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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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kamaludin Dingle reports financial support was provided by Kuwait Foundation for the Advancement of Sciences., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: The authors declare no competing interests., (Copyright © 2022 Xuehong Chen et al.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Du, Li, Liu, Ren, Zhang and Guan.)

Purpose: This study aimed to assess the efficacy of vaginally versus orally administered estradiol (E 2 ) 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 E 2 and DG either orally or vaginally. Treatment efficacy was compared between the two groups regarding blood E 2 concentrations, endometrial thickness, histology using hematoxylin and eosin staining, immunohistochemical analysis of ER expression, and PR and pinopodes morphology using scanning electron microscopy., Results: E 2 concentrations differed significantly between oral and vaginal E 2 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 E 2 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., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Feng et al.)

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), I 2  = 71%, P = 0.81]; [RR 0.99, 95% CI (0.83-1.17), I 2  = 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), I 2  = 66%, P = 0.69; NRCT: OR 1.03 95% CI 0.84-1.26), I 2  = 50%, P = 0.79]. The PPOS protocol had a lower rate of OHSS [RR 0.52, 95% CI (0.36-0.75), I 2  = 0%, P = 0.0006]. The secondary results showed that compared to the control protocol, the endometrium was thicker [95% CI (0.00-0.78), I 2  = 0%, P = 0.05], the number of obtained embryos was higher [95% CI (0.04-0.65), I 2  = 17%, P = 0.03] and more hMG was needed [in NRCT: 95% CI (307.44, 572.73), I 2  = 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.

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.

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., (© 2020 Japan Society of Obstetrics and Gynecology.)

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., Competing Interests: The authors report no conflicts of interest in this work., (© 2019 Huang et al.)

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., Competing Interests: The authors report no conflicts of interest in this work.

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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., (© 2019 Japan Society of Obstetrics and Gynecology.)

Biotransformation of a synthetic progestonic hormone dydrogesterone (1), C 21 H 28 O 2 , with a plant pathogenic fungus Macrophomina phaseolina yielded two new 2 and 3, and a known 4 metabolites. These analogues were identified as, 3β,11α-dihydroxy-5β,9β,10α-pregna-7-ene-6,20-dione (2), 15β-hydroxy-9β,10α-pregna-4,6-diene-3,20-dione (3), and 8α-hydroxy-9β,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 (IC 50  = 4.2 ± 0.3 μg/mL), as compared to standard drug Ibuprofen (IC 50  = 11.2 ± 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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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.

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., (© 2018 Japan Society of Obstetrics and Gynecology.)

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, 17β-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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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.

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.

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.

The objective of the study is to summarize the clinical characteristics of 33 patients' cohort (46,XX pure gonadal dysgenesis, 46,XX PGD), discuss the management, and propose treatment suggestions. Patients' information, medical history, and medical records were obtained. All patients were closely followed up. At the time of diagnosis, the patients presented 19.53 ± 3.60 years old, 165 ± 6.49 cm height, breast development of Tanner stage I, and infantile female genitalia. High level of follicle-stimulating hormone (87.41 ± 21.50 mIU/mL) and LH (27.10 ± 8.47 mIU/mL) and low level of E2 (8.85 ± 6.13 pg/mL) were observed. Individualized hormone replacement therapy (HRT) was initiated after diagnosis. After 2 years of treatment, all patients had obvious breast development; the uterus showed (2.38 ± 0.60) × (1.38 ± 0.70) × (1.38 ± 0.55) cm growth. The incidence of osteopenia changed from 69.70% to 22.22% and that of osteoporosis changed from 18.18% to 0. Dysgeminoma was found in one patient. We concluded that gonadal dysgenesis in 46,XX PGD causes secondary sexual characteristic absence, tendency of taller, osteoporosis, infertility, and sexual health problems. There is minor chance of tumor occurrence for the patients. Optimal care including HRT and close follow-up are required.

Oral administration of dydrogesterone during second half of menstrual cycle has been shown to reduce menstrual irregularities. This prospective, observational study aimed to determine continued effectiveness of dydrogesterone (prescribed between 1 and 6 cycles or longer) in menstrual cycle regularization in Indian women aged ≥18 years with irregular menstrual cycle for at least 3 months. Those achieving regular cycles (21 to 35 days, inclusive) during treatment were followed up for 6 months after cessation of dydrogesterone treatment. Of the 910 women completing dydrogesterone treatment, 880 (96.7%) achieved cycle regularization (p<0.0001 for 90% success rate) at end of treatment (EOT). Of the 788 subjects available for follow up at 6 months, 747 (94.8%) reported cycle regularity (p<0.0001 for 90% success rate). At EOT, the mean cycle duration reduced by 16.14 (±24.04) days and mean amount of menstrual bleeding decreased by 0.45 (±1.20) pads/day. While five subjects reported worst pain at baseline, none experienced it at EOT. One serious adverse event (appendicitis) and three non-serious adverse events were reported. Dydrogesterone regularizes and improves the duration of the menstrual cycle, reduces the amount of bleeding, relieves menstrual pain and prevents relapse of irregular cycles at six months after discontinuation of treatment.

