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Miscarriage remains an important global problem: 23 million miscarriages are registered annually in the world, i.e. 44 pregnancy losses every minute, and the total risk of miscarriage is 15.3% of all pregnancies. Effective methods of pregnancy preservation (in case of idiopathic miscarriage and threatened miscarriage) include lifestyle modification and progestagen therapy. Progesterone is the main hormone necessary to maintain pregnancy.The effectiveness of progestogens among medical methods that increase the chances of pregnancy preservation has been proven by numerous studies. Effectiveness and safety of various types of progestogens during pregnancy have been studied. As a result, progesterone and dydrogesterone became the only progestogens approved for use in obstetrics – micronized progesterone and dydrogesterone reduce the frequency of miscarriage in women with clinical diagnoses of threatened miscarriage and idiopathic recurrent miscarriage. In addition, the progestogens safety has been carefully studied in modern randomized studies, prospective trials and meta-analyses and the same safety profile of dydrogesterone and micronized progesterone for pregnant women and the fetus has been proven.Studies have shown that oral dydrogesterone has relatively low antagonistic activity at glucocorticoid and mineralocorticoid receptors compared to progesterone and therefore well tolerated. Oral dydrogesterone due to the peculiarities of structure has improved bioavailability compared to progesterone, which allows a woman to avoid the inconvenience and discomfort associated with the intravaginal or intramuscular use of progesterone. In addition, dydrogesterone has a 1.5 times higher affinity for progesterone receptors compared to micronized progesterone and a pronounced anti-inflammatory and immunomodulation effect, which provides certain clinical advantages for patients after recurrent pregnancy losses.Thus, progestogens are indicated for all patients with recurrent pregnancy losses from the moment of receiving a positive pregnancy test, as they reduce the risk of miscarriage. It is important that the use of progestagen drugs during the first and second trimester of pregnancy is not associated with side effects, Невиношування вагітності лишається важливою проблемою світового масштабу: щорічно у світі реєструється 23 млн викиднів, тобто 44 втрати вагітності щохвилини, а загальний ризик викидня становить 15,3% від усіх вагітностей. До ефективних методів збереження вагітності (у разі ідіопатичного невиношування вагітності та загрози викидня) належать модифікація способу життя та терапія прогестагенами. Прогестерон є основним гормоном, необхідним для збереження вагітності.Ефективність прогестагенів серед медикаментозних методів, що підвищують шанси на збереження вагітності, доведена численними дослідженнями. Загалом досліджувалися різні види прогестагенів щодо їхньої ефективності та безпеки застосування під час вагітності. Зрештою прогестерон і дидрогестерон стали єдиними прогестагенами, що затверджені для використання в акушерстві: у жінок із клінічними діагнозамизагрози викидня та ідіопатичним рецидивним викиднем мікронізований прогестерон і дидрогестерон достовірно знижують частоту викидня. Крім того, у сучасних рандомізованих дослідженнях, проспективних випробуваннях і метааналізах ретельно вивчені питання безпечного застосування прогестагенів і доведено однаковий профіль безпеки дидрогестерону й мікронізованого прогестерону для вагітних і плода.Дослідження продемонстрували, що пероральний дидрогестерон характеризується відносно низькою антагоністичною активністю щодо глюкокортикоїдних і мінералокортикоїдних рецепторів порівняно з прогестероном, а тому добре переноситься. Завдяки особливостям своєї структури дидрогестерон має покращену біодоступність при пероральному застосуванні порівняно з прогестероном, що дозволяє жінціуникати незручностей і дискомфорту, пов’язаних із інтравагінальним або внутрішньом’язовим уведенням прогестерону. Крім того, дидрогестерон має в 1,5 раза вищу спорідненість до рецепторів прогестерону порівняно з мікронізованим прогестероном і виражену протизапальну та імуномодулювальну дію, що забезпечує певні клінічні переваги для пацієнток після повторних втрат вагітності.Отже, прогестагени показані всім пацієнткам зі звичним викиднем з моменту отримання позитивного тесту на вагітність, оскільки знижують ризик викидня. Важливо, що використання прогестагенних препаратів протягом першого та другого триместру вагітності не пов’язане з побічними ефектами.

