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

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

Diagnostic and therapeutic use of oral micronized progesterone in endocrinology.

Progesterone is a natural steroid hormone, while progestins are synthetic molecules. In the female reproductive system, progesterone contributes to the control of luteinizing hormone and follicle-stimulating hormone secretion and their pulsatility, via its receptors on the kisspeptin, neurokinin B, and dynorphin neurons in the hypothalamus. Progesterone together with estradiol controls the cyclic changes of proliferation and decidualization of the endometrium; exerts anti-mitogenic actions on endometrial epithelial cells; regulates normal menstrual bleeding; contributes to fertilization and pregnancy maintenance; participates in the onset of labor. In addition, it exerts numerous effects on other endocrine systems. Micronized progesterone (MP) is natural progesterone with increased bioavailability, due to its pharmacotechnical micronized structure, which makes it an attractive diagnostic and therapeutic tool. This critical literature review aims to summarize and put forward the potential diagnostic and therapeutic uses of MP in the field of endocrinology. During reproductive life, MP is used for diagnostic purposes in the evaluation of primary or secondary amenorrhea as a challenge test. Moreover, it can be prescribed to women presenting with amenorrhea or oligomenorrhea for induction of withdrawal bleeding, in order to time blood-sampling for diagnostic purposes in early follicular phase. Therapeutically, MP, alone or combined with estrogens, is a useful tool in various endocrine disorders including primary amenorrhea, abnormal uterine bleeding due to disordered ovulation, luteal phase deficiency, premenstrual syndrome, polycystic ovary syndrome, secondary amenorrhea [functional hypothalamic amenorrhea, premature ovarian insufficiency], perimenopause and menopause. When administrated per os, acting as a neurosteroid directly or through its metabolites, it exerts beneficial effects on brain function such as alleviation of symptoms of anxiety and depression, asw well as of sleep problems, while it improves working memory in peri- and menopausal women. Micronized progesterone preserves full potential of progesterone activity, without presenting many of the side-effects of progestins. Although it has been associated with more frequent drowsiness and dizziness, it can be well tolerated with nocturnal administration. Because of its better safety profile, especially with regard to metabolic ailments, breast cancer risk and veno-thromboembolism risk, MP is the preferred option for individuals with an increased risk of cardiovascular and metabolic diseases and of all-cause mortality.

Cytoplasmic sperm injection (ICSI) - A systematic review of the literature.

Background: Progestin-primed ovarian stimulation (PPOS) stimulates ovaries to block the premature surge of luteinizing hormone (LH) by using micronized progesterone or a progestin during the follicular phase instead of the conventional gonadotropin-releasing hormone (GnRH) analogues or GnRH antagonists downregulating LH to obtain multi-follicle engagement. Current work aims to assess the influence of progestogen treatment on ovarian stimulation and the ability to control LH surge, its efficacy and suitability in retrieving oocytes, without affecting the embryo quality and its benefit among infertile women long-term outcomes on children compared to standard stimulation protocols. Materials and Methods: The literature review used the randomized control trials published in the Pubmed database from January 2015 to April 2021. To generate the citation list, the following keywords were used: 'progestin-primed ovarian stimulation', 'PPOS', 'micronized progesterone', 'medroxyprogesterone', and/or 'dydrogesterone'. The selected articles analyzed the cohort, intervention, and scheme of the progestin-primed ovarian stimulation protocol in controlled ovarian stimulation (COS) for in-vitro fertilization (IVF)/intra cytoplasmic sperm injection (ICSI) used in Assisted Reproductive Technologies (ART). Results: Overall we concluded that PPOS for IVF/ICSI in ART results in a higher number of obtained embryos, lower incidence of OHSS, equal duration of stimulation, number of retrieved oocytes, and number of MII oocytes. It is also suggested that long-term safety in children shows no significant difference between the study and control groups. Conclusions: Despite the outcomes of progestin stimulation cycles among all cohorts, we concluded that poor ovarian responders, patients with PCOS, women of advanced age and oocyte donors benefit the most from using PPOS.

