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•GenSci070 is a water-soluble progesterone injection.•GenSci070 is bioequivalent to the marketed progesterone injection (Lubion).•GenSci070 exhibits a good safety profile.•GenSci070 provides a new treatment option for patients on China's mainland. To study the pharmacokinetic characteristics of progesterone (GenSci070) in healthy Chinese postmenopausal women volunteers and to evaluate the bioequivalence and safety of GenSci070 and reference formulation. In this randomized, open-label, single-center, single-dose, 2-period, 2-sequence, 2-way crossover study, 50 postmenopausal healthy women were recruited and received a single subcutaneous injection of test (GenSci070) or reference formulation 25 mg, respectively. Plasma progesterone concentrations were measured using liquid chromatography–tandem mass spectrometry, and pharmacokinetic parameters were calculated by noncompartmental analysis method using Phoenix WinNonlin 8.3.1 software to evaluate the bioequivalence. The safety profile was evaluated by adverse events, physical examination, vital signs, laboratory tests, 12-lead ECG, etc. The geometric mean ratios (90% CIs) for Cmax, AUC0–t, and AUC0–∞ of the test and reference formulations were 92.70% (87.29%–98.44%), 96.26% (94.02%–98.55%), and 95.46% (93.27%–97.71%), respectively. They were all within the acceptable bioequivalence range of 80% to 125%. Thirty-one treatment-emergent adverse events occurred in 22 participants (44.0%) who received test formulation and 21 treatment-emergent adverse events occurred in 16 participants (32.0%) who received reference formulation, all events were mild. The water-soluble progesterone injection (GenSci070) demonstrated bioequivalence to the marketed progesterone injection (Lubion) and exhibited a good safety profile in this study.

Abstract Rationale The aromatase inhibitor anastrozole blocks the conversion of androgens to estrogen and blunts pulmonary hypertension in animals, but its efficacy in treating patients with pulmonary arterial hypertension (PAH) is unknown. Objectives We aimed to determine the safety and efficacy of anastrozole in PAH. Methods We performed a randomized, double-blind, placebo-controlled trial of anastrozole in patients with PAH who received background therapy at two centers. Measurements and Main Results A total of 18 patients with PAH were randomized to anastrozole 1 mg or matching placebo in a 2:1 ratio. The two co–primary outcomes were percent change from baseline in 17β-estradiol levels (E2) and tricuspid annular plane systolic excursion (TAPSE) at 3 months. Anastrozole significantly reduced E2 levels compared with placebo (percent change: −40%; interquartile range [IQR], −61 to −26% vs. −4%; IQR, −14 to +4%; P = 0.003), but there was no difference in TAPSE. Anastrozole significantly increased the 6-minute-walk distance (median change = +26 m) compared with placebo (median change = −12 m) (median percent change: anastrozole group, 8%; IQR, 2 to 17% vs. placebo −2%; IQR, −7 to +1%; P = 0.042). Anastrozole had no effect on circulating biomarkers, functional class, or health-related quality of life. There was no difference in adverse events. Conclusions Anastrozole significantly reduced E2 levels in patients with PAH but had no effect on TAPSE. Anastrozole was safe, well tolerated, and improved 6-minute-walk distance in this small “proof-of-principle” study. Larger and longer phase II clinical trials of anastrozole may be warranted in patients with PAH. Clinical trial registered with www.clinicaltrials.gov (NCT 1545336).

Although research has demonstrated a relationship between proinflammatory cytokine activity and depressive symptoms, the neurocognitive processes underlying this relationship have remained largely unexplored. Here, we examined the effect of proinflammatory cytokine activation on the neural correlates of socially painful experience and associated depressed mood. Participants received either low-dose endotoxin or placebo through intravenous injection. Levels of the proinflammatory cytokine, IL-6, were repeatedly assessed through hourly blood draws; self-reported depressed mood was assessed hourly as well. Two hours post-injection, participants completed a neuroimaging session in which they were socially excluded during an online ball-tossing game. Replicating previous research, individuals exposed to endotoxin, compared to placebo, showed increases in IL-6 levels and depressed mood. Although there were no meaningful differences between the endotoxin and control groups in neural responses to social exclusion, there were sex differences in the relationships between IL-6 increases and neural responses to exclusion among subjects exposed to endotoxin. Among females, but not males, exposed to endotoxin, increases in IL-6 were associated with increases in social pain-related neural activity (dorsal anterior cingulate cortex, anterior insula) that mediated the relationship between IL-6 increases and depressed mood increases. Implications of these sex differences in the neural correlates of cytokine-associated depressed mood and social pain are discussed.

