Quantitative analyses of cytokine profiles reveal hormone-mediated modulation of cytokine profiles in recurrent spontaneous miscarriage.

PURPOSE: Cytokines play important roles in pregnancy complications. Some hormones such as estrogen, progesterone, and dydrogesterone have been shown to alter cytokine profiles. Understanding how cytokine profiles are affected by these hormones is therefore an important step towards immunomodulatory therapies for pregnancy complications. We analyse previously published data on the effects of estrogen, progesterone, and dydrogesterone on cytokine balances in women having recurrent spontaneous miscarriages. MATERIALS AND METHODS: Levels of eight cytokines (IFN-γ, IL-2, IL-6, IL-10, IL-13, IL-17, IL-23, TNF-α) from n = 22 women presenting unexplained recurrent spontaneous miscarriages were studied. Cytokine values were recorded after in vitro exposure of peripheral blood cells to estrogen, progesterone, and dydrogesterone. We expand on earlier analysis of the dataset by employing different statistical techniques including effect sizes for individual cytokine values, a more powerful statistical test, and adjusting p-values for multiple comparisons. We employ multivariate analysis methods, including to determine the relative magnitude of the effects of the hormone therapies on cytokines. A new statistical method is introduced based on pairwise distances able to accommodate complex relations in cytokine profiles. RESULTS: We report several statistically significant differences in individual cytokine values between the control group and each hormone treated group, with estrogen affecting the fewest cytokines, and progesterone and dydrogesterone both affecting seven out of eight cytokines. Exposure to estrogen produces no large effects sizes however, while IFN-γ and IL-17 show large effect sizes for both progesterone and dydrogesterone, among other cytokines. Our new method for identifying which collections (i.e. subsets) of cytokines best distinguish contrasting groups identifies IFN-γ, IL-10 and IL-23 as especially noteworthy for both progesterone and dydrogesterone treatments. CONCLUSIONS: While some statistically significant differences in cytokine levels after exposure to estrogen are found, these have small effect sizes and are unlikely to be clinically relevant. Progesterone and dydrogesterone both induce statistically significant and large effect-size differences in cytokine levels, hence therapy with these two progestogens is more likely to be clinically relevant. Univariate and multivariate methods for identifying cytokine importances provide insight into which groups of cytokines are most affected and in what ways by therapies.

Effects of Dydrogesterone Tablets Combined with Zishen Yutai Pills on Threatened Abortion in Early Pregnancy and Pregnancy Outcomes.

Objective: To explore the effect of dydrogesterone tablets combined with Zishen Yutai pills on threatened abortion in early pregnancy and pregnancy outcomes. Methods: This study retrospectively analyzed the clinical data of 100 patients with threatened abortion in early pregnancy who came to the Linhai Second People's Hospital/Taizhou Municipal Hospital from January 13, 2021, to January 13, 2022. According to different treatment methods, 48 patients treated with progesterone injection were assigned to the control group (CG), while 52 cases with the combined therapy of dydrogesterone tablets and Zishen Yutai pills were assigned to the observation group (OG). The two groups were compared in terms of the following parameters: treatment efficacy, whole blood high shear viscosity, hematocrit (HCT), plasma fibrinogen (FIB) level, spiral artery pulsatility index (PI), uterine spiral artery blood flow resistance index (RI), lumbar and abdominal pain relief time, hemostasis time, estrogen levels, pregnancy outcomes, neonatal adverse outcomes, and incidence of adverse reactions. Results: Compared with CG, the therapeutic effect in OG was observed to be evidently better, and its pain relief time and hemostasis time in the waist and abdomen were markedly shorter. After treatment, the whole blood high shear viscosity, FIB, RI, PI, and estrogen levels of both groups improved statistically compared with those before treatment, with more significant improvements in OG compared with CG. OG was also superior to CG with markedly lower incidence of preterm birth, miscarriage, neonatal adverse outcomes, and adverse reactions and a drastically higher full-term pregnancy rate. Conclusion: Zishen Yutai pill combined with dydrogesterone tablets is of remarkable therapeutic effect in treatment of early threatened abortion, which can significantly improve clinical symptoms and pregnancy outcomes of patients, with a high safety profile, which is worthy of clinical application.

Comparison of Dydrogesterone and Medroxyprogesterone in the Progestin-Primed Ovarian Stimulation Protocol for Patients With Poor Ovarian Response.