Oral micronized progesterone versus vaginal progesterone for luteal phase support in fresh embryo transfer cycles: a multicenter, randomized, non-inferiority trial.

STUDY QUESTION: Does oral micronized progesterone result in a non-inferior ongoing pregnancy rate compared to vaginal progesterone gel as luteal phase support (LPS) in fresh embryo transfer cycles? SUMMARY ANSWER: The ongoing pregnancy rate in the group administered oral micronized progesterone 400 mg per day was non-inferior to that in the group administered vaginal progesterone gel 90 mg per day. WHAT IS KNOWN ALREADY: LPS is an integrated component of fresh IVF, for which an optimal treatment regimen is still lacking. The high cost and administration route of the commonly used vaginal progesterone make it less acceptable than oral micronized progesterone; however, the efficacy of oral micronized progesterone is unclear owing to concerns regarding its low bioavailability after the hepatic first pass. STUDY DESIGN, SIZE, DURATION: This non-inferiority randomized trial was conducted in eight academic fertility centers in China from November 2018 to November 2019. The follow-up was completed in April 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1310 infertile women who underwent their first or second IVF cycles were enrolled. On the day of hCG administration, the patients were randomly assigned to one of three groups for LPS: oral micronized progesterone 400 mg/day (n = 430), oral micronized progesterone 600 mg/day (n = 440) or vaginal progesterone 90 mg/day (n = 440). LPS was started on the day of oocyte retrieval and continued till 11-12 weeks of gestation. The primary outcome was the rate of ongoing pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE: In the intention-to-treat analysis, the rate of ongoing pregnancy in the oral micronized progesterone 400 mg/day group was non-inferior to that of the vaginal progesterone gel group [35.3% versus 38.0%, absolute difference (AD): -2.6%; 95% CI: -9.0% to 3.8%, P-value for non-inferiority test: 0.010]. There was insufficient evidence to support the non-inferiority in the rate of ongoing pregnancy between the oral micronized progesterone 600 mg/day group and the vaginal progesterone gel group (31.6% versus 38.0%, AD: -6.4%; 95% CI: -12.6% to -0.1%, P-value for non-inferiority test: 0.130). In addition, we did not observe a statistically significant difference in the rate of live births between the groups. LIMITATIONS, REASONS FOR CAUTION: The primary outcome of our trial was the ongoing pregnancy rate; however, the live birth rate may be of greater clinical interest. Although the results did not show a difference in the rate of live births, they should be confirmed by further trials with larger sample sizes. In addition, in this study, final oocyte maturation was triggered by hCG, and the findings may not be extrapolatable to cycles with gonadotropin-releasing hormone agonist triggers. WIDER IMPLICATIONS OF THE FINDINGS: Oral micronized progesterone 400 mg/day may be an alternative to vaginal progesterone gel in patients reluctant to accept the vaginal route of administration. However, whether a higher dose of oral micronized progesterone is associated with a poorer pregnancy rate or a higher rate of preterm delivery warrants further investigation. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by a grant from the National Natural Science Foundation of China (82071718). None of the authors have any conflicts of interest to declare. TRIAL REGISTRATION NUMBER: This trial was registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/) with the number ChiCTR1800015958. TRIAL REGISTRATION DATE: May 2018. DATE OF FIRST PATIENT'S ENROLMENT: November 2018.

Effects of Estradiol/Micronized Progesterone vs. Conjugated Equine Estrogens/Medroxyprogesterone Acetate on Breast Cancer Gene Expression in Healthy Postmenopausal Women.