Mood disorders are twice as frequent in women than in men. Risk mechanisms for major depression include adverse responses to acute changes in sex-steroid hormone levels, eg, postpartum in women. Such adverse responses may involve an altered processing of rewards. Here, we examine how women's vulnerability for mood disorders is linked to sex-steroid dynamics by investigating the effects of a pharmacologically induced fluctuation in ovarian sex steroids on the brain response to monetary rewards. In a double-blinded placebo controlled study, healthy women were randomized to receive either placebo or the gonadotropin-releasing hormone agonist (GnRHa) goserelin, which causes a net decrease in sex-steroid levels. Fifty-eight women performed a gambling task while undergoing functional MRI at baseline, during the mid-follicular phase, and again following the intervention. The gambling task enabled us to map regional brain activity related to the magnitude of risk during choice and to monetary reward. The GnRHa intervention caused a net reduction in ovarian sex steroids (estradiol and testosterone) and increased depression symptoms. Compared with placebo, GnRHa reduced amygdala's reactivity to high monetary rewards. There was a positive association between the individual changes in testosterone and changes in bilateral insula response to monetary rewards. Our data provide evidence for the involvement of sex-steroid hormones in reward processing. A blunted amygdala response to rewarding stimuli following a rapid decline in sex-steroid hormones may reflect a reduced engagement in positive experiences. Abnormal reward processing may constitute a neurobiological mechanism by which sex-steroid fluctuations provoke mood disorders in susceptible women.

Endometrial receptivity biomarkers, specifically the regulatory proteins HOXA-10 and HOXA-11 as well as the integrin αvβ3, play vital roles in implantation during the window of implantation. This Double-blinded, randomized clinical trial compares the effects of two initial doses of oral estrogen regimens on endometrial receptivity markers during the window of implantation in endometrial preparation for frozen-thawed embryo transfer. The study includes infertile patients who underwent in vitro fertilization and planned frozen-thawed embryo transfer at the infertility clinic between June 2018 and March 2019. Fifty patients were randomized to a low-dose (4 mg/day) or standard-dose (6 mg/day) estradiol group for artificial endometrial preparation. On the first visit (day 12 of the cycle), measurements of mean endometrial thickness and estradiol and progesterone levels were taken. Following this visit, patients received 600 mg daily of micronized progesterone for 7 days. On the second visit (day 19 of the cycle), hormonal levels were reassessed, and an endometrial biopsy was performed for immunohistochemical analysis. The primary outcome was the expression level of HOXA-10. Secondary outcomes included the expression levels of HOXA-11 and integrin αvβ3, mean endometrial thickness, as well as serum estradiol and progesterone levels measured at various phases of the endometrial cycle. The mean age of the participants was 36 years. The standard-dose group exhibited significantly greater intensity scores for the expression of the regulatory proteins HOXA-10 and HOXA-11 and the integrin αVβ3 than did the low-dose group (75.84 ± 11.25 vs 61.53 ± 11.05, 107.08 ± 19.42 vs 87.62 ± 9.40, and 90.25 ± 10.42 vs 76.32 ± 12.98, respectively; P < 0.001). The groups had no significant differences in mean serum estradiol level, progesterone level, or endometrial thickness during the artificial cycle at the first or second visit. Optimal artificial endometrial preparation for embryo transfer in a frozen-thawed embryo transfer cycle is crucial for maximizing implantation outcomes. This study suggests that the administration of a fixed standard dose of 6 mg of estradiol for artificial endometrial preparation should be considered.