Objective of this review is a systematic analysis of the data available in the current literature on the efficacy and safety of progestogens for the prevention of atypical endometrial hyperplasia (EH) in patients of reproductive age. EH is an excessive proliferation that results in increased volume and changes in endometrial tissue architectonics with an increase in the endometrial glands to stroma ratio of more than 1:1. This review will consider the use of progestogens for the prevention of (EH) based on evidence-based scientific evidence over the past 5 years. The expansion of the range of effective treatment options allows the adaptation of treatment to the needs of patients and offers a personalized approach to their management. Progestogens are an effective and safe method for the prevention of atypical hyperplasia, with a wide range of therapeutic benefits associated with reliable favorable fertility prognosis, especially in young women.

This paper describes a methodology for simultaneous determination of 19 steroid hormones, viz. estrone, estradiol, estriol, testosterone, 5α-dihydrotestosterone, androstenedione, androstenediol, dehydroepiandrosterone, progesterone, pregnenolone, 17α-OH-progesterone, 17α-OH-pregnenolone, cortisone, cortisol, 11-deoxycortisol, 11-deoxycorticosterone, 11-dehydrocorticosterone, aldosterone, and corticosterone, in 500-µL of urine or serum/plasma. The method was optimized using isotopically labeled internal standards and liquid-liquid extraction followed by detection using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-MS/MS). Dansylation of estrogens significantly improved their sensitivities (~11- to 23-fold) and chromatographic separation. The respective limit of detection (LOD) and limit of quantification (LOQ) of all analytes were 0.04–0.28 and 0.14–0.92 ng/mL in human urine, and 0.11–0.35 and 0.38–1.18 ng/mL in human serum/plasma. Recoveries of all analytes (except for progesterone) fortified at 10, 20, and 200 ng/mL in urine and serum were 80–120%, with standard deviations ranging from 0 to 17.3%. Repeated analysis of similarly fortified urine and serum samples yielded intra-day and inter-day variations of 0–21.7% and 0.16–11.5%, respectively. All analytes except cortisone exhibited weak matrix effects in urine and serum (−13.9–18.2%). The method was further validated through the analysis of the National Institute of Standards and Technology (NIST) plasma Standard Reference Material (SRM1950) with certified concentrations for cortisol, progesterone, and testosterone (coefficient of variation: 3–11%). The developed method was applied in the analysis of urine samples from 20 volunteers, which revealed the occurrence of 16 analytes with detection frequencies (DFs) > 80%. Furthermore, 15 analytes were found in plasma SRM1950, indicating the feasibility of our method in the analysis of steroid hormones in urine and serum/plasma. This method will facilitate analysis of steroid hormones in population-based biomonitoring studies.