Recent studies suggest estradiol (E2)/natural progesterone (P) confers less breast cancer risk compared with conjugated equine estrogens (CEE)/synthetic progestogens. We investigate if differences in the regulation of breast cancer-related gene expression could provide some explanation. This study is a subset of a monocentric, 2-way, open observer-blinded, phase 4 randomized controlled trial on healthy postmenopausal women with climacteric symptoms (ClinicalTrials.gov; EUCTR-2005/001016-51). Study medication was two 28-day cycles of sequential hormone treatment with oral 0.625 mg CEE and 5 mg of oral medroxyprogesterone acetate (MPA) or 1.5 mg E2 as percutaneous gel/day with the addition of 200 mg oral micronized P. MPA and P were added days 15-28/cycle. Material from two core-needle breast biopsies in 15 women in each group was subject to quantitative PCR (Q-PCR). The primary endpoint was a change in breast carcinoma development gene expression. In the first eight consecutive women, RNA was extracted at baseline and after two months of treatment and subjected to microarray for 28856 genes and Ingenuity Pathways Analysis (IPA) to identify risk factor genes. Microarray analysis showed 3272 genes regulated with a fold-change of >±1.4. IPA showed 225 genes belonging to mammary-tumor development function: 198 for CEE/MPA vs. 34 for E2/P. Sixteen genes involved in mammary tumor inclination were subject to Q-PCR, inclining the CEE/MPA group towards an increased risk for breast carcinoma compared to the E2/P group at a very high significance level (p = 3.1 × 10-8, z-score 1.94). The combination of E2/P affected breast cancer-related genes much less than CEE/MPA.

Progestogen Use in Gender-Affirming Hormone Therapy: A Systematic Review.

OBJECTIVE: Transgender women take gender-affirming hormone therapy (GAHT) to affirm their gender identity and improve quality of life and well-being. Usually, GAHT in transgender women consists of estrogen plus a testosterone-lowering medication. The use of progestogens in GAHT for transgender women has been a controversial topic due to lack of evidence for benefit and potential for increased harm. METHODS: A systematic review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using 4 databases (PubMed/MEDLINE, Ovid, and Cochrane). Manuscripts were reviewed from January 2000 to March 2022 to identify effects of progestogens in transgender women over the age of 16 years on breast development, cardiovascular disease, bone density, quality of life, and stroke incidence. RESULTS: Ten articles were deemed eligible based on specific inclusion and exclusion criteria. Studies analyzing users of cyproterone acetate were also included if there was a comparator group. No relevant studies were found assessing stroke incidence in the transgender population using a progestogen compound. CONCLUSION: Overall, findings were significant for a decreased high-density lipoprotein level and increased thromboembolism risk in transgender women using progestogens. No conclusive evidence was found regarding improved quality of life or breast development. Further research needs to be conducted assessing the effects of progestogens in transgender women.

Impact of progesterone on the gastrointestinal tract: a comprehensive literature review.

Women are more prone to gastrointestinal symptoms than men. A comprehensive literature search was performed to assess the impact of sex steroid hormone, especially progesterone, on the (healthy and diseased) gastrointestinal tract. Overall, 37 articles were identified. Based on these we conclude that progesterone has a dose-dependent and sex-dependent effect on gastric emptying (especially in mammals), slows down gastrointestinal motility, reduces the gallbladder's response to contractile stimulants, may support gastroesophageal reflux by reducing the esophageal sphincter pressure, may protect from Helicobacter pylori infection gastrointestinal sequelae (especially in mammals) and does not affect inflammatory bowel disease-specific symptoms. However, for several gastrointestinal symptoms and diseases no studies have yet been performed addressing the impact of sex hormone steroids.

The impact of micronized progesterone on cardiovascular events - a systematic review.