Objective: To compare the clinical outcomes of dydrogesterone (DYG) and medroxyprogesterone (MPA) in the progestin-primed ovarian stimulation (PPOS) protocol for patients with poor ovarian response (POR). Patients and Methods: This was a retrospective cohort study. Women with POR who underwent IVF/ICSI at the Reproductive Center of Third Affiliated Hospital of Zhengzhou University between January 2020 and January 2021 were included. The primary outcome measure of our study was the number of oocytes retrieved. The secondary outcome measures in the present study were the number of 2PN, number of available embryos, oocyte retrieval rate, fertilization rate, viable embryo rate per oocyte retrieved, cancellation rate and pregnancy outcomes of the first embryo transfer cycle, including the biochemical pregnancy, clinical pregnancy and miscarriage rates. Results: In total, 118 women underwent hMG +DYG protocols, and 692 women who underwent hMG +MPA met the Bologna criteria for POR. After baseline characteristics were balanced using the PSM model, 118 hMG +DYG protocols were matched to 118 hMG +MPA protocols, and the baseline characteristics were comparable between the two groups. The numbers of oocytes retrieved, 2PN, and available embryos and the oocyte retrieval rate, fertilization rate, viable embryo rate per oocyte retrieved and cancellation rate of the hMG+DYG and hMG+MPA protocols were comparable. Altogether, 66 women in the hMG+DYG group and 87 women in the hMG+MPA group underwent first embryo transfers. In the hMG+DYG group, 81.8% (54/66) of the patients underwent cleavage embryo transfers; similarly, 79.3% (69/87) of patients in the hMG+MPA group had cleavage embryo transfers (P=0.70).The biochemical pregnancy rate of the hMG+DYG group was 42.4%, and this was comparable to the rate in the hMG+DYG group, at 34.5% (P=0.32). The clinical pregnancy rates were similar between the two groups (36.4% vs. 31.0%, P=0.49), and there was no significant difference in the rate of miscarriage between the two groups (12.5% vs. 29.6%, P=0.14). Conclusion: For women with POR, the clinical outcome of the hMG + DYG group was similar to that of the hMG + MPA group, indicating that both combinations can be useful options for PPOS protocols.

Effect of Oral versus Vaginal Administration of Estradiol and Dydrogesterone on the Proliferative and Secretory Transformation of Endometrium in Patients with Premature Ovarian Failure and Preparing for Assisted Reproductive Technology.

PURPOSE: This study aimed to assess the efficacy of vaginally versus orally administered estradiol (E2) and dydrogesterone (DG) on the proliferative and secretory transformation of endometrium in patients with premature ovarian failure (POF) and preparing for assisted reproductive technology. METHODS: Twenty patients with POF who were awaiting oocyte donation were included in the study; they were randomly assigned to two groups to receive E2 and DG either orally or vaginally. Treatment efficacy was compared between the two groups regarding blood E2 concentrations, endometrial thickness, histology using hematoxylin and eosin staining, immunohistochemical analysis of ER expression, and PR and pinopodes morphology using scanning electron microscopy. RESULTS: E2 concentrations differed significantly between oral and vaginal E2 and DG administration for 14 days (82.3 vs 1015.6 pg/mL; P < 0.001) and 21 days (85.0 vs 809.8 pg/mL; P < 0.001). Endometrial thickening was more pronounced in the vaginal treatment group, and also ER staining was stronger on days 14 and 21 in the vaginal treatment group. PR staining in the endometrium appeared more intense in the oral treatment group, which was, however, not significant. The abundance of developing pinopodes was higher in the vaginal treatment group (P = 0.04). CONCLUSION: Vaginal administration of E2 and DG is more effective than oral administration regarding proliferative and secretory transformation of the endometrium in POF patients and preparing for assisted reproductive technology.

Effectiveness of progesterone-primed ovarian stimulation in assisted reproductive technology: a systematic review and meta-analysis.