BACKGROUND Menopausal symptoms can be very distressing and considerably affect a woman’s personal and social life. It is becoming more and more evident that leaving bothersome symptoms untreated in midlife may lead to altered quality of life, reduced work productivity and, possibly, overall impaired health. Hormone therapy (HT) for the relief of menopausal symptoms has been the object of much controversy over the past two decades. At the beginning of the century, a shadow was cast on the use of HT owing to the concern for cardiovascular and cerebrovascular risks, and breast cancer, arising following publication of a large randomized placebo-controlled trial. Findings of a subanalysis of the trial data and extended follow-up studies, along with other more modern clinical trials and observational studies, have provided new evidence on the effects of HT. OBJECTIVE AND RATIONALE The goal of the following paper is to appraise the most significant clinical literature on the effects of hormones in postmenopausal women, and to report the benefits and risks of HT for the relief of menopausal symptoms. SEARCH METHODS A Pubmed search of clinical trials was performed using the following terms: estrogens, progestogens, bazedoxifene, tibolone, selective estrogen receptor modulators, tissue-selective estrogen complex, androgens, and menopause. OUTCOMES HT is an effective treatment for bothersome menopausal vasomotor symptoms, genitourinary syndrome, and prevention of osteoporotic fractures. Women should be made aware that there is a small increased risk of stroke that tends to persist over the years as well as breast cancer risk with long-term estrogen–progestin use. However, healthy women who begin HT soon after menopause will probably earn more benefit than harm from the treatment. HT can improve bothersome symptoms, all the while conferring offset benefits such as cardiovascular risk reduction, an increase in bone mineral density and a reduction in bone fracture risk. Moreover, a decrease in colorectal cancer risk is obtainable in women treated with estrogen–progestin therapy, and an overall but nonsignificant reduction in mortality has been observed in women treated with conjugated equine estrogens alone or combined with estrogen–progestin therapy. Where possible, transdermal routes of HT administration should be preferred as they have the least impact on coagulation. With combined treatment, natural progesterone should be favored as it is devoid of the antiapoptotic properties of other progestogens on breast cells. When beginning HT, low doses should be used and increased gradually until effective control of symptoms is achieved. Unless contraindications develop, patients may choose to continue HT as long as the benefits outweigh the risks. Regular reassessment of the woman’s health status is mandatory. Women with premature menopause who begin HT before 50 years of age seem to have the most significant advantage in terms of longevity. WIDER IMPLICATIONS In women with bothersome menopausal symptoms, HT should be considered one of the mainstays of treatment. Clinical practitioners should tailor HT based on patient history, physical characteristics, and current health status so that benefits outweigh the risks.

Brown bears are obese when they enter the den, and after 6 mo of hibernation and physical inactivity, bears show none of the adverse consequences of a sedentary lifestyle in humans, such as cardiovascular disease, type 2 diabetes, and kidney failure. The metabolic mechanisms that drive hibernation physiology in bears are poorly defined, but systemic endocrine regulators are likely involved. To investigate the potential role of steroid hormones, we quantified the total levels of 12 steroid hormones, the precursor cholesterol, sex hormone-binding globulin (SHBG), and corticosterone-binding globulin (CBG) in paired serum samples from subadult free-ranging Scandinavian brown bears during the active and hibernation states. During hibernation, androstenedione and testosterone were significantly decreased in subadult female bears ( n = 13 ), whereas they increased in all males but one ( n = 6 ) and therefore did not reach a significant difference. Despite this difference, SHBG increased more than 20-fold during hibernation for all bears. Compared with SHBG concentrations in humans, bear levels were very low in the active state, but during hibernation, levels equaled high levels in humans. The increased SHBG levels likely maintain a state of relative quiescence of the reproductive hormones in hibernating bears. Interestingly, the combination of SHBG and testosterone levels results in similar free bioavailable testosterone levels of 70-80 pM in both subadult and adult sexually active male bears, suggesting a role for SHBG in controlling androgen action during hibernation in males. Dehydroepiandrosterone sulfate, dihydrotestosterone, and estradiol levels were below the detection limit in all but one animal. The metabolically active glucocorticoids were significantly higher in both sexes during hibernation, whereas the inactive metabolite cortisone was reduced and CBG was low approaching the detection limit. A potential caveat is that the glucocorticoid levels might be affected by the ketamine applied in the anesthetic mixture for hibernating bears. However, increased hibernating cortisol levels have consistently been reported in both black bears and brown bears. Thus, we suggest that high glucocorticoid activity may support the hibernation state, likely serving to promote lipolysis and gluconeogenesis while limiting tissue glucose uptake to maintain a continuous glucose supply to the brain.