Biologically identical menopausal hormone therapy (MHT) including micronized progesterone (MP) has gained much attention. We aimed to assess the impact of MP in combined MHT on venous and arterial thromboembolism (VTE/ATE) (e.g. deep venous thrombosis/pulmonary embolism, myocardial infarction [MI] and ischemic stroke). Articles were eligible if they provided endpoints regarding cardiovascular events and use of exogenous MP. Literature searches were designed and executed for the databases Medline, Embase, CINAHL, the Cochrane Library, ClinicalTrials.gov and interdisciplinary database Web of Science. Twelve studies consisting of randomized controlled trials (RCTs), case-control studies and prospective or retrospective cohort studies were included, and risk of bias was assessed. Only a minority assessed thromboembolic events as a primary endpoint, showing that in contrast to norpregnane derivatives, primary and recurrent VTE risk was not altered by combining estrogens with MP, which was also true for ischemic stroke risk. Similarly, in placebo-controlled RCTs assessing VTE/ATE as adverse events there were no significant intergroup differences. Studies on MI as a primary endpoint are missing. In conclusion, while available data suggest that MP as a component in combined MHT may have a neutral effect on the vascular system, more RCTs investigating the impact of MP alone or in combined MHT on vascular primary endpoints are needed.

Additional luteal support might improve IVF outcomes in patients with low progesterone level in middle luteal phase following a GnRH agonist protocol.

AIM: The purpose of the study was to explore the efficacy of additional luteal support (ALS) for patients with low progesterone (P4) level in the middle luteal phase. METHODS: A retrospective study of 1401 women who underwent their first in vitro fertilization (IVF) treatment with a GnRH agonist protocol was analyzed. Patients were divided into five groups according to P4 level in the middle luteal phase (group I>40ng/mL, group II 31-40 ng/mL, group III 21-30 ng/mL, group IV 11-20 ng/mL and group V 0-10 ng/mL. Besides routine luteal support, the group V was offered with additional oral dydrogesterone 10 mg twice daily to HCG test (ALS group). RESULTS: After a multiple regression analysis, a similar higher hCG positive rate, clinic pregnancy rate and lower early pregnancy loss rate were achieved in group I and group V. In contrast to group I, group IV demonstrated significant lower HCG positive rate (OR = 0.65 [0.43; 0.99], p = .05), lower clinic pregnancy rate (OR = 0.60 [0.41; 0.88], p < .01) and significant higher early pregnancy loss rate (OR = 1.80 [1.08; 2.99], p = .02). The group III also resulted in significant lower clinic pregnancy rate (OR = 0.56 [0.36; 0.87], p = .01). The live birth rate tended to be higher in group I and group V but without a significant difference. CONCLUSION: Following agonist protocol, additional luteal support might improve IVF outcomes in patients with low serum P4 level in the middle luteal phase.

The effectiveness of micronized progesterone in the complex therapy of 'thin endometry' syndrome.

The article presents the results of examination of 30 patients with a history of miscarriage and 'thin' endometrium in comparison with 20 patients without reproductive loss and the presence of normal endometrial thickness. The dynamics of intracellular production of γ-INF, IL-1 and IL-10 by cytotoxic endometrial lymphocytes was studied by flow cytometry. It was found that before treatment in patients with miscarriage and thin endometrium syndrome there was a significant (12-fold) decrease in the level of CD8+ cytotoxic/suppressor lymphocytes (p < .01), a 2.8-fold decrease in the level of CD56+ cells, and also a sharp inhibition of the level of intracellular production of cytokines - γ-INF (8 times), IL-1 (11 times) and IL-10 (15 times). Against the background of complex therapy, including the elimination of pathogenic pathogens, antiplatelet therapy, intrauterine ultrasound cavitation and personalized hormonal therapy using intravaginal micronized progesterone (Luteina), an increase of endometrial thickness was observed: M-echo from 5.9 ± 0.1 to 10.2 ± 0.2 mm; the frequency of visualization of uterine vessels increased to 80-100%; in the spiral arteries, the pulsation index significantly decreased-PI (1.43 ± 0.04 vs. 0.79 ± 0.06), resistance index RI (0.96 ± 0.05 vs. 0.54 ± 0.04), systolic-diastolic ratio S/D in the uterine (4.5 ± 0.04 vs. 2.3 ± 0.05) and arcuate arteries (3.67 ± 0.04 vs. 2.41 ± 0.02); and there was also a positive dynamics of intracellular cytokine production with a significant (p < .05) increase in the level of IL-1 and IL-10, as well as the level of γ-IFN CD56+ by endometrial lymphocytes.