PURPOSE: Progestin-primed ovarian stimulation (PPOS) is a new ovarian stimulation protocol that has been used over the last decade to enhance reproductive function. The purpose of this study is to evaluate whether PPOS is as effective as conventional protocols (without GnRHa downregulation). METHOD: Search terms included "medroxyprogesterone", "dydrogesterone", "progestin-primed ovarian stimulation", "PPOS", "oocyte retrieval", "in vitro fertilization", "IVF", "ICSI", "ART", and "reproductive". The selection criteria were nonrandomized studies and randomized controlled studies. For data collection and analysis, the Review Manager software, Newcastle-Ottowa Quality Assessment Scale and GRADE approach were used. RESULTS: The clinical pregnancy rates were not significantly different in either RCTs or NRCTs [RR 0.96, 95% CI (0.69-1.33), I2 = 71%, P = 0.81]; [RR 0.99, 95% CI (0.83-1.17), I2 = 38%, P = 0.88]. The live birth rates of RCTs and NRCTs did not differ [RCT: RR 1.08, 95% CI (0.74, 1.57), I2 = 66%, P = 0.69; NRCT: OR 1.03 95% CI 0.84-1.26), I2 = 50%, P = 0.79]. The PPOS protocol had a lower rate of OHSS [RR 0.52, 95% CI (0.36-0.75), I2 = 0%, P = 0.0006]. The secondary results showed that compared to the control protocol, the endometrium was thicker [95% CI (0.00-0.78), I2 = 0%, P = 0.05], the number of obtained embryos was higher [95% CI (0.04-0.65), I2 = 17%, P = 0.03] and more hMG was needed [in NRCT: 95% CI (307.44, 572.73), I2 = 0%, P < 0.00001] with the PPOS protocol. CONCLUSION: The PPOS protocol produces more obtained embryos and a thicker endometrium than the control protocol, with a lower rate of OHSS and an equal live birth rate. The PPOS protocol could be a safe option as a personalized protocol for infertile patients. TRIAL REGISTRATION: Registration at PROSPERO: CRD42020176577.

Dydrogesterone-primed ovarian stimulation is an effective alternative to gonadotropin-releasing hormone antagonist protocol for freeze-all cycles in polycystic ovary syndrome.

OBJECTIVE: To compare the effects of progestin-primed ovarian stimulation using dydrogesterone (DYD) and a gonadotropin-releasing hormone (GnRH) antagonist protocol on cycle characteristics and pregnancy rates in freeze-all cycles in patients with polycystic ovary syndrome (PCOS). METHODS: Medical records of PCOS patients who underwent freeze-all in vitro fertilization cycles between April 2017 and April 2019 at the Novafertil in vitro fertilization Center were retrospectively evaluated. The primary outcome measure was the incidence of premature luteinizing hormone surge. Secondary outcome measures were the total number of mature oocytes retrieved, fertilization rate, clinical pregnancy rates and ongoing pregnancy rates. RESULTS: A total of 525 patients were included in the study. DYD-primed ovarian stimulation and a GnRH antagonist protocol were applied in 258 and 267 patients, respectively. The baseline parameters were similar between the two groups. The numbers of mature and fertilized oocytes were similar in the cetrorelix (CET) group and DYD group (11.43 ± 3.48 vs. 11.29 ± 4.34, respectively, P = 0.692; and 8.98 ± 2.93 vs. 8.62 ± 3.67, respectively, P = 0.208). Premature luteinization was rare in both groups, and the difference between the groups was not statistically significant (2.9% vs. 1.5%, respectively, P = 0.268). There was no significant difference in clinical pregnancy rate of the first frozen embryo transfer cycle between the DYG group and the CET group (56% [120/214] vs. 55.6% [113/203], respectively, P = 0.283). There were no significant differences in biochemical pregnancy rates, implantation rates, miscarriage rates or ongoing pregnancy rates between the two groups (P > 0.05). CONCLUSION: Dydrogesterone-primed ovarian stimulation seems to be an effective alternative to the GnRH antagonist protocol for freeze-all cycles in PCOS patients.

PGRMC1 in animal breast cancer tissue and blood is associated with increased tumor growth with norethisterone in contrast to progesterone and dydrogesterone: four-arm randomized placebo-controlled xenograft study.

Progesterone receptor membrane component 1 (PGRMC1) is mediating strong breast cancer cell proliferation induced by certain synthetic progestogens which we have shown within already published in vitro studies. Aim was now to use an animal model, to compare tumor growth using progesterone and its isomer dydrogesterone with norethisterone, which elicited in our in vitro studies the strongest proliferating effect. For the first time, we wanted to investigate if growth can be correlated both with blood concentrations and tissue expression of PGRMC1 to identify if PGRMC1 could be a new tumor marker. Prospective, randomized, blinded, placebo-controlled four-arm study (45-50 days); PGRMC1-transfected or empty-vector T47D- and MCF7-xenotransplants were each treated with estradiol (E2) +placebo; E2 + progesterone; E2 + norethisterone; E2 + dydrogesterone; blood PGRMC1 assessed by a novel ELISA, tissue expression by immunohistochemistry. PGRMC1-transfected tumors further increased with E2 + norethisterone but not with E2-dydrogesterone or E2-progesterone. In both PGRMC1-xenograft groups (T47D, MCF7) with E2/norethisterone, the blood concentrations and tissue expression of PGRMC1 were higher than in all other 14 groups (p < .05), with positive significant correlation between blood PGRMCI concentrations and tissue PGRMC1 expression. In the presence of PGRMC1, certain progestogens could increase the growth of breast tumor, which now also should be tested in clinical studies.