Introduction: Menopausal symptoms can be very overwhelming for women. Over the years, many pharmacotherapeutic options have been tested, and others are still being developed. Hormone therapy (HT) is the most efficient therapy for managing vasomotor symptoms and related disturbances. The term HT comprises estrogens and progestogens, androgens, tibolone, the tissue-selective estrogen complex (TSEC), a combination of bazedoxifene and conjugated estrogens, and the selective estrogen receptor modulators, such as ospemifene. Estrogens and progestogens and androgens may differ significantly for chemical structure and can be delivered through different routes, thereby displaying various pharmacological and clinical properties. Tibolone, TSEC and SERM also exhibit unique pharmacodynamics that can be exploited to obtain distinctive therapeutic effects. Non-hormonal options fall mainly into the selective serotonin reuptake inhibitor (SSRI) and selective noradrenergic reuptake inhibitor (SNRI), GABA-analogue drug classes.Areas covered: Herein, the authors describe the pharmacokinetics and pharmacodynamics of hormonal (androgens, estrogens, progestogens, tibolone, TSEC, SERMs) and non-hormonal (SSRIs, SNRIs, Gabapentin, Pregabalin, Oxybutynin, Neurokinin antagonists) treatments for menopausal symptoms and report essential clinical trial data in humans.Expert opinion: Patient tailoring of treatment is key to managing symptoms of menopause. Physicians must have in-depth knowledge of the pharmacology of compounds to tailor therapy to the individual patient's characteristics and needs.

Background: Recurrent pregnancy loss (RPL) is defined as the loss of two or more pregnancies. Several treatment options are available, including progesterone, which is one of the few treatments that improve live birth rates in RPL patients. Objective: To compare the live birth rates, medical and obstetric characteristics, and RPL evaluation results of women with and without progesterone treatment. These women attended the RPL clinic at Soroka University Medical Center. Methods: A retrospective cohort study based on 866 patients was conducted. The patients were divided into two groups and examined: the dydrogesterone treatment group consisting of 509 women and a group of 357 patients who did not receive the treatment. All the patients had a subsequent (index) pregnancy. Results: The two groups were not statistically different in terms of their demographic and clinical characteristics or evaluation results. In a univariate analysis, no statistically significant differences were found between the groups in terms of live birth rates (80.6% vs. 84%; p-value = 0.209). In a multivariate logistic analysis adjusted for maternal age, the ratio of pregnancy losses to the number of pregnancies, other administered treatments, antiphospholipid syndrome, and body mass index, dydrogesterone treatment was found to be independently associated with a higher rate of live births than the control group (adjusted OR = 1.592; CI 95% 1.051–2.413; p-value = 0.028). Conclusions: Progesterone treatment is associated with an increased live birth rate in RPL patients. Studies with larger sample sizes are recommended to strengthen these results.