Objectives: To determine the effects of estrogen and progestogen treatment on atherosclerotic inflammation and vascular remodeling., Methods: Atherosclerosis was induced by feeding ovariectomized ApoE (-/-) mice a cholesterol-rich diet. Estrogen and progestogen were supplied as estradiol valerate (E2V, orally, 0.07 mg/kg/day) and dydrogesterone (DG, orally, 0.2 mg/kg/day), respectively, for 8 weeks. Levels of the vascular inflammatory marker nuclear factor kappa B (NF-κB) and arterial remodeling marker matrix metalloproteinase 9 (MMP-9) were examined. Estrogen receptor (ER) involvement was analyzed by treating with antagonists., Results: E2V and DG treatment reduced NF-κB mRNA and protein levels in atherosclerotic tissue from ovariectomized ApoE (-/-) mice, and the difference in expression trended towards statistical significance. Moreover, treatment with the ERβ-specific antagonist significantly increased NF-κB mRNA and protein levels in both the E2V treatment group and the E2V and DG combined treatment group (p < 0.05), suggesting that E2V inhibits NF-κB overexpression in atherosclerotic tissue through ERβ-mediated signaling. However, E2V and DG co-treatment did not significantly affect MMP-9 mRNA or protein expression in atherosclerotic tissue. Introduction of ER antagonists to E2V and DG co-treatment still did not significantly affect MMP-9 expression., Conclusion: E2V and DG treatment may inhibit arterial inflammation by regulating ERβ-related signaling pathways.

Progesterone is indispensable for the maintenance of pregnancy, both via its endocrine effects and its role in creating a favorable immunological environment for the fetus. This review focuses on the immunological effects of progesterone. Progestogens have been shown to have very interesting effects on cytokine production and decidual natural killer (NK) cell activity. The orally-administered progestogen, dydrogesterone, has the ability to modulate cytokine production patterns in a manner that could be conducive to successful pregnancy. The adverse effects of progesterone deficiency and the beneficial effects of progesterone supplementation in pregnancy pathologies will be discussed.

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.

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.

Dydrogesterone is an oral retroprogesterone widely used to treat progesterone deficiencies, including irregular menstrual cycles (MCs). This prospective, non-interventional, single-arm, post-marketing, observational study evaluated the effects of dydrogesterone on MC regularization. Women aged 18-40 years who had been prescribed dydrogesterone to treat irregular MCs due to progesterone deficiency were enrolled across 64 centers in Russia, Ukraine, Kazakhstan and Uzbekistan. Study objectives included: patients reporting ≥1 regular MC during treatment; the number of regular MCs after the end of treatment over a 6-month follow-up (FU) period. In total, 996 women were enrolled. Of those who completed treatment, 946/955 patients (99.1%) achieved ≥1 regular MC. During FU, 680/860 patients (79.1%) maintained ≥6 regular MCs. Patient grading of menstrual pain and anxiety decreased significantly during treatment (p ≤ 0.0001 versus baseline); this persisted during FU. Dydrogesterone was associated with high or very high patient satisfaction (856/955; 89.6%); the clinical response was considered good or excellent in 819/955 patients (85.8%). In total, 16/986 patients (1.6%) reported an adverse event (AE); two had serious AEs (SAEs) (unrelated to treatment) and three discontinued treatment due to non-SAEs. Dydrogesterone therapy was effective in achieving MC regularization and reducing menstrual pain and anxiety, during both treatment and 6-month FU.

Problem: Previous studies have shown that dydrogesterone, the orally administered progestogen, upregulates the production of Th2 cytokines and downregulates Th1 cytokine production. This study was designed to ascertain whether dihydrodydrogesterone (DHD), the major metabolite of dydrogesterone, is similarly capable of modulating cytokine production by peripheral blood mononuclear cells (PBMC) from women with a history of unexplained recurrent miscarriage., Method of Study: Mitogen-stimulated PBMC from women with unexplained recurrent miscarriage were exposed to progesterone or dydrogesterone or DHD, and the levels of pro-inflammatory (IFN-γ, TNF-α) and anti-inflammatory (IL-4, IL-10, IL-13) cytokines were estimated by ELISA. To ascertain whether DHD mediates its effects via the progesterone receptor, RU486, a progesterone agonist, was added to cultures along with mitogen and DHD., Results: The metabolite DHD, like its parent molecule dydrogesterone, suppresses the production of the pro-inflammatory cytokines IFN- γ and TNF-α and upregulates the production of the anti-inflammatory cytokine IL-4. The progesterone antagonist RU486 reverses the effect of DHD, suggesting that this molecule mediates its cytokine-modulating effect via the progesterone receptor., Conclusion: Dihydrodydrogesterone retains the immunomodulatory effects of the progestogen dydrogesterone by bringing about a shift in cytokine production profiles that might be conducive to the success of pregnancy., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Menopause can cause cognitive decline. Hormone Replacement Therapy (HRT) is the most effective treatment for the climacteric symptoms. However, its cognitive effect has not been well clarified, especially for the progestin component. The study investigated the effects of dydrogesterone (DG) on spatial learning and memory of the ovariectomized (OVX) rat models and the impact of aging on its cognitive effects. Eighty female Sprague-Dawley rats were included in the experiment. They belonged to two cohorts, the adult (7 months) and the aged (18 months). Each cohort was divided into five groups: Sham, OVX, OVX+E2 (OVX+17β-estrogen), OVX+E2/DG and OVX+DG. The replacement therapy lasted for 20 weeks. Two classical behavioral tests were performed: open field test (OFT) and the Morris water maze (MWM). The breast morphology and uterine weight were obtained to assess the safety and complication of dydrogesterone. In MWM, the OVX group displayed prolonged latency and less target quadrant time than the other groups. Across 5 days' testing, all the adult groups receiving hormone therapy, except the OVX+DG group, performed better than the OVX group (P<0.001); but there was no significant difference among the aged groups. The uterus weight/body weight ratio of OVX+E2/DG group was lower than the sham and OVX+E2 group. The mammary glands of OVX+E2/DG group displayed normal structure or mild hyperplasia. The results suggested that DG-alone treatment had no significant benefit for the OVX rats of both adult and aged groups on the behavioral tests. DG combined with E2 could ameliorate cognition in adult rats with uterus protection and without breast harm. The cognitive-improve effects were more remarkable for the adult rats than the aged ones. The findings support the potential clinical application of dydrogesterone combined with estrogen in preventing cognitive decline, especially for the early iatrogenic menopausal women., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