Neonatal outcomes and congenital malformations in children born after dydrogesterone application in progestin-primed ovarian stimulation protocol for IVF: a retrospective cohort study.

PURPOSE: Dydrogesterone (DYG) has been demonstrated to be an alternative progestin in the progestin-primed ovarian stimulation (PPOS) protocol with comparable oocyte retrieval and pregnancy outcomes. However, its safety regarding neonatal outcomes and congenital malformations is still unclear. PATIENTS AND METHODS: This retrospective cohort study included 3556 live-born infants after in vitro fertilization and vitrified embryo transfer cycles using the DYG + human menopausal gonadotropin (hMG) protocol (n=1429) or gonadotropin-releasing hormone (GnRH)-agonist short protocol (n=2127) from January 2014 to December 2017. Newborn information was gathered from standardized follow-up questionnaires and/or access to medical records within 7 days after birth. Associations between ovarian stimulation protocols and outcome measures were analyzed by binary logistic regression after adjusting for confounding factors. RESULTS: In both singletons and twins, birth characteristics regarding mode of delivery, newborn gender, gestational age, birthweight, length at birth and Z-scores were comparable between the two protocols. For adverse neonatal outcomes, the two protocols showed no significant differences on the rates of low birthweight, very low birthweight, preterm birth, very preterm birth, small-for-gestational age, large-for-gestational age and early neonatal death after adjustment. Furthermore, the incidence of major congenital malformations in the DYG + hMG protocol (1.12%) was similar to that in the GnRH-agonist short protocol (1.08%), with the adjusted odds ratio of 0.98 (95% confidence interval [CI]: 0.40-2.39) and 0.90 (95% CI: 0.33-2.41) in singletons and twins, respectively. CONCLUSION: Our data suggested that compared with the conventional GnRH-agonist short protocol, application of DYG in the PPOS protocol was a safe option for the newborn population without compromising neonatal outcomes or increasing congenital malformation risks.

Progestogens and PGRMC1-dependent breast cancer tumor growth: An in-vitro and xenograft study.

OBJECTIVES: A few observational studies have suggested that progesterone and dydrogesterone may have a lower risk of breast cancer than other progestogens. In our earlier xenograft animal experiments, progesterone did not stimulate breast tumors. The aim of this study was to test dydrogesterone for the first time. The study also evaluated the effects of PGRMC1 on proliferation with progestogens. METHODS (1): In-vitro study. The proliferative effects of dydrogesterone and of progesterone were assessed in vitro using T47D cells transfected with PGRMC1 or empty vector in the presence or absence of estradiol. Additionally, to find the strongest proliferator for inclusion as a comparator in the xenograft animal study, norethisterone, levonorgestrel, desogestrel, dienogest, drospirenone, nomegestrol, and cyproterone acetate were tested. METHODS (2): Xenograft main study. PGRMC1-transfected or empty-vector T47D and MCF7 xenotransplants were each treated with four different hormonal preparations: E2+placebo; E2+dydrogesterone; E2+progesterone; E2+norethisterone. A total of 112 castrated mice were randomly allocated to the 16 groups. This was thus a prospective, randomized, blinded, placebo-controlled four-arm study (45-50 days) with the two T47D and two MCF7 xenografts. Tumor volumes were monitored twice weekly. RESULTS (1): In-vitro study. The strongest proliferation was with norethisterone, but only with PGRMC1-transfected cells. There was significant proliferation with dydrogesterone, but not with progesterone in the absence of estradiol. However, no increase in proliferation was achieved by adding dydrogesterone to estradiol compared with the proliferation induced with estradiol alone, in contrast to norethisterone. RESULTS (2): Xenograft main study. There was significantly faster tumor growth with norethisterone + E2 than with E2+placebo in T47D and MCF7 PGRMC1 xenografts, but not with dydrogesterone + E2 or progesterone + E2. There was less tumor growth in empty-vector xenografts, without between-group differences. CONCLUSION: PGRMC1 increases the breast-cell proliferation effects of certain progestogens, including dydrogesterone, in contrast to progesterone, but not during estradiol-induced proliferation, either in vitro or in a xenograft animal model, in contrast to norethisterone. Thus the proliferative potency of dydrogesterone may be similar to that of progesterone. Clinical studies in women overexpressing PGRMC1 are recommended.