The population of animals in Brazil has been growing significantly over the years and in an attempt to control female dogs, many owners use contraceptives indiscriminately. Thus, the present work focuses on the analysis and discussion of the objective and epidemiological aspects of the population in the use of contraceptive drugs in decades. There were a total of 18 medication forms corresponding to the use or not of income, encompassing the personal profile of each population, as well as age, gender, family and education, knowledge about the consequences of this animal and about the indication of this conduct to other people. The main findings elaborated that were affirmed to higher education in 89.3% of the administration of contraceptives were never made of its administration, concomitantly with the findings of prevalence of incomplete (64.07%) ) minimum income and complete monthly income (20.95 %) and family members of up to 1 salary (35%) and income of 1 to 3 higher monthly payments (35%). To conclude that the decision to use medication can be evaluated through stimuli from external and intrinsic factors, such as financial, educational, ease of delivery, age and gender. La población de animales en Brasil ha ido creciendo significativamente a lo largo de los años y, en un intento por controlar a las perras, muchos dueños usan anticonceptivos de forma indiscriminada. Así, el presente trabajo se centra en el análisis y discusión de los aspectos objetivos y epidemiológicos de la población en el uso de medicamentos anticonceptivos en décadas. Foram o total de 18 formulários de medicamentos correspondentes ao uso ou não de renda, englobando o perfil pessoal de cada população, assim como a idade, gênero, familiar e escolaridade, o conhecimento a respeito das consequências desse animal e sobre a indicação dessa conduta a otras personas. Los principales hallazgos elaborados que se afirmaron a la educación superior en el 89,3% de la administración de anticonceptivos nunca se hizo de su administración, concomitantemente con los hallazgos de prevalencia de ingreso mínimo incompleto (64,07%) y ingreso mensual completo (20,95%) y familiar. afiliados de hasta 1 salario (35%) e ingresos de 1 a 3 mensualidades superiores (35%). Concluir que la decisión de uso de medicamentos puede ser evaluada a través de estímulos de factores externos e intrínsecos, como económicos, educativos, facilidad de entrega, edad y género. A população de animais no Brasil vem crescendo de forma significativa ao longo dos anos e na tentativa do controle reprodutivo em cadelas, muitos tutores usam contraceptivos de forma indiscriminada. Assim, o presente trabalho se objetivou na análise e discussão dos aspectos físicos e epidemiológicos da população na utilização de fármacos contraceptivos em cadelas. Foram analisadas o total de 187 formulários correspondentes ao uso ou não de progestágenos em cadelas, englobando o perfil pessoal de cada população, assim como a idade, gênero, renda familiar e escolaridade, o conhecimento a respeito das consequências desse medicamento no animal e sobre a indicação dessa conduta a outras pessoas. Os principais achados mostraram que 89,3% da população afirmaram nunca ter feito a administração de anticoncepcionais em suas cadelas, enquanto 10,7% da população afirmaram ter feito tal administração, concomitante aos achados de prevalência de ensino superior incompleto (64,07%) e ensino superior completo (20,95%) e renda familiar mensal de até 1 salário mínimo (35%) e de 1 a 3 salários mínimos (35%). Conclui-se que a decisão pelo uso de tais medicações pode prevalecer através de estímulos de fatores externos e intrínsecos, como financeiro, educacional, facilidade de obtenção, idade e gêneros.

Gromova O. L. Analysis of the objective and preventative treatment and efficacy of therapeutic approaches in women with non-atypical endometrial hyperplasia. Journal of Education, Health and Sport. 2020;10(11):346-361. eISSN 2391-8306. DOI http://dx.doi.org/10.12775/JEHS.2020.10.11.035 https://apcz.umk.pl/czasopisma/index.php/JEHS/article/view/JEHS.2020.10.11.035 https://zenodo.org/record/4631382 The journal has had 5 points in Ministry of Science and Higher Education parametric evaluation. § 8. 2) and § 12. 1. 2) 22.02.2019. © The Authors 2020; This article is published with open access at Licensee Open Journal Systems of Nicolaus Copernicus University in Torun, Poland Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author (s) and source are credited. This is an open access article licensed under the terms of the Creative Commons Attribution Non commercial license Share alike. (http://creativecommons.org/licenses/by-nc-sa/4.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited. The authors declare that there is no conflict of interests regarding the publication of this paper. Received: 16.10.2020. Revised: 30.10.2020. Accepted: 30.11.2020. ANALYSIS OF THE OBJECTIVE AND PREVENTATIVE TREATMENT AND EFFICACY OF THERAPEUTIC APPROACHES IN WOMEN WITH NON-ATYPICAL ENDOMETRIAL HYPERPLASIA O. L. Gromova Bogomolets National Medical University Department of Obstetrics and Gynecology Faculty of Postgraduete Education, Kiev, Ukraine Oleksandra Gromova, MD, PhD., Assistant of the Department of Obstetrics and Gynecology Postgraduate Education Bogomolets National Medical University tel. +38093 692 80 98; e-mail alex.gynecolog@gmail.com; https://orcid.org/0000-0003-3963-3940 Abstract Non-atypical endometrial hyperplasia (EH) is prone to recurrence and has an unspecified residual monitoring and treatment algorithm. The main factors that influence the possibility of recurrence and progression are not known yet. The objective: examination of the frequency of hyperproliferative endometrial pathology (HPE) in premenopausal women, organization of treatment and prophylactic measures and their influence on the recurrence or progression of HPE. Design of the study: a retrospective observational study. Results of the study: The results of monitoring and treatment were analysed in 380 premenopausal women according to STRAW+10 criteria. The structure was dominated by non-atypycal endomrtrial hyperplasia (EH)- in 356 (93.7%) cases, atypycal hyperplasia (AH) - in 16 (4.2%), endometrial cancer (EC) - in 8 (2.6%). 60 women underwent hysterectomy (24 - AH and EC, 36 - concomitant pathology). Results from 320 women with EH excluding hysterectomy, have beenmonitored over 3 years. Hormonal treatment with gestagens was given to 138 of 320 women (43.1%), 78 (24.3%) received oral progestins without an interruption for 3 months, 34 (10.6%) for 6 months and 26 (8.1%) received LNG-IUDs 52 mg, in 182 (56.8%) no treatment was provided. The effectiveness of EH therapy in women with LNG-IUDs was achieved in 92.3% of cases, with gestagen treatment at 6 months in 70.6%, and at 3 months in 39.7%. With no therapy, regression of the disease was 28.8%. The incidence of EH at the 3rd year of follow-up in women without treatment was 2.4 times higher than at the 6-month course of oral gestagen therapy (71.4 vs 29.4%) and was not significantly different from the 3-month course (71.4 vs 60.3%). There is a lack of clarity in the treatment and monitoring system for women with EH in the study centres; short timing of gestagen prescriptions are insufficiently effective and contribute to a high rate of recurrence; the LNG IUD showed the best efficacy results (93.7%) and absence of recurrence over the course of the study. Key words: endometrial hyperplasia; premenopause; progestogens; reccurens; results of treatment; observation