Anti-glycation and α-glucosidase inhibition activities of microbial transformed compounds of dydrogesterone (1); 20R-hydroxy-9β,10αa-pregna-4,6-diene-3-one (2), 17β-hydroxy-9β,10α-androsta-4,6-diene-3-one (3) and 9β,10α-androsta-4,6-diene-3,17-dione (4) were evaluated. Compounds 1 and 4 showed potent α-glucosidase inhibitory activities, while 2 and 3 were found to be weak inhibitors, whereas anti-glycation activities of 1-4 were not observed.

Aim: To study the effects of estrogen therapy, alone or combined with progestogens, and of tibolone on the expression of proliferation and apoptosis markers in normal breast tissue., Methods: Thirty 250-day-old Wistar rats were castrated and 3 weeks later received one of the following treatments by gavage for 5 weeks: (1) estradiol benzoate; (2) estradiol benzoate + medroxyprogesterone acetate; (3) estradiol benzoate + norethisterone acetate; (4) estradiol benzoate + dydrogesterone; (5) tibolone; (6) placebo. Following treatment, the expression of proliferating cell nuclear antigen (PCNA) and caspase-3 was analyzed by quantitative immunohistochemistry in the breast tissue, and proliferation and apoptosis were analyzed semiquantitatively by microscopic imaging., Results: There was a statistically significant difference among the groups for PCNA, caspase-3 and the caspase-3 : PCNA ratio. Tibolone was associated with the lowest proliferative activity, followed by estradiol benzoate + dydrogesterone; however, estradiol benzoate + dydrogesterone showed the greatest rate of apoptosis., Conclusions: The various progestogens can have more or less proliferative and pro-apoptotic effects than estradiol alone. Among the treatment schemes analyzed, the estradiol + dydrogesterone combination resulted in a higher apoptosis rate in relation to the proliferation rate and tibolone was associated with the lowest proliferation.

Aim: To study the effects of estrogen therapy, alone or combined with progestogens, and of tibolone on the expression of heparanase (HSPE), extracellular matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), perlecan and proliferating cell nuclear antigen (PCNA) in normal breast tissue., Methods: Thirty 250-day-old Wistar rats were castrated and 3 weeks later received one of the following treatments by gavage for 5 weeks: (1) estradiol benzoate; (2) estradiol benzoate + medroxyprogesterone acetate; (3) estradiol benzoate + norethisterone acetate; (4) estradiol benzoate + dydrogesterone; (5) tibolone; (6) placebo. Following treatment, the expressions of mRNA for HSPE, MMP-2 and MMP-9 were analyzed by real-time PCR and the protein expressions of HSPE, MMP-2, MMP-9, perlecan and PCNA were quantified by immunohistochemistry., Results: There was a statistically significant difference among the groups for the expression of HSPE mRNA due to high levels in the tibolone group. The groups differed in terms of PCNA, with lower levels found in the tibolone group followed by the estradiol benzoate + dydrogesterone group. A statistically significant positive correlation was observed for PCNA versus perlecan and MMP-9., Conclusions: There was no difference in the effects of combinations of estradiol and different progestogens on extracellular matrix components, and breast cell proliferation was associated with increases in perlecan and MMP-9.

Nuclear receptors (NRs) are an important group of ligand-dependent transcriptional factors. Presently, no natural or synthetic ligand has been identified for a large group of orphan NRs. Small molecules to target these orphan NRs will provide unique resources for uncovering regulatory systems that impact human health and to modulate these pathways with drugs. The orphan NR tailless (TLX, NR2E1), a transcriptional repressor, is a major player in neurogenesis and Neural Stem Cell (NSC) derived brain tumors. No chemical probes that modulate TLX activity are available, and it is not clear whether TLX is druggable. To assess TLX ligand binding capacity, we created homology models of the TLX ligand binding domain (LBD). Results suggest that TLX belongs to an emerging class of NRs that lack LBD helices α1 and α2 and that it has potential to form a large open ligand binding pocket (LBP). Using a medium throughput screening strategy, we investigated direct binding of 20,000 compounds to purified human TLX protein and verified interactions with a secondary (orthogonal) assay. We then assessed effects of verified binders on TLX activity using luciferase assays. As a result, we report identification of three compounds (ccrp1, ccrp2 and ccrp3) that bind to recombinant TLX protein with affinities in the high nanomolar to low micromolar range and enhance TLX transcriptional repressive activity. We conclude that TLX is druggable and propose that our lead compounds could serve as scaffolds to derive more potent ligands. While our ligands potentiate TLX repressive activity, the question of whether it is possible to develop ligands to de-repress TLX activity remains open.