Vaginal Progesterone Supplementation in the Management of Preterm Labor: A Randomized Controlled Trial.

OBJECTIVES: The primary objective in this study was to evaluate the effects of vaginal progesterone supplementation for the prolongation of the latency period in preterm labor. The secondary objectives were to evaluate gestational age at delivery, rates of preterm birth less than 34 and 37 weeks, obstetric outcomes, maternal compliance with medication use, and side effects. METHODS: A randomized controlled, unblinded trial was performed. Ninety women with preterm labor occurring at 24 to 34 weeks were either randomized to a vaginal progesterone group (44 women) receiving tocolytic and antenatal corticosteroids treatment combined with vaginal micronized progesterone (400 mg everyday) or to the no-progesterone group (46 women) receiving tocolytic and antenatal corticosteroids treatment only. RESULTS: Latency periods were more prolonged in the vaginal progesterone group than in the no-progesterone group (32.8 ± 18.7 vs. 25.8 ± 22.7 days, p = 0.045). Gestational age at delivery in the vaginal progesterone group was also higher than in the no-progesterone group (37 vs. 35 weeks, p = 0.027). There were significant reduction rates of preterm birth less than 34 weeks (13.6% vs. 39.1%, p = 0.012), low birth weight (29.5% vs. 50%, p = 0.048), neonatal respiratory distress syndrome (13.6% vs. 37%, p = 0.021), and neonatal intensive care unit admission (6.8% vs. 28.3%, p = 0.017). CONCLUSIONS: Combined treatment with vaginal progesterone 400 mg could prolong the latency period in preterm labor when compared with no progesterone.

Cyclic Progesterone Therapy in Androgenic Polycystic Ovary Syndrome (PCOS)-A 6-Month Pilot Study of a Single Woman's Experience Changes.

Background and Objectives: Women with androgenic Polycystic Ovary Syndrome (PCOS) have increased endometrial cancer risk that cyclic progesterone will prevent; it may also reverse PCOS's neuroendocrine origins. This pilot study's purpose was to document 6-month experience changes in a woman with PCOS taking cyclic progesterone therapy because she was intolerant of combined hormonal contraceptive therapy, the current PCOS standard of care. A 31-year-old normal-weight woman with PCOS had heavy flow, irregular cycles, and was combined hormonal contraceptives-intolerant. She was prescribed cyclic oral micronized progesterone (OMP) (300 mg/h.s. cycle days 14-27). She kept Menstrual Cycle Diary© (Diary) records, starting with the 1st treatment cycle for six cycles; she was on no other therapy. Statistical analysis a priori hypothesized progesterone decreases high estradiol (E2) experiences (flow, cervical mucus, fluid retention, front-of-the-breast tenderness and anxiety); analysis focused on these. Our objectives: (1) changes from cycles 1 to 6 in E2-related experiences; and (2) follicular phase E2-related changes from cycle 1 (no therapy) to cycles 3 and 6. Materials and Methods: Data from consecutive Diaries were entered into an SPSS database and analyzed by Wilcoxon Signed Rank Test (Objective #1) within-person whole cycle ordinal data, and (Objective #2 follicular phase) repeated measures ANOVA. Results: Cyclic OMP was associated with regular, shorter cycles (±SD) (28.2 ± 0.8 days). Comparison of cycles 1-6 showed decreased fluid retention (p = 0.001), breast tenderness (p = 0.002), and cervical mucus (p = 0.048); there were no changes in flow or anxiety. Fluid retention in the follicular phase also significantly decreased over time (F (1.2, 14.7) = 6.7, p = 0.017). Conclusions: Pilot daily Diary data suggest women with PCOS have improved everyday experiences on cyclic progesterone therapy. Larger prospective studies with more objective outcomes and randomized controlled trials of this innovative PCOS therapy are needed.