Background. Most common clinical manifestations of endometriosis (N80) include pelvic pain and infertility, while adenomyosis is associated with abnormal uterine bleeding. At present, approach to the treatment of endometriosis has been revised towards shifting surgery to the second-line therapy; medications are considered as the first-line therapy: gonadotropin releasing hormone agonists, progestogens, aromatase inhibitors. Aim. Comparison of clinical and anamnestic characteristics and therapeutic procedures in women who were treated on an outpatient basis and those who were hospitalized and underwent surgical intervention. Materials and methods. Clinical-anamnestic and morphological characteristics were studied in two groups of women: 1st group (n=27) received drug therapy, 2nd group (n=28) underwent surgical intervention. Results and discussion. In the 1st group, 25.9% of patients received microdosed combined oral contraceptives which contain dienogest as a progestogen component, 44.4% of patients received monotherapy with dienogest, and 22.2% of patients received dydrogesterone in a prolonged mode. In the 2nd group, 39 foci of endometriosis, isolated and in a combination of various loci, were revealed during surgery, of which 30.8% were ovarian cysts, 10.2% were foci on the sacro-uterine ligaments, 23.1% were on the pelvis peritoneum. Surgical approach was determined by the urgency of intervention, an expect localization of endometriosis foci, a comorbidity of endometriosis with another pathology of the internal genitalia, 82.1% of surgery were performed by laparoscopic approach. Conclusions. The choice of treatment method depends on the severity of symptoms, the severity of endometriosis, the woman age and her reproductive intentions. When choosing a surgical treatment, one should be guided not only by the need for the most radical removal of endometriosis foci, but also should consider a surgical approach to minimize discomfort and provide a good quality of life after surgery. A three-stage model for the management of patients with endometriosis is proposed, which includes an assessment of treatment effectiveness and the need to develop a rehabilitation program.