The purpose of this work is to know the effect of flutamide and a novel synthetic steroid 3β-p-Iodobenzoyloxypregnan-4,16- diene-6,20-dione (IBP) on the levels of dopamine, 5-HIAA (5-hydroxyindole acetic acid), and some oxidative stress markers in animal model with Huntington disease. Thirty male Wistar rats divided in groups of 6 animals each were subjected to the following treatment: group A, 3-nitro propionic acid (3-NPA, as inducer of Huntington); group B, flutamide; group C, 3-NPA + flutamide; group D, IBP; and group E, 3-NPA + IBP. Treatment scheme for all groups were at 4 mg/kg/day administered intraperitoneally. The measurement of haemoglobin was carried out from blood while the concentrations of ATPase, 5α-reductase, reduced glutathione (GSH), calcium, H2O2, 5-HIAA, and dopamine were determined from brain and prostate tissues using validated methods. The results depicted a significant decrease of dopamine and GSH in cerebellum/Medulla oblongata of animals treated with IBP. The prostate gland of the same group of treatment also showed a significant decrease in the concentrations of TBARS, H2O2, and total ATPase. In hemispheres of groups D and E, dopamine, H2O2, and total ATPase decreased significantly while in prostate, hemispheres, and cerebellum/Medulla oblongata of groups B and C; calcium, 5α-reductase, ATPase, H2O2, and TBARS were found to witness a significant decrease. Results showed an antiandrogenic activity of flutamide, while the novel steroid IBP showed neuroprotective properties by changes on oxidative stress biomarkers as critical pathways leading to prostate and brain degeneration. Probably steroid homeostasis disequilibrium could have led to alterations in dopamine metabolism GSH in Huntington's disease animal models.

HRT is known to be effective for the relief of menopausal symptoms and prevention of osteoporosis. HRT should be tailored to the woman, enhancing the beneficial effects of the treatment while minimizing the risks. It is difficult to evaluate data on particular preparations of HRT and the different dosages in isolation. The purpose of this review is to highlight the efficacy and safety specific to oral estradiol and dydrogesterone combinations of four different dose strengths. A systematic literature search using Medline was carried out to identify studies containing efficacy or safety data. The findings of the retrieved publications confirm that estradiol and dydrogesterone combinations give very effective menopausal symptom relief and prevention of osteoporosis whilst maintaining a good safety profile. Data also show that these combinations of HRT give additional benefit to certain metabolic parameters including lipids, insulin, glucose and body fat distribution. By selecting the treatment and dose most suitable for each individual woman at her particular stage of menopause, the benefits can be optimized whilst mitigating the risks. HRT plays an important role in improving and maintaining women's health when used appropriately., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: To investigate the effects of oral dydrogesterone for luteal phase support after frozen embryo transfer (FET) cycles on the clinical outcomes., Methods: A total of 1643 FET cycles in our center between January, 2010 and September, 2011 were analyzed. The patients were divided into group A with natural-cycle FET and group B with hormone replacement cycle (HRT-FET). The two groups were further divided into two subgroups to receive oral dydrogesterone (groups AI and BI, n=358 and 185, respectively) or intramuscular progesterone with progynova (groups AII and BII, n=634 and 466, respectively) as luteal phase support. The clinical pregnancy rates, implantation rates, early miscarriage rates, ectopic pregnancy rates, ongoing pregnancy rates and delivery rates were compared between the subgroups., Results: There were no significant differences in the clinical outcomes between the patients receiving dydrogesterone and intramuscular progesterone as luteal phase support in either natural-cycle FET or HRT FET (P>0.05)., Conclusion: In the FET cycles, oral dydrogesterone tablets for luteal support can achieve good clinical outcomes comparable with those by intramuscular progesterone and serves as a good alternative for luteal phase support.