Clinical Re-evaluation on Bioequivalence and Relative Bioavailability of Micronized Progesterone Hard Capsule (Yimaxin) and Micronized Progesterone Soft Capsule (Utrogestan) under Vaginal and Oral Administration Routes.

BACKGROUND AND OBJECTIVE: To clinically re-evaluate relative bioavailability and bioequivalence of micronized progesterone (hard capsule) Yimaxin and micronized progesterone (soft capsule) Utrogestan under vaginal and oral administration routes. METHODS: From December 2017 to June 2018, a total of 16 postmenopausal healthy women were recruited and received a total of four rounds of drug treatment with cross-over design, respectively Yimaxin and Utrogestan under vaginal and oral administration routes. Changes in the subjects' hormone levels after medication were monitored and an endometrial biopsy after a course of treatment was performed in our hospital. RESULT: The Geomeans of AUC0-t of Yimaxin and Utrogestan under vaginal administration route were 252.15 and 115.46, respectively, with a ratio of 2.19, and under oral administration route were 244.64 and 413.68, respectively, with a ratio of 0.59. The Geomeans of Cmax of Yimaxin and Utrogestan under vaginal administration route were 28.11 and 12.21, respectively, with a ratio of 2.30, and under oral administration route were 53.12 and 129.85, respectively, with a ratio of 0.41. CONCLUSION: Yimaxin was not bioequivalent to Utrogestan. Yimaxin had higher exposure to the drug in vivo at the same dose when administered vaginally, and Utrogestan had higher exposure to the drug in vivo at the same dose when administered orally.

Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence.

Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone supplementation may reduce the risk of miscarriage in women with recurrent or threatened miscarriage. Cochrane Reviews summarized the evidence and found that the trials were small with substantial methodologic weaknesses. Since then, the effects of first-trimester use of vaginal micronized progesterone have been evaluated in 2 large, high-quality, multicenter placebo-controlled trials, one targeting women with unexplained recurrent miscarriages (the PROMISE [PROgesterone in recurrent MIScarriagE] trial) and the other targeting women with early pregnancy bleeding (the PRISM [PRogesterone In Spontaneous Miscarriage] trial). The PROMISE trial studied 836 women from 45 hospitals in the United Kingdom and the Netherlands and found a 3% greater live birth rate with progesterone but with substantial statistical uncertainty. The PRISM trial studied 4153 women from 48 hospitals in the United Kingdom and found a 3% greater live birth rate with progesterone, but with a P value of .08. A key finding, first observed in the PROMISE trial, and then replicated in the PRISM trial, was that treatment with vaginal micronized progesterone 400 mg twice daily was associated with increasing live birth rates according to the number of previous miscarriages. Prespecified PRISM trial subgroup analysis in women with the dual risk factors of previous miscarriage(s) and current pregnancy bleeding fulfilled all 11 conditions for credible subgroup analysis. For the subgroup of women with a history of 1 or more miscarriage(s) and current pregnancy bleeding, the live birth rate was 75% (689/914) with progesterone vs 70% (619/886) with placebo (rate difference 5%; risk ratio, 1.09, 95% confidence interval, 1.03-1.15; P=.003). The benefit was greater for the subgroup of women with 3 or more previous miscarriages and current pregnancy bleeding; live birth rate was 72% (98/137) with progesterone vs 57% (85/148) with placebo (rate difference 15%; risk ratio, 1.28, 95% confidence interval, 1.08-1.51; P=.004). No short-term safety concerns were identified from the PROMISE and PRISM trials. Therefore, women with a history of miscarriage who present with bleeding in early pregnancy may benefit from the use of vaginal micronized progesterone 400 mg twice daily. Women and their care providers should use the findings for shared decision-making.

Hormone Therapy in Menopause.