Habitual miscarriage is a fairly common complication of early pregnancy. In the opinion of most authors, the term habitual miscarriage is used to describe a loss of two or more pregnancies during the first 22 weeks of pregnancy. Issues of terminology and management continue to be relevant and debatable in medical professional communities and need further discussion. In addition to the medical sides of the issue, habitual miscarriage has a significant psychological impact on women and their partners. Regardless of the gestational age, the loss of pregnancy for most couples is similar in importance to the loss of a newborn and is associated with the loss of hope and plans that future parents connected with a baby who has not yet been born. After repeated losses, bereavement and emotional upheaval are further exacerbated irrespective of the term of abortion. Repeated pregnancy loss is a significant negative event in the life of a couple both from a medical and psychological point of view, that’s why the provision of adequate medical care is one of the objectives of a specialist managing pregnancy. This also involves the choice of effective disease management. Previously it was shown that luteal phase deficiency might be the cause of this phenomenon, and that hormonal deficiency had to be replenished. Many modern publications confirm that progesterone and its derivatives have an important immunomodulatory role in the habitual miscarriage. The article describes the role of progesterone in maintaining pregnancy and the results of studies devoted to the role of dydrogesterone. It also presents data of international studies on the treatment of women with habitual miscarriage.

Objectives: To evaluate the oncologic and reproductive outcomes of patients with atypical endometrial hyperplasia and low grade stage 1 endometrial cancer who received medical treatment. Methods: We carried out a retrospective study on all patients aged 20-42 years with complex, atypical endometrial hyperplasia, and low-grade stage 1 endometrial cancer, who wished to preserve fertility and were treated at the Royal Hospital. We held this study between January 2006 and December 2016. The patients received oral megestrol acetate with or without a levonorgestrel intrauterine system. We assessed their response to progestin treatment in terms of treatment duration, time to response, pregnancy, time of surgery, and oncological outcome. We performed the statistical analysis using the SPSS 20.0 software. Results: Twenty patients met the inclusion criteria, and among them 90% had complete remission. Among these 90%, 55% had complete remission within six months of treatment. The recurrence rate was recorded in 11 patients (55%) and it was more frequent in obese patients with body mass index (BMI) ≥30 (p=0.001), who had complete response in > 6 months of hormonal treatment. About 15% of the patients required hysterectomy, and 12 (60%) patients conceived after full treatment. Conclusions: Fertility-sparing treatment of atypical endometrial hyperplasia and grade 1 stage 1 endometrial cancer in reproductive-age women is feasible. However, obese patients (BMI ≥ 30) had a higher recurrence rate.

Objective: Atypical polypoid adenomyoma (APA) is a rare uterine premalignant lesion mainly occurring in premenopausal and nulliparous women. Although hysteroscopic resection (HR) has showed promising results, the conservative management of APA in young women is not standardized, and few data are available in the literature. We aimed to assess oncologic outcomes of the conservative treatment of APA. Methods: A multicenter observational retrospective cohort study was performed including all patients with APA who underwent conservative treatment from January 2006 to June 2020. Rates of each oncologic outcome (i.e. initial complete response, persistence, progression to cancer, recurrence, long-term treatment success, and treatment failure) were calculated for all conservative treatment together and separately. Results: Twenty-five patients were included. Conservative treatments consisted of HR alone (n=14) and HR+progestin (n=11). Overall, 24 (96%) patients showed initial complete response, of which 21 (84%) showed long-term treatment success; four (16%) patients had progression to cancer, of which two (8%) first recurred as APA. Long-term treatment success was achieved in 13 of 14 (92.9%) patients with HR alone and 8 of 11 (72.3%) with HR+progestin. Conclusion: Conservative treatment appears to be a safe option in women with APA. The four-steps HR might be considered as the first-line conservative approach, while the addition of progestin does not seem to improve oncologic outcomes. However, the risk of progression to cancer highlights the need for a close and long-term follow up with ultrasonography and hysteroscopic biopsies, and for hysterectomy in patients not desiring pregnancy.