Endometriosis is defined as the presence of endometrial glands and stroma outside the uterine cavity. This disease is associated with diminished protective effects of progesterone, which are usually explained by inadequate activation of progesterone receptors and also enhanced pre-receptor metabolism of progesterone. Endometriosis is often treated with progestins, which act as progesterone receptor agonists, although their exact mechanisms of action are not completely understood. The aim of the present study was to investigate how the progestins medroxyprogesterone acetate, dydrogesterone and dienogest, as well as progesterone, impact on the expression of genes of pre-receptor progesterone metabolism in Z-12 epithelial cell line, a model system of peritoneal endometriosis. Our data demonstrate that these progestins affect local pre-receptor metabolism to a different extent. The most favorable effects were seen for dydrogesterone and dienogest, where the first, dydrogesterone, significantly reduced SRD5A1, AKR1C2 and AKR1C3 expression, and additionally had a nonsignificant impact on progesterone receptor B (PR-B) protein levels. This might slow down the first step of pre-receptor metabolism, the conversion of progesterone to 5α-dihydroprogestrone by SRD5A1, and it might also affect further reduction of 3-keto and 20-keto groups catalyzed by AKR1C2 and AKR1C3. Similarly favorable effects were seen for dienogest, which promoted significant reduction of AKR1C1 and AKR1C2 expression and also showed no effect on PR-B protein levels. Different effects were seen for progesterone, which significantly decreased SRD5A1, PR-B and HSD17B2 protein levels. In contrast, treatment with medroxyprogesterone acetate resulted in increased AKR1C1 expression and decreased levels of PR-B, which might lead to enhanced progesterone metabolism and reduced signaling through progesterone receptors. Altogether, our data in this Z-12 cell model suggest that the beneficial effects of treatment with progestin observed in endometriosis patients might arise from decreased pre-receptor metabolism of the protective progesterone by the SRD5A1 and AKR1C enzymes., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate the influence of dydrogesterone on estimated cardiovascular risk of users of hormone replacement therapy (HRT) (with percutaneous 17β-estradiol in monotherapy and in combination with dydrogesterone) and HRT non-users through the Framingham score tool for a period of 2 years., Methods: Framingham scores were calculated from the medical records of patients treated for at least 2 years with 17β-estradiol alone or in combination with dydrogesterone, along with HRT non-users, through the analysis of patient medical records, followed for at least 2 years at Instituto Estadual de Diabetes e Endocrinologia Luiz Capriglione., Results: Improvements in lipid profile, glucose and blood pressure levels, which reduced the estimated cardiovascular risk, were observed in the 17β-estradiol group. Similar changes were observed in the users of 17β-estradiol + dydrogesterone, suggesting that this progestogen does not attenuate the effects caused by 17β-estradiol., Conclusions: Both HRT groups showed a reduction in their Framingham score. In contrast to data from other HRT investigations on cardiovascular risk, these formulations proved to be safe, even in the first year of use.

Endometriosis is a common estrogen-dependent gynecological disease. In patients with endometriosis estradiol can be synthesized locally in the endometriotic lesions from inactive precursors of adrenal or ovarian origin, via the aromatase pathway. These increased estradiol levels stimulate proliferation of endometriotic tissue. The progestins have been used in the therapy of endometriosis for more than 40 years but their pharmacological action is still not understood in detail. In the present study we therefore aimed to evaluate the effects of three progestins most commonly used in the therapy of endometriosis; medroxyprogesterone acetate, dydrogesterone and dienogest on expression of all genes encoding enzymes of the aromatase pathway and estrogen receptors in the Z-12 model epithelial cell line of peritoneal endometriosis, by qPCR and Western blotting. Our results show that application of medroxyprogestrone acetate, dydrogesterone and dienogest significantly decreases HSD17B1 and CYP19A1 expression and significantly increases HSD17B2 expression. Dydrogesterone and dienogest also significantly suppress ESR1 and ESR2 transcription, whereas medroxyprogestrone acetate and dydrogesterone significantly reduce mRNA levels of GPER. Our results thus suggest that in peritoneal endometriosis the beneficial effects of these progestins can be explained by lower HSD17B1 and higher HSD17B2 mRNA and protein levels, which lead to reduced local E2 biosynthesis. Although progestins significantly decrease CYP19A1 mRNA levels, the protein itself was not detectable by Western blotting. As progestins down-regulate expression of ESR1, ESR2 and GPER, they might also prevent E2-mediated proliferation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The human aldo-keto reductase AKR1C2 converts 5α-dihydrotestosterone to the less active 3α-androstanediol and has a minor 20-ketosteroid reductase activity that metabolises progesterone to 20α-hydroxyprogesterone. AKR1C2 is expressed in different peripheral tissues, but its role in uterine diseases like endometriosis has not been studied in detail. Some progestins used for treatment of endometriosis inhibit AKR1C1 and AKR1C3, with unknown effects on AKR1C2. In this study we investigated expression of AKR1C2 in the model cell lines of peritoneal endometriosis, and examined the ability of recombinant AKR1C2 to metabolise progesterone and progestin dydrogesterone, as well as its potential inhibition by progestins. AKR1C2 is expressed in epithelial and stromal endometriotic cell lines at the mRNA level. The recombinant enzyme catalyses reduction of progesterone to 20α-hydroxyprogesterone with a 10-fold lower catalytic efficiency than the major 20-ketosteroid reductase, AKR1C1. AKR1C2 also metabolises progestin dydrogesterone to its 20α-dihydrodydrogesterone, with 8.6-fold higher catalytic efficiency than 5α-dihydrotestosterone. Among the progestins that are currently used for treatment of endometriosis, dydrogesterone, medroxyprogesterone acetate and 20α-dihydrodydrogesterone act as AKR1C2 inhibitors with low μM K(i) values in vitro. Their potential in vivo effects should be further studied., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Clinical observations and basic studies show that progesterone and progestins have a variable influence on endothelial function. Dydrogesterone (DG) is a widely used progestin, but its endothelial actions have not been thoroughly assessed. In this study, we investigated the effects of DG and its metabolite 20-α-dihydro-dydrogesterone (DHD), natural progesterone as well as medroxyprogesterone acetate, on the expression of leukocyte adhesion molecules in human endothelial cells using an in vitro experimental endothelial inflammation system. Our findings show that all progestins significantly suppress endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and inter-cellular adhesion molecule-1 (ICAM-1) induced by bacterial lypopolysaccharide (LPS). These inhibitory effects of DG and DHD require activation of progesterone receptor. DG and DHD decrease adhesion molecule expression associated with LPS administration by preventing nuclear translocation of the pro-inflammatory transcription factor nuclear factor-κB. In addition, DG and DHD do not alter the anti-inflammatory effects of 17β-estradiol. In conclusion, DG and DHD decrease endothelial inflammatory responses induced by LPS, via reduced expression of the pro-atherogenic adhesion molecules VCAM-1 and ICAM-1. These actions may be relevant for the vascular effects of DG.