Efficacy of progesterone on threatened miscarriage: Difference in drug types.

AIM: To investigate whether treatment with progesterone would decrease the incidence of miscarriage in women who faced threatened miscarriage. METHODS: Randomized controlled trials (RCT) were identified by searching PubMed, Embase, Cochrane Library and Web of Science. Trials were included if they compared progesterone with placebo, no treatment or any other treatment given in an effort to treat threatened miscarriage. Pregnant prophylaxis drugs were not included without strict progesterone type, language and progesterone management. The primary outcome was the incidence of miscarriage. The summary measures were reported as relative risk (RR) with 95% confidence interval (CI). RESULTS: Eight RCT including 845 women who faced threatened miscarriage were analyzed. Pooled data from the eight trials showed that women with threatened miscarriage who were randomized to the progesterone group had a lower risk of threatened miscarriage (RR = 0.64, 95% CI 0.48-0.85). Dydrogesterone was shown to have a lower risk of miscarriage (RR = 0.49, 95% CI 0.33-0.75) than natural progesterone (RR = 0.69, 95% CI 0.40-1.19). Oral management was demonstrated to have a lower risk of miscarriage (RR = 0.55, 95% CI 0.38-0.79) compared with vaginal administration (RR = 0.58, 95% CI 0.28-1.21). CONCLUSION: Our findings show that progesterone agents are effective in reducing the incidence of miscarriage in threatened miscarriage. Dydrogesterone, but not natural progesterone, was associated with a lower risk of miscarriage. Given the limitations of the studies included in our meta-analysis, it is difficult to recommend route and dose of progesterone therapy. Further head-to-head trials of gestational weeks and long-time follow-up are required.

Effect of Menopausal Hormone Therapy on Bone Mineral Density in Chinese Women: A 2-Year, Prospective, Open-Label, Randomized-Controlled Trial.

BACKGROUND This study was designed to explore the effect of menopausal hormone therapy (MHT) on bone mineral density (BMD) in Chinese women. MATERIAL AND METHODS This was a prospective, open-label, randomized-controlled clinical trial. We randomly assigned 123 postmenopausal women to 3 groups: group A received 0.625 mg conjugated equine estrogen (CEE) plus 100 mg micronized progesterone (MP), group B received 0.3 mg CEE daily plus 100 mg MP, and group C received 0.625 mg CEE daily plus 10 mg dydrogesterone (DHG). All subjects received a 2-year intervention and drugs were given in a continuous sequential pattern. RESULTS Ninety-six patients were followed up. At 1 year, groups A and B gained 2.31% and 1.95% BMD, respectively (P<0.01); at 2 years, groups B and C gained 2.37% and 4.15% BMD (P<0.01) respectively. At 2 years, group A gained 3.28% BMD in the femoral neck and 3.77% BMD in Ward's triangle (P<0.05). At 1 year, group B lost 2.14% BMD in the trochanter and 1.20% BMD in the total hip (P<0.05); at 2 years, group B lost 1.51% BMD in the total hip (P<0.01). ALP, Ca, P, and Ca/Cr levels were all decreased in the 3 groups (P<0.05). The changes in Cr level at 1 and 2 years were not significant when compared with baseline in all groups (P>0.05). CONCLUSIONS Both lower-dose and standard-dose CEE increased lumbar BMD, sustain femoral neck BMD, and Ward's triangle BMD, while there was a reduced bone turnover rate. Standard-dose CEE combined with MP can increase BMD at these 2 sites. CEE combined with MP is recommended because it has better clinical benefits.

Biotransformation of progestonic hormone dydrogesterone with Macrophomina phaseolina, and study of the effect of biotransformed products on phagocytes oxidative burst.

Biotransformation of a synthetic progestonic hormone dydrogesterone (1), C21H28O2, with a plant pathogenic fungus Macrophomina phaseolina yielded two new 2 and 3, and a known 4 metabolites. These analogues were identified as, 3ß,11α-dihydroxy-5ß,9ß,10α-pregna-7-ene-6,20-dione (2), 15ß-hydroxy-9ß,10α-pregna-4,6-diene-3,20-dione (3), and 8α-hydroxy-9ß,10α-pregna-4,6-diene-3,20-dione (4). Major structural changes were observed in metabolite 2. New metabolite 3 showed anti-inflammatory potential, and was found to be the potent inhibitor of intracellular reactive oxygen species (ROS) from whole blood phagocytes (IC50 = 4.2 ±â€¯0.3 µg/mL), as compared to standard drug Ibuprofen (IC50 = 11.2 ±â€¯1.9 µg/mL). The metabolites 2, 3, and 4 were found to be non-toxic to NIH-3T3 (CRL-1658) normal cell line. This indicated anti-inflammatory potential of resulting metabolites.