As longevity expands, women are spending a third of their existence in menopause and beyond. The vast majority suffer from symptoms that negatively impact their quality of life. Systemic vasomotor symptoms (VMS) are the classic cluster affecting 80% of peri- and post-menopausal women. Once thought to be relatively brief, they sometimes persist more than 10 years. Compelling, yet enigmatic, is the recent finding that women with bothersome and long VMS compared with age-matched peers often have worst underlying preclinical markers of cardiovascular disease (CVD).Local vulvovaginal and urinary symptoms, now termed genitourinary syndrome of menopause (GSM), are seen in 50% of postmenopausal women, and it negatively impacts quality of life. Estrogen remains the most effective treatment for both VMS and GSM, for osteoporosis prevention, and for symptom relief as well as chronic disease prevention in women who experience premature menopause whether from primary ovarian insufficiency (POI) or iatrogenic etiologies. For women who have contraindications to estrogen therapy or who personally object, a panoply of nonhormonal modalities can be offered to treat both systemic and local menopausal symptoms. A historical review of estrogen studies reveals why its persona has vacillated from hero to villain (after the WHI) and back to hero. The "timing hypothesis" and its underlying mechanism shed light on the pleiotropic nature of estrogen. Finally reviewed is the compelling argument from notable thought-leaders that estrogen, in those without contraindications, should be considered for primary prevention of cardiovascular disease as well as the prevention of chronic disease.

Methods of preventive intervention in women with multiple pregnancies in non-assymptomic circulation.

OBJECTIVE: The aim: The purpose of the study is a comparative evaluating the effectiveness of using the different methods of treatment of miscarriage in multiple pregnancies taking into account the condition of the cervix. PATIENTS AND METHODS: Materials and methods: 86 pregnant women with diarrheal twins were monitored. On the basis of studying the premorbid background, somatic and reproductive history, features of the gestational period, leading antenatal risk factors for the development of complications in multiple pregnancies were identified. With the help of transvaginal cervicometry the prognostic ultrasound criteria of the condition of the cervix and its obstructive capacity in case of premature birth are investigated. RESULTS: Results: In the event of uncomplicated pregnancy multiple birth is characterized by a gradual shortening of the cervix in dynamics from 43.2 ± 3.9 mm to 38.2 ± 4.0 mm by 20 weeks, from 37.7 ± 4.1 mm to 30.2 ± 3.9 mm to 30 weeks, to 21.1 ± 3.1 mm to 37 weeks. In the period of 25-27 weeks, the appearance of a V-shaped opening of the uterine cervix in half of the women was observed, which remained until the end of gestation. Shortening of the cervix was the most significant in patients with the risk of abortion who received only tocolytic therapy. In the 2nd trimester revealed a V- or U-shaped opening of the cervical canal. In pregnant women at risk who had an obstetric pessary, a decrease in the length of the cervix was found, which was similar to the rate of its shortening in uncomplicated multiple pregnancies. The condition of the cervix in the presence of a pessary before delivery probably did not differ from the condition of the cervix with the normal course of multiple pregnancies. CONCLUSION: Conclusions: Pregnant women with uncomplicated multiple pregnancies revealed a decrease in the length of the cervix with an increase in gestation. At the end of pregnancy, the internal jaws acquired a predominantly Y-shape. In pregnant women with the risk of pregnancy termination who received tocolytic therapy, the cervix was the shortest. In late gestation, V- and U-shaped internal jaws were observed. Changes in the cervix after the placement of obstetric pessaries are similar to changes in uncomplicated pregnancy.

Impact of micronized progesterone on body weight, body mass index, and glucose metabolism: a systematic review.