Objective: The aim of this study was to evaluate the verbal learning and memory performance of postmenopausal women who received tualang honey (Agro Mas) in comparison with women receiving estrogen plus progestin therapy and untreated controls., Methods: A total of 102 postmenopausal women were recruited and randomly assigned to three groups: tualang honey (20 g/d)[corrected], estrogen plus progestin therapy (Femoston 1/5), and untreated control. Their verbal learning and memory performances were assessed using the Malay version of the Auditory Verbal Learning Test before and after 16 weeks of intervention. Data were analyzed using the repeated-measures analysis of variance, and a P value of less than 0.05 was considered significant., Results: There were significant differences in the mean scores of total learning as well as the mean scores of trials A1, A5, A6, and A7 between the three groups. There were also significant differences in the overall mean scores of total learning and trials A1 and A5 between both estrogen plus progestin therapy and tualang honey groups when compared with the untreated control group. However, significant differences in the mean score for trials A6 and A7 were only observed between the estrogen plus progestin therapy and untreated control groups., Conclusions: Postmenopausal women who received tualang honey showed improvement in their immediate memory but not in immediate memory after the interference and delayed recall. This is comparable with the improvement seen in women receiving estrogen plus progestin therapy.

Dydrogesterone is widely used for menstrual disorders, endometriosis, threatened and habitual abortion and postmenopausal hormone replacement therapy. Although progestins have a promiscuous nature, dydrogesterone does not have clinically relevant androgenic, estrogenic, glucocorticoid or mineralocorticoid activities. To date, systematic biochemical characterization of this progestin and its active main metabolite, 20α-dihydrodydrogesterone, has not been performed in comparison to progesterone. The objective of this study was to evaluate the selectivity and potential androgenic/antiandrogenic effects of dydrogesterone and its metabolite in comparison to progesterone and medroxyprogesterone acetate by analyzing their interference with AR signaling in vitro. We characterized dydrogesterone and its metabolite for their binding and transactivation of androgen and other steroid hormone receptors and for their potential inhibitory effects against androgen biosynthetic enzymes, 17β-hydroxysteroid dehydrogenase types 3 and 5 and 5α-reductase types 1 and 2. We found that dydrogesterone resembled progesterone mainly in its progestogenic effects and less in its androgenic, anti-androgenic, glucocorticoid and antiglucocorticoid effects; whereas, 20α-dihydrodydrogesterone showed reduced progestogenic potency with no androgenic, glucocorticoid and mineralocorticoid effects. Effects on the androgen and glucocorticoid receptor differed depending on the technology used to investigate transactivation. Progesterone, but not dydrogesterone and 20α-dihydrodydrogesterone, exerted anti-androgenic effects at the pre-receptor level by inhibiting 5α-reductase type 2. Dydrogesterone, 20α-dihydrodydrogesterone and progesterone inhibited the biosynthesis of testosterone catalyzed by 17β-hydroxysteroid dehydrogenase types 3 and 5; however, due to their micromolar K(i) values, these activities appeared to be not of relevance at therapeutic levels. Overall, our data show that the anti-androgenic potential of dydrogesterone and 20α-dihydrodydrogesterone is less pronounced compared to progesterone., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Femoston Low is a hormone replacement therapy that combines low dosages of steroids, i.e. 0.5 mg of estradiol and 2.5 mg of dydrogesterone. This oral preparation should be taken continuously to treat climacteric symptoms in menopausal women. Femoston Low is in agreement with the recent recommendations for menopausal hormone replacement therapy, which give the preference to low dosage therapy whenever possible. The goals are to potentially minimize the risk of breast cancer, the danger of venous or arterial thrombosis and the glucose and lipid metabolic disturbances. Nevertheless, the preparation should efficaciously oppose to endometrial hyperplasia and yield a high degree of amenorrhea.

Oral hormone therapy is associated with an increased risk of venous thrombosis. Drug agencies recommend the use of the lowest efficient dose to treat menopausal symptoms for a better risk/ratio profile, although this profile has not been totally investigated yet. The aim of the study was to compare the effect of the standard dose of 17beta-estradiol to a lower one on thrombin generation (TG). In a 2-month study, healthy menopausal women were randomized to receive daily 1mg or 2 mg of 17beta-estradiol (E1, n = 24 and E2, n = 26; respectively) with 10 mg dydrogesterone or placebo (PL, n = 22). Plasma levels factors VII, X, VIII and II were assessed before and after treatment as well as Tissue factor triggered TG, which allows the investigation of the different phases of coagulation process. The peak of thrombin was higher in hormone therapy groups (E1: 42.39 +/- 50.23 nm, E2: 31.08 +/- 85.86 nm vs. 10.52 +/- 40.63 nm in PL, P = 0.002 and P = 0.01). Time to reach the peak was also shortened (PL: 0.26 +/- 0.69 min vs. E1: -0.26 +/- 0.80 min, E2: -0.55 +/- 0.79 min, P <10(-3) for both comparisons) and mean rate index of the propagation phase of TG was significantly increased. Among the studied clotting factors, only the levels of FVII were significantly increased after treatment administration. The two doses of 17beta-estradiol induced in a similar degree an acceleration of the initiation and propagation phase of tissue factor triggered thrombin generation and a significant increase of FVII coagulant activity.