The efficacy and safety of dydrogesterone for treatment of dysmenorrhea: An open-label multicenter clinical study.

AIMS: Dydrogesterone is a retro-progesterone preparation widely used for over a half century. We sought to evaluate the efficacy and safety of dydrogesterone in Japanese women with dysmenorrhea. METHODS: This study was conducted as an open-label, single-arm, multicenter study. One dydrogesterone 5-mg tablet (Duphaston) was administered orally twice daily for 21 days from the 5th to 25th day of each menstrual cycle. A total of 44 (safety analysis) and 31 patients (efficacy analysis) were enrolled. Total dysmenorrhea score, dysmenorrhea subscale scores, dysmenorrhea visual analog scale, severity of menstruation-related lower abdominal pain, low back pain, headache, and nausea/vomiting, basal body temperature, and serum estradiol and progesterone levels were evaluated. RESULTS: Baseline of the total dysmenorrhea score was 4.61, which went down over time following the administration of dydrogesterone, and the decrease was statistically significant at and after 2nd cycle of menstruation. Mean change from baseline at the final evaluation point was -1.84 (P < 0.001). Severity of menstruation-related lower abdominal pain, low back pain, headache, and nausea/vomiting, in the evaluated menstruation cycles tended to decrease over time. Basal body temperature showed a biphasic pattern in 70% at baseline, 50% in 2nd menstruation cycle, and 61% in 5th menstruation cycle, and at least half of the patients may have had ovulation during the treatment. Incidence of adverse drug reactions was 31.8%, and the most common adverse event was metrorrhagia. CONCLUSION: Dydrogesterone is efficacious, safe, and clinically beneficial in patients with dysmenorrhea, thereby indicating that dydrogesterone can be considered as a treatment option for patients with dysmenorrhea.

Progestin-Primed Ovarian Stimulation with Dydrogesterone versus Medroxyprogesterone Acetate in Women with Polycystic Ovarian Syndrome for in vitro Fertilization: A Retrospective Cohort Study.

PURPOSE: Dydrogesterone (DYG) is an alternative progestin in progestin-primed ovarian stimulation (PPOS) protocol with weaker pituitary suppression than medroxyprogesterone acetate (MPA) in normal ovulatory women. However, the endocrinological characteristics, oocyte retrieval and pregnancy outcomes of DYG application in polycystic ovarian syndrome (PCOS) patients undergoing in vitro fertilization (IVF) remain unclear. PATIENTS AND METHODS: This retrospective cohort study included 420 PCOS patients who underwent controlled ovarian stimulation with human menopausal gonadotropin (hMG) and DYG (n=105) or MPA (n=315) from January 2014 to December 2017. Baseline characteristics of the two groups were balanced with propensity score matching using the nearest-neighbor random matching algorithm in a ratio of 1:3. The primary outcome measure was the number of oocytes retrieved. Other main outcome measures included the number of viable embryos, incidence of premature luteinizing hormone (LH) surge and live birth rate per frozen-thawed embryo transfer (FET) cycle. RESULTS: A similar number of oocytes was retrieved in the two protocols (16.1±6.5 vs 15.1±10.0, P=0.342). Patients in both groups achieved consistent LH suppression with no premature LH surge detected. In the DYG + hMG group, the mean LH levels were significantly higher than the MPA + hMG group on cycle day 9-11 and trigger day (all P<0.001), and the dose of hMG was significantly lower (1710.7±431.6 vs 1891.3±402.2 IU, P<0.001). No significant between-group differences were found in the number of viable embryos (5.3±3.1 vs 5.0±4.1, P=0.139) and live birth rate per FET cycle (43.5% vs 47.7%, P=0.383). None of the participants experienced moderate-to-severe ovarian hyperstimulation syndrome in either group. CONCLUSION: Our results showed that the application of DYG in PPOS protocol could achieve comparable oocyte retrieval and pregnancy outcomes to MPA, but significantly reduce the consumption of gonadotropins in PCOS women for IVF treatment.

The steroid hormone dydrogesterone inhibits myometrial contraction independently of the progesterone/progesterone receptor pathway.