Objective This study aimed to evaluate the impact of adding 4 mg estradiol valerate to progesterone for luteal support on pregnancy rates in IVF cycles following a long protocol with reduced luteal serum estradiol levels post-hCG triggering. Design, setting, and participants The prospective randomized controlled trial was conducted at a public tertiary hospital reproductive center with 241 patients who experienced a significant decrease in serum estrogen levels post-oocyte retrieval. Interventions Participants received either a daily 4 mg dose of estradiol valerate in addition to standard progesterone or standard progesterone alone for luteal support. Results The ongoing pregnancy rate did not show a significant difference between the E2 group and the control group (56.6% vs. 52.2%, with an absolute rate difference (RD) of 4.4%, 95% CI -0.087 to 0.179, P  = 0.262). Similarly, the live birth rate, implantation rate, clinical pregnancy rate, early abortion rate, and severe OHSS rate were comparable between the two groups. Notably, the E2 group had no biochemical miscarriages, contrasting significantly with the control group (0.0% vs. 10.7%, RD -10.7%, 95% CI -0.178 to -0.041, P  = 0.000). In the blastocyst stage category, the clinical pregnancy rate was notably higher in the E2 group compared to the control group (75.6% vs. 60.8%, RD 14.9%, 95% CI 0.012 to 0.294, P  = 0.016). Conclusion Adding 4 mg estradiol valerate to progesterone for luteal support does not affect the ongoing pregnancy rate in embryo transfer cycles using a long protocol with a significant decrease in serum estradiol levels after hCG triggering. However, it may reduce biochemical miscarriages and positively impact clinical pregnancy rates in blastocyst embryo transfer cycles. Trial registration ChiCTR1800020342.

Adequate luteal phase progesterone exposure is necessary to induce endometrial changes required for a successful pregnancy outcome. The relationship between low midluteal progesterone concentration and the outcome of live birth in ovarian stimulation with intrauterine insemination (OS-IUI) treatments is not defined. To determine the level of midluteal progesterone portending a low chance of live birth after OS-IUI in couples with unexplained infertility. Secondary analyses of data from a prospective, randomized, multicenter clinical trial that determined pregnancy outcomes following OS-IUI with clomiphene citrate, letrozole, or gonadotropins for couples with unexplained infertility. Couples (n = 900) underwent 2376 OS-IUI cycles during the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation clinical trial. Live birth as it relates to midluteal progesterone level and thresholds below which no live births occur by treatment group. Thresholds for non-live birth cycles were similar for clomiphene (14.4 ng/mL) and letrozole (13.1 ng/mL) yet were lower for gonadotropin (4.3 ng/mL) treatments. A midluteal progesterone level >10th percentile specific for each treatment group independently was associated with greater odds for a live birth in all OS-IUI cycles (adjusted OR: 2.17; 95% CI: 1.05, 4.48). During OS-IUI, a low midluteal progesterone level was associated with a low probability of live birth. Thresholds differed by medication, with the lowest threshold for gonadotropin. Several pathophysiologic mechanisms may account for low progesterone levels. Refinement of the predictive range associated with particular ovarian stimulation medications during treatment of unexplained infertility may improve accuracy.