Clinical symptoms of endometriosis, such as pain and infertility, can be described as persistent stressors. Such continuous exposure to stress may severely affect the equilibrium and bidirectional communication of the endocrine and immune system, hereby further aggravating the progression of endometriosis. In the present study, we aimed to tease apart mediators that are involved in the stress response as well as in the progression of endometriosis. Women undergoing diagnostic laparoscopy due to infertility were recruited (n = 69). Within this cohort, early stage of endometriosis were diagnosed in n = 30 and advanced stage of endometriosis in n = 8. Levels of progesterone in serum were determined. Frequency of progesterone receptor (PR) expression on CD56(+) and CD8(+) peritoneal lymphocytes was analysed by flow cytometry. The production of tumour necrosis factor (TNF) and interleukin (IL)-10 by peritoneal leukocytes upon stimulation with the potent stress mediator corticotropin-releasing hormone (CRH) and the progesterone derivative dydrogesterone, or both, were evaluated. Furthermore, the production of progesterone-induced blocking factor (PIBF) by peritoneal leukocytes and the expression of PR in endometriotic tissue were investigated. Levels of progesterone in serum were decreased in women with endometriosis and inversely correlated to pain scores. Furthermore, an increased frequency of CD56(+)PR(+) and CD8(+)PR(+) peritoneal lymphocytes was present in advanced endometriosis. The TNF/IL-10 ratio, reflecting cytokine secretion by peritoneal cells, was higher in cells derived from endometriosis patients and could be further heightened by CRH stimulation, whereas stimulation with dydrogesterone abrogated the CRH-mediated inflammation. Finally, the expression of PIBF by peritoneal leukocytes was increased in endometriosis. Low levels of progesterone in the follicular phase could be responsible for the progression of endometriosis and related pain. Peripheral CRH, increasing upon high psychological stress, might contribute to the peritoneal inflammation present in endometriosis. The therapeutic application of progesterone derivatives, CRH blocking agents as well as improvement of stress coping may disrupt the vicious circle between the chronic peritoneal inflammation and high perception of psychological stress in endometriosis.

Dydrogesterone has a molecular structure closely related to that of natural progesterone, but it has enhanced oral availability compared with progesterone. The hormonal profile and the progestational potency of dydrogesterone has been determined in vitro, in vivo and in humans, in combination with estrogens or without. It showed varying affinity for progesterone-binding proteins in uterine tissue in vitro, depending on the species. It exerted a clear progestational response in the rabbit in vivo, although the potency was influenced somewhat by the route of administration. When used in hormone replacement therapy, 10mg dydrogesterone given sequentially provides adequate protection against endometrial hyperplasia in postmenopausal women using 2mg estradiol. Similarly, a dydrogesterone dose of 5mg also protects the endometrium when continuously combined with 1mg estradiol. Dydrogesterone also has beneficial effects in women with amenorrhea/oligomenorrhea, dysfunctional uterine bleeding and irregular cycles. In conclusion, having a similar profile to progesterone but with better oral availability, dydrogesterone has been used successfully to treat disorders related to absolute or relative progesterone deficiency., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Progestins are successfully used in the treatment of endometriosis; however, the exact mechanisms of their action are still unsolved. We here focused on the effect of different progestins on parameters of extracellular matrix degradation and angiogenesis involved in the establishment and maintenance of ectopic endometrial lesions. Human endometrium was intraperitoneally transplanted into nude mice. After 7 and 28 days of treatment with progesterone, dydrogesterone, or its metabolite dihydrodydrogesterone, respectively, ectopic lesions were evaluated for proliferation and apoptosis. Expression of estrogen receptor alpha, progesterone receptor-AB, the angiogenetic factors, cysteine-rich angiogenic inducer (CYR61), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGFA) and the matrix metalloproteinase (MMP)-2, -3, -7 and -9 was investigated. Functional impact on angiogenesis was evaluated by density of microvessels and of vessels stabilized by pericytes within the ectopic lesions. Although dydrogesterone significantly reduced proliferation of endometrial stromal cells after 28 days, suppression of apoptosis was independent from progestins. Expression of MMP-2 was significantly reduced by all progestins and MMP-3 by dydrogesterone. In the grafted endometrial tissue, transcription of bFGF was suppressed by progesterone and dihydrodydrogesterone, and VEGFA and CYR61 by dihydrodydrogesterone and dydrogesterone. In parallel, microvessel density was slightly suppressed by progestins, whereas number of stabilized vessels increased. Thus, progestins regulate factors important for the establishment and maintenance of ectopic endometrial lesions.