AIMS: In this study, we aimed to investigate the direct effects of steroid hormones on pregnant myometrial contraction. MAIN METHODS: The effect of steroids on oxytocin-induced contraction was examined in vitro using pregnant rat or human myometrium. Subsequently, we evaluated whether RU486, a potent progesterone antagonist, influenced the effects of progestin on myometrial contraction. Additionally, we evaluated the effects of progestin on high-concentration KCl-induced contraction caused by voltage-dependent calcium channels in order to investigate the mechanisms involved in this process. KEY FINDINGS: Of the natural steroids examined, 17ß-estradiol, progesterone, testosterone, cortisol, and aldosterone did not influence oxytocin-induced contraction at concentrations <10-6 M. Of the tested progestins, medroxyprogesterone acetate, norethisterone, chlormadinone acetate, levonorgesterol, 17α-hydroxyprogesterone capronate, and dienogest had no effect on contraction at <10-6 M. However, dydrogesterone showed rapid and direct inhibition of contraction at 10-6 M, and this inhibitory effect was dependent on dose and time. RU486 did not block the inhibitory effects of dydrogesterone on contraction. High-concentration KCl-induced contraction was also inhibited by dydrogesterone, and the inhibitory effects of dydrogesterone were observed at concentrations as low as 10-7 M. Additionally, oxytocin-induced contraction in pregnant human myometrium was inhibited by 10-6 M dydrogesterone. SIGNIFICANCE: These results suggested that the rapid and direct effects of dydrogesterone on myometrial contraction were caused by a nongenomic pathway and that the progesterone receptor was not required for dydrogesterone action. Additionally, the mechanism of dydrogesterone action may involve voltage-dependent calcium channels.

Combination therapeutic options in the treatment of the luteal phase deficiency.

Luteal phase deficiency (LPD) is described as a condition of insufficient progesterone exposure to maintain a regular secretory endometrium and allow for normal embryo implantation and growth. There is evidence that both follicular and luteal phase abnormalities can result in LPD cycles. The aim of this randomized prospective noncomparative study is to evaluate the effectiveness of combination therapy in patients with LPD. This prospective study included 35 women of the reproductive age. They were diagnosed with the LPD with sonographically and laboratory-verified methods. The age of patients was 36 ± 0.46 years. The results of the study sonographically demonstrated an increase in the diameter of the corpus luteum from 1.36 ± 0.32 (initially) to 2.16 ± 0.21 mm after combination therapy. In addition, there was a statistically significant increase in the level of estrogens and progesterone in the corresponding phases of the menstrual cycle. Thus, the combination therapy for patients with LPD contributes to the recovery of cyclic events in the hypothalamic-pituitary-gonadal system, which determines the restoration of the endocrine function of the ovaries and promotes adequate secretory rearrangement of the endometrium in women of reproductive age.

The effect of different progestogens on sleep in postmenopausal women: a randomized trial.

BACKGROUND: While progesterone affects sleep, different types of it might affect sleep differently. METHODS: One hundred Thai women, who complained of insomnia, visited the Menopause Clinic at Maharaj Nakorn Chiang Mai Hospital, Chiang Mai, Thailand from February 2014 to March 2015, and were divided randomly into two groups. Both groups received daily hormonal treatment that included estradiol valerate (progynova) at 1 mg. The first group also received dydrogesterone (duphaston®) at 10 mg and the second group micronized progesterone (utrogestran®) at 100 mg. The clinical symptoms and Pittsburgh Sleep Quality Index (PSQI) were recorded for three consecutive months after treatment. This study was registered with clinicaltrial.gov (code number NCT02086032). RESULTS: Sleep quality improved in both groups (10.52 ± 4.27 to 4.91 ± 3.15 in the dydrogesterone group and 10.16 ± 3.60 to 6.27 ± 3.04 in the micronized progesterone group, p value 0.08). Women in the micronized progesterone group had fewer overall side effects than those in the dydrogesterone group. CONCLUSION: Sleep quality of peri-postmenopausal women with insomnia improved dramatically after the first month of hormonal treatment. However, more participating patients are necessary to ascertain the differences in sleep quality from dydrogesterone and micronized progesterone treatment.

Dydrogesterone has no effect on uterine fibroids when used to prevent miscarriage in pregnant women with uterine fibroids.

