed increased pattern as the development progressed from PFs' exposed to culture medium for 3 min to in vitro maturation stage. The steroid production was observed at all stages of in vitro development in altered supplemented conditions. The steroid synthesis in the spent medium was highest in the 6 day cultured PFs' in Standard medium + KP matured in vitro for 24 h. Therefore, supplementation of kisspeptin along with other growth factors promoted steroid production in cultured preantral follicles far better than in other media.

Glucocorticoid supplementation during ovulation induction for assisted reproductive technology: a systematic review and meta-analysis.

BACKGROUND: There is ongoing interest in glucocorticoid treatment during oocyte stimulation to treat infertility in women who have undergone Assisted Reproductive Technology (ART). OBJECTIVE: This meta-analysis was performed to evaluate the efficiency and safety of adjuvant glucocorticoid therapy on pregnancy outcomes in infertile women undergoing ART cycles. STUDY DESIGN: A literature search was performed in PubMed, EMBASE, Web of Science, and the Cochrane Library up to December 2022. To assess the efficacy and safety of additional glucocorticoid treatment during ovulation induction in women who underwent IVF or ICSI treatment, only randomized controlled trials were included. RESULTS: Overall, glucocorticoid therapy during ovulation showed a nonsignificant effect of prednisolone improving the live birth rate (OR = 1.03, 95% CI [.75, 1.43], I2 = .0%, p = .84), abortion rate (OR = 1.14, 95% CI [.62, 2.08], I2 = 31%, p = .68), and implantation rate (OR = 1.1, 95% CI [.82, 1.5], I2 = 8%, p = .52) of infertile women compared to the control group. The present meta-analysis revealed that the clinical pregnancy rate per cycle tended to increase after glucocorticoid treatment (OR = 1.29, 95% CI [1.02, 1.63], I2 = 8%, p = .52). CONCLUSIONS: The present meta-analysis suggested that ovarian stimulation prednisolone therapy does not significantly improve clinical outcomes in women undergoing IVF/ICSI. Although the results indicated that adjuvant glucocorticoid therapy during ovarian stimulation may increase the clinical pregnancy rate, subgroup analysis showed that it was affected by infertility factors, dose schedules, and length of treatment. Therefore, these results should be interpreted with caution.

The effects of rumen protected methionine supplementation on the performance of primiparous dairy cows using the Presynch-Ovsynch protocol.

The purpose of this study was to examine the effects of rumen-protected methionine (RPM) supplementation on the reproductive and productive performance of primiparous dairy cows fed two levels of protein. The Presynch-Ovsynch protocol was used to synchronize 36 lactating Holstein cows that were assigned randomly to one of six dietary treatments: (1) 14% CP and without RPM diet (14CP-0RPM; n = 6), (2) 14% CP and 15 g/head/day RPM (14CP-15RPM; n = 6), (3) 14% CP and 25 g/head/day RPM (14CP-25RPM; n = 6), (4) 16% CP and without RPM diet (16CP-0RPM; n = 6), (5) 16% CP and 15 g/head/day RPM (16CP-15RPM; n = 6), and (6) 16% CP and 25 g/head/day RPM (16CP-25RPM; n = 6). Independent of CP levels, feeding RPM had reduced the calving interval (P < 0.01). Feeding RPM increased (P < 0.01) overall plasma progesterone (P4). Feeding 16CP-15RPM increased (P < 0.01) overall plasma P4. Feeding 16% CP increased (P < 0.01) 4% fat corrected milk, energy corrected milk, milk fat and protein yield, and milk casein. Moreover, feeding the 25RPM has increased (P < 0.01) 4% fat corrected milk, energy corrected milk, milk fat, and protein yield. Compared with other treatments, feeding 16CP-25RPM or 16CP-15RPM enhanced (P < 0.01) milk yield and milk fat yield. In conclusion, feeding 16% CP with RPM boosted the productivity and reduced the calving interval in primiparous lactating dairy cows.

The association between the type of progesterone supplementation and miscarriage risk in women who have had a positive pregnancy test following embryo transfer: a retrospective cohort study.

PURPOSE: The purpose of this study was to identify if switching from intramuscular (IM) to vaginal progesterone compared to staying on IM progesterone after a positive pregnancy test following embryo transfer (ET) is associated with miscarriage risk. METHODS: A retrospective cohort study was performed in a private university-affiliated fertility clinic and included women aged 18-50 years with a positive pregnancy test following ET. The two groups studied were: women who stayed on IM progesterone following a positive pregnancy test and those who switched to vaginal progesterone after a positive test. The main outcome measured was risk of miscarriage < 24 weeks gestation as a proportion of non-biochemical pregnancies. RESULTS: 1988 women were included in the analysis. Among the baseline characteristics, the presence of prior miscarriages as well as prior failed ETs, and frozen cycles (vs fresh) as type of transfer were associated with IM progesterone use (p values ≤ 0.01). As per miscarriage risk < 24 weeks, 22.4% (274/1221) of patients in the IM progesterone group experienced a miscarriage compared with 20.7% (159/767) in the vaginal progesterone group (OR 0.90; 95% CI 0.73-1.13). A multivariable logistic regression model revealed an adjusted OR (aOR) of 0.97 (95% CI 0.77-1.22). CONCLUSION: This study suggests that switching from IM to vaginal progesterone after a positive pregnancy test following an ET is not associated with miscarriage risk. Considering that IM progesterone imposes substantial discomfort, this study offers reassurance and some flexibility in treatment protocols. Further prospective studies are necessary to corroborate the results of this study.

Fish oil supplementation protects against protein undernutrition-induced testicular and ovarian biochemical alterations in rats.

Proteins are required for biological functions and their inadequacy might impair the growth and development of the reproductive system. The study investigated the effects of fish oil (FO) supplementation on low-protein diet-induced alterations in male and female reproductive organs. Male and female rats were assigned randomly to four groups respectively. The NPD rats had five rats per group and were given 16% casein diet while the LPD rats had eight rats per group and received 5% casein diet. After the 8th week, FO was administered for 3 weeks via oral gavage at a concentration of 400 mg Kg-1 after which the rats were sacrificed and testes and ovaries were excised. LPD-fed rats showed lower body weights for both genders. In LPD-fed rats, NO was significantly increased while GSH, vitamins C and E levels, the activities of CAT (except in ovaries), and GST were significantly reduced in both tissues. The activities of SOD and GPx were only reduced in the testes including sperm count, motility, and increase deformed sperm cells. Testosterone and progesterone levels were also reduced and lipid homeostasis was disrupted in the plasma of LPD-fed rats. FO supplementation reduces the NO, CHOL, TG, LDL (in females), and VLDL but significantly improves HDL (in females), testosterone, and progesterone levels, sperm count, motility, and morphology. The antioxidant status of both tissues also increased significantly in LPD-fed rats. Conclusively, FO might be effective in improving testicular and ovarian functions and for the maintenance of plasma lipid homeostasis in LPD-fed rats.