Objective: To compare the short-term effects of two oral continuous combined oestrogen-progestogen treatment regimens on blood concentrations of several cardiovascular risk markers in healthy postmenopausal women., Study Design: In a 12-week randomised controlled study, 48 healthy non-hysterectomised postmenopausal women, aged 41-58 years, received either no treatment (control group; n=16), or daily oral continuous combined treatment with 1 mg micronised 17beta-oestradiol plus 5 mg dydrogesterone (E/D group; n=18) or 0.625 mg conjugated equine oestrogens plus 5 mg medroxyprogesterone acetate (CEE/MPA group; n=14). Fasting blood sampling was performed at baseline and after 12 weeks of follow-up., Results: Compared with the control group, 12-week treatment with E/D or CEE/MPA reduced fibrinogen (-7.7%, p=0.004 and -3.3%, p=0.083, respectively), factor VII-act (-8.7%, p=0.14 and -9.7%, p=0.06, respectively), homocysteine (-20.5%, p=0.02 and -26.7%, p=0.005, respectively), and IGF-1 (-27.9%, p<0.001 and -18.1%, p=0.002, respectively), but increased factor VII-ag (+10.1%, p=0.03 and +4.4%, p=0.46, respectively), endothelin-1 (+15.2%, p=0.12 and +20.0%, p=0.13, respectively) and C-reactive protein (+88.8%, p=0.18 and +71.0%, p=0.44, respectively). Fibrinolytic factors were not affected by either hormone therapy (HT)., Conclusions: Short-term oral continuous combined therapy with oestradiol/dydrogesterone and conjugated equine oestrogens/medroxyprogesterone acetate had comparable effects on the investigated cardiovascular risk markers.

The present study investigated the effect of acute systemic administration of six progesterone metabolites on formalin-induced pain in the rat. The 3alpha-hydroxylated metabolites allopregnanolone and pregnanolone are highly potent positive modulators at the GABA(A) receptor and produced a biphasic effect on pain in the formalin test. Dose-dependent antinociception was observed at lower doses (maximal antinociception at 0.16mg/kg) and was reversed at higher doses. Bicuculline abolished the antinociceptive effect. The 3beta-hydroxylated epipregnanolone and isopregnanolone are inactive or only weekly active at the GABA(A) receptor, and did not affect formalin-induced pain. 5alpha- and 5beta-dihydroprogesterone have also been shown to have low affinity for the GABA(A) receptor, but can be rapidly metabolized to their 3alpha-hydroxylated counterparts. In the formalin test, they produced a biphasic effect on pain similar to that of pregnanolone and allopregnanolone, but with lower potency. The effect was reversible by bicuculline, showing involvement of the GABA(A) receptor, and was blocked by indomethacin, implying that the antinociceptive effect is dependent on their conversion to allopregnanolone or pregnanolone. The results indicate that GABA-ergic progesterone metabolites modulate nociception. A change in levels of GABA-ergic progesterone metabolites, such as is observed in depression, chronic fatigue and premenstrual dysphoric disorder could, therefore, contribute to the pain complaints associated with these disorders.

Pregnancy is not as successful as one might think; it can be compromised by several complications such as recurrent spontaneous miscarriage, pre-term delivery, pre-eclampsia etc. Much attention has been paid to the possibility of the maternal immune system mediating deleterious effects on pregnancy. Research conducted during the last two decades has shed much light on cell-mediated immunologic effectors that might underlie these pregnancy complications. Of particular interest are the effects that pro-inflammatory and anti-inflammatory cytokines have on the foetus and placenta, and thus on the success and failure of pregnancy. This review presents evidences that certain cytokine profiles are associated with recurrent miscarriage and pre-term delivery and discusses possible pathways of effector function of cytokines in pregnancy loss and the redirection of cytokine profiles from one that is antagonistic to pregnancy towards one that is conducive to the success of pregnancy. Among the promising agents for the modulation of the Th1/Th2 balance are progestogens like progesterone and dydrogesterone; this review also discusses recent evidence that progestogens are capable of modulating cytokine production patterns in pregnancy loss.

Objectives: Fulvestrant is an estrogen receptor (ER) antagonist that binds, blocks and degrades the estrogen receptor and is currently used in adjuvant treatment in postmenopausal women with ER-positive breast cancer as an alternative for tamoxifen. As an antagonist, it may induce or aggravate climacteric symptoms. In order to alleviate these symptoms, one could consider hormone therapy. The objective of this study was to analyze the effect of fulvestrant alone or in combination with different steroids in human breast cancer cells in vitro, and to demonstrate whether these steroids will compromise the efficacy of fulvestrant in ER-positive breast cancer cells., Methods: We performed experiments in vitro with various hormone therapy preparations (estradiol (E2), dihydrodydrogesterone (DHD) and tibolone) at a concentration of 10(-6) mol/l alone or combined with fulvestrant in different breast cancer cell lines, ER-positive and ER-negative. After an incubation of 144 h, proliferation and apoptosis were measured. The first was measured by quantification of the expression of cyclin D1 mRNA, the latter by the Nicoletti fragmentation assay., Results: This in vitro study revealed clear differences in results when various hormone therapy preparations, alone or combined with fulvestrant, are added to ER-positive and ER-negative breast cancer cell lines., Conclusions: Our study demonstrated that fulvestrant, an ER antagonist used in the treatment of ER-positive breast cancer, combined with E2 and DHD or in combination with tibolone, is not compromised in its efficacy in inducing apoptosis in ER-positive breast cancer cell lines in vitro.