Background. Previous studies have suggested that Fetuin-B seems to be a secreted adipokine related to metabolic diseases. However, the results have been inconsistent. Here, our objective is to investigate the changes in circulating Fetuin-B levels in women with polycystic ovary syndrome (PCOS) and analyze the association of Fetuin-B and insulin resistance (IR). Methods. The current study is comprised of a cross-sectional study and a series of interventional studies. Oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp (EHC) were engaged to assess glucose tolerance and insulin sensitivity. Serum Fetuin-B levels were determined by ELISA. Results. Serum Fetuin-B and TNF-α levels were markedly increased in women with PCOS compared to healthy women. Circulating Fetuin-B was positively associated with body mass index, waist-to-hip ratio, the percentage of body fat (FAT%), systolic blood pressure, triglyceride, low-density lipoprotein cholesterol, fasting blood glucose, 2 h blood glucose after glucose overload, fasting insulin, 2 h insulin after glucose overload, HOMA-insulin resistance index (HOMA-IR), the area under the curve for insulin (AUCi), AUCg, and TNF-α, while negatively associated with M value and follicular stimulating hormone (FSH). During the EHC, Fetuin-B levels were found to be significantly increased in PCOS women. After a glucose challenge, serum Fetuin-B levels in healthy women were significantly increased. Lipid infusion reduced serum Fetuin-B levels in 30 healthy subjects. After six months of glucagon-like peptide-1 receptor agonist (GLP-1RA) intervention, serum Fetuin-B concentrations in PCOS women markedly decreased following ameliorated IR. Conclusion. Our results indicate that Fetuin-B may be a biomarker of IR in individuals with PCOS. This trial is registered with ChiCTR-IIR-16007901.

Preclinical and human laboratory research suggests that (a) progesterone may decrease drug reward, craving, and smoking behavior, and (b) estradiol may enhance drug reward and smoking behavior. A modest majority of treatment research examining the relationship between menstrual cycle phase and outcomes suggests that the luteal menstrual phase, with its uniquely higher progesterone levels, is associated with better cessation outcomes. However, no studies to date have examined the effects of naturally occurring variation in progesterone and estradiol levels on medication-assisted smoking cessation. The present study sought to fill this notable gap in the treatment literature. Weekly plasma progesterone and estradiol levels were obtained from nicotine-dependent female smokers enrolled in a 4-week cessation trial. Participants (N = 108) were randomized to receive a 4-week course of either varenicline (VAR) tablets and placebo patches or placebo tablets and nicotine patches. Plasma samples were obtained 1 week before their cessation attempt and weekly during medication administration. Abstinence was assessed weekly. Weekly hormone data replicated commonly observed menstrual cycle patterns of progesterone and estradiol levels. Importantly, increases in progesterone level were associated with a 23% increase in the odds for being abstinent within each week of treatment. This effect was driven primarily by nicotine patch-treated versus VAR-treated females. This study was the first to identify an association between progesterone level (increasing) and abstinence outcomes in free-cycling women smokers who participated in a medication-based treatment. Furthermore, the potential benefits of progesterone may vary across different pharmacotherapies. Implications of these findings for smoking cessation intervention are discussed.

It is unclear whether exercise modality (moderate-intensity continuous [MCE]; high-intensity interval [HIE]) and menstrual cycle phase (follicular [FP]; luteal [LP]), individually or in combination, mediate the commonly observed exercise-induced elevation in cardiac troponin T (cTnT). This study examines cTnT responses to MCE and HIE during both the FP and LP. Randomised crossover study. Seventeen healthy, eumenorrheic women completed four trials including MCE (60% VO2max steady-state cycling until 300kJ) and work‐equivalent HIE (repeated 4-min cycling at 90% VO2max interspersed with 3-min rest) during both the FP and LP. The FP and LP were verified based on ovarian hormones. Serum cTnT was assessed using a high-sensitivity assay before, immediately after, and 1 (1HR), 3 (3HR) and 4 (4HR) hours after exercise. cTnT values were corrected for plasma volume changes. cTnT was significantly elevated (p<0.05) post-exercise in both MCE (at 3HR and 4HR) and HIE (at 1HR, 3HR and 4HR). No statistically significant difference (p>0.05) in peak post-exercise cTnT, which mostly occurred at 3HR, was seen among the four trials (median [range], ngl−1: 5.2 [1.7–18.1] after MCE during FP; 4.8 [1.7–24.9] after MCE during LP, 8.2 [3.9–24.8] after HIE during FP and 6.9 [1.7–23.1] after HIE during LP). A single 300kJ bout of both MCE or HIE resulted in a significant post-exercise increase in cTnT, with no differences in peak cTnT response between menstrual cycle phases or between exercise modes, but the cTnT elevation occurs slightly earlier after HIE.