OBJECTIVES: To analyse the effect of dydrogesterone use during pregnancy on uterine fibroids, pregnancy complications, and pregnancy outcome. MATERIAL AND METHODS: In all, 372 pregnant women with uterine fibroids who were treated at the Affiliated Provincial Hospital of Shandong University were included in this study. Thirty-three of these women received dydrogesterone and constituted the treatment group, and the 27 women who were found to have uterine fibroids during the first trimester but did not receive intervention to prevent miscarriage composed the control group. The changes in uterine fibroids before and after pregnancy and the pregnancy complications were recorded; immunohistochemistry was used to detect the expression of progesterone receptor (PR) and proliferation- and apoptosis-related proteins in the uterine fibroid tissue. RESULTS: No significant difference was observed in the change in uterine fibroid volume during pregnancy between the treatment group and the control group (p > 0.05). The percentage of uterine fibroids with red degeneration was lower in the treatment group than in the control group, but the difference was not statistically significant. No significant difference was observed in newborn weight, height, Apgar score, threatened miscarriage, or premature birth, among other characteristics, between the two groups (p > 0.05). Immunohistochemistry showed no significant difference in the expression of PR, cyclinD1, insulin-like growth factor (IGF1), or B-cell lymphoma 2 (Bcl2) between the two groups. CONCLUSIONS: The use of dydrogesterone during pregnancy has no significant effect on uterine fibroids, pregnancy progression, or pregnancy outcomes in pregnant patients with uterine fibroids.

[Effects of Shoutai Pill Containing Serum on Bioactivity Behavior of Trophoblast Cells of Spontaneous Abortion Patients].

OBJECTIVE: To explore the effect of Shoutai Pill (STP) containing serum on bioactivity behaviors of trophoblast cells in spontaneous abortion (SA) patients such as cell proliferation, invasion, migration and secretion. METHODS: Trophoblast cells in artificial abortion in normal pregnancy and SA patients were isolated and cultured in vitro, which were then treated with STP containing serum at various concentrations (5%, 10%, 20%, respectively). Blank serum was taken as the normal control group and dydrogesterone containing serum as the dydrogesterone control group. The proliferation, cycle distribution, invasion and migration capacity, and beta human chorionic gonadotropin (p-HCG) level were detected by methyl thiazolyl tetrazolium (MTT) colorimetry, flow cytometry (FCM), Transwell experiments, and ELISA, respectively. RESULTS: Compared with the normal control group, the activity of cell proliferation obviously decreased, ratios of apoptotic cells (SubGO/G1) and G2/M phase were obviously elevated, S phase cell ratio was obviously reduced (all P < 0.05). Transwell experiments indicated invasion and migration capacity obviously decreased, secreted beta-HCG level were obviously reduced after 72-h intervention (P < 0.05). Compared with the SA group, the activity of cell proliferation obviously increased, ratios of apoptotic cells and G2/M phase were obviously reduced, S phase cell ratio was obviously elevated, invasion and migration capacity were obviously enhanced, secreted beta-HCG level were obviously elevated after 72-h intervention in the dydrogesterone control group and each STP containing serum group (all P < 0.05). The activity of trophoblastic cell proliferation, S phase cell ratio, invasion and migration capacity, and secreted beta-HCG level were strengthened along with increased STP containing serum. Besides, the effects of 20% STP containing serum group were significantly superior to those of the dydrogesterone control group (P < 0.05). CONCLUSION: STP containing serum could dose-dependently enhance the proliferative activity of trophoblastic cells, invasion and migration capacity, secretion of beta-HCG, and reduce the apoptosis of trophoblast cells, which might be one of mechanisms for STP preventing and treating SA.

[Study of the effects of three luteal phase supporting strategies on clinical outcomes of intrauterine insemination].

OBJECTIVE: To explore the effects of three luteal phase supporting strategies on clinical outcomes of intrauterine insemination (IUI). METHODS: 1 779 subjects who underwent IUI at the Center of Reproductive Medicine, Peking University Third Hospital from November 2014 to June 2015 were enrolled in this retrospectively study.According to the luteal phase supporting strategies, all the subjects were divided into three groups: subjects receiving Dydrogesterone were group A; subjects receiving oral micronized progesterone were group B; subjects receiving vaginal micronized progesterone were group C. The pregnancy outcomes, including clinical pregnancy rate, early miscarriage rate, biochemical pregnancy rate and ectopic pregnancy rate were compared in the three groups. RESULTS: There was no significant difference in the three groups in constituent ratio, average IUI times, rate of the natural cycle, rate ofovulation cycle and dropout rate(P>0.05). Similarly, there was also no significant difference in pregnancy outcomes in all groups.Subsequent stratified analysis demonstrated that pregnancy outcomes in subjects of natural cycle and ovulation cycle still showed no significant difference(P>0.05). CONCLUSION: Our study suggested that the effects of three luteal phase supporting strategies on clinical outcomes of IUI were similar.The medication in clinic should be individualized.