In women, body weight increases with age. Often menopausal hormone therapy (MHT) is blamed for enhancing this effect. In recent years, the debate on bioidentical MHT including micronized progesterone (MP) has increased. Among others, the question has been raised of whether MHT containing MP has an impact on body weight and glucose metabolism. Based on a systematic literature review on the impact of MHT containing MP on body weight, body mass index (BMI), and glucose metabolism, the following conclusions can be drawn: estrogens combined with MP (1) either do not change or reduce body weight in normal weight postmenopausal women, (2) do not change BMI in normal and overweight postmenopausal women, (3) do not change or improve fasting serum glucose levels in (non-)diabetic postmenopausal women, (4) do not change or improve fasting serum insulin levels in (non-)diabetic postmenopausal women, and (5) do not have an impact on serum glycated hemoglobin in postmenopausal diabetic women. This beneficial effect is probably mostly due to the estrogen MHT component.

Changes in breast density during hormone treatment with transdermal estrogens alone or in combination with progesterone.

A retrospective observational study to assess whether hormonal treatment (HT) with transdermal estrogens alone or in combination with micronized progesterone increases breast density and to compare these changes to those of a control group of 4120 patients were not given HT. We included 150 patients whose baseline breast density was assessed with photon-counting spectral mammography and 1 year after hormone treatment. The reduction in breast density was compared using an analysis of covariance. The difference in breast density between mammographies in the HT group was -0.40 ± 5.5 and -0.85 ± 4.2 in the control group. The changes in density according to the type of HT, we found that women on treatment with estrogen alone presented a difference of 0.44 ± 5.8, and -1.35 ± 5 (p = 0.13) in women on combined treatment. After adjusting changes in density for age and average number of days between mammographies, we observed a difference of -0.36 95% confidence intervals (CI) [-1.04 to -0.31] in the women on HT and -0.71 95% CI [-1.65 to -0.21] in the control group. No increased breast density was observed in women on HT treatment, nor did we observe an increase according to HT type. The difference in breast density loss was smaller in the HT group versus the control group.

Progesterone, progestins and the breast in menopause treatment.

Breast cancer is the main risk associated with menopause hormone therapy (MHT). It is a hormone-dependent cancer. In postmenopausal women, about 80% of cases are estradiol receptor-positive. In cohort studies only estradiol receptor-positive breast cancers are promoted by MHT. Different levels of risk with estrogen-only treatment and combined treatment with estrogen + progestin are shown in randomized trials and observational studies. Several non-randomized studies show a lower risk with progesterone and retroprogesterone than with synthetic progestins. Progesterone and progestin are non-selective ligands for the progesterone receptor and bind also with other steroid receptors, with agonistic or antagonistic effects according to the structure of the molecule. Their half-life and metabolism are also different, progesterone being rapidly degraded with a short half-life. These aspects will be discussed in this review.

Progesterone for treatment of symptomatic menopausal women.

This review's purpose is to highlight evidence that oral micronized progesterone (progesterone) is effective for hot flushes and night sweats (vasomotor symptoms, VMS), improves sleep and is likely safe in menopausal women (who are more than 1 year since last menstruation). Methods include randomized controlled clinical trials (RCT) supplemented with basic science, population and observational data as needed. The barrier to use of progesterone is lack of awareness that safety concerns with estrogen-including 'menopausal hormone therapy' (MHT) are not applicable to progesterone. In a single 3-month RCT, progesterone (300 mg at bedtime) was effective treatment of VMS in 133 healthy menopausal women. It caused an overall 55% VMS decrease, no withdrawal-related VMS rebound and a greater VMS decrease in 46 women with ≥50 moderate-intense VMS/week. Progesterone is equally or more effective than estradiol in improving cardiovascular endothelial function and caused no cardiovascular safety concerns in a 3-month RCT. An 8-year prospective cohort study (E3N) in more than 80 000 menopausal women showed progesterone prevented breast cancer in estrogen-treated women. Multiple RCTs confirm that progesterone (300 mg daily at bedtime) does not cause depression and improves deep sleep. In conclusion, progesterone effectively treats VMS, improves sleep and may be the only therapy that symptomatic women, who are menopausal at a normal age and without osteoporosis, need.