Progesterone (P4) plays a pivotal role in maintenance of pregnancy in many mammalian species. Species-specific P4 metabolites have been shown to function as primary acting progestogen and the receptor binding capacity varies between species. The European roe deer (Capreolus capreolus) displays a 4-5 month period of embryonic diapause, which decouples fertilization from implantation. The majority of roe deer have two corpora lutea that secrete P4. No changes in P4 concentrations have been observed during pre-implantation embryo development. As 5α-DHP is known to play a major role during pregnancy in elephants and horses, we hypothesized that 5α-DHP functions as additional progestogen facilitating embryo reactivation. The profile of 11 progestogens was quantified in roe deer plasma over the course of diapause and resumption of embryo development including P4, 3α- and 3β-DHP, 20α- and 20β-DHP, 5α- and 5β-DHP, 3α,5α- and 3α,5β-THP, as well as 3β,5α- and 3β,5β-THP. While P4 was most abundant during diapause and resumption of development, 20α-DHP was the most abundant P4 metabolite. This is different than in pregnant elephants, where 5α-DHP was most abundant, and the luteal phase in cattle, where 3α,5α-THP was most abundant. With the exception of a weak correlation of 3β,5α-THP, none of the progestogens significantly correlated with embryonic development in the roe deer. Thus, plasma 5α-DHP does not seem to play a role in embryo reactivation. We propose that progestogens might contribute to priming the endometrium for supporting embryo development and preparation for implantation.

ObjectiveTo evaluate the effect of maintenance therapy for patients with atypical endometrial hyperplasia (AEH) and early endometrial cancer (EC) after successful fertility-preserving management on prognosis and pregnancy outcome.MethodsWe performed a retrospectively analysis of 109 young women with atypical endometrial hyperplasia and early endometrioid endometrial cancer who had received complete response after fertility-preserving treatment at 5centers between May 2005 and March 2021. Maintenance therapy regimes included low-dose oral progesterone, levonorgestrel intrauterine device(LNG-IUD) and combination oral contraceptive (COC). The patients were divided into two groups, maintenance therapy group and non-maintenance therapy group. Clinical characteristics, treatment regimens, prognosis, and pregnancy outcome were compared between the two groups.ResultsThe overall disease recurrence rate of the maintenance therapy group was significantly lower than that of the non-maintenance therapy group (P < 0.001). The recurrence rate of atypical endometrial hyperplasia and endometrial cancer in the maintenance therapy group were significantly lower than those in the non-maintenance group (P < 0.001). Maintenance therapy can reduce pregnancy rates and live birth rates. Maintenance therapy can protect the endometrium in patients treated with assisted reproductive technology (ART), greatly reducing the recurrence rate after ART (PConclusionMaintenance therapy plays a very important protective role in fertility-preserving treatment for patients with atypical endometrial hyperplasia and endometrial cancer, which could significantly reduce the risk of recurrence. It is recommended that patients could receive maintenance therapy as long as possible during the period from achieving complete response to pregnancy preparation if possible. It may provide recurrence-free survival long enough for childless young women to prepare for pregnancy in the future. It can also protect the endometrium of those who are preparing to use assisted reproductive technology, possibly by reducing the risk of recurrence by excessive stimulation with assisted reproductive drugs.

The objective: a study of the risk factors and the frequency of recurrence of uterine fibroids (UF) after conservative myomectomy. Materials and methods. A clinical and statistical retrospective analysis of the long-term outcomes of surgical treatment of 40 patients in reproductive age (from 19 to 42 years) with UF was carried out based on the data of case histories, outpatient cards and data from a questionnaire/telephone survey. All women had a complicated gynecological and reproductive history. In the postoperative period, the patients received hormonal therapy with progestogens (in cyclic regime) and oral contraceptives for 6–12 months. For the diagnosis of UF recurrence, clinical examination, bimanual examination, transvaginal echography were performed every 3 months during the first 3 years, then every six months. The fact of UF recurrence was ascertained of the appearance at least of one myomatous node more than 1 cm in diameter. Results. The long-term results were studied in 36 out of 40 patients after conservative myomectomy. At the time of assessment, the average age of patients after surgery was 39.7±6.17 years, 4 (11 %) women of them were in active reproductive age, 11 (33.3 %) – late reproductive age, and 10 (27.7 %) – premenopausal period. The mean period of observations was 6.22±1.71 years. Recurrence of UF was diagnosed in 22 (55 %) patients, 3 (7.5 %) of them required repeated surgery (2 women after supravaginal amputation of the uterus, 1 – transcervical resection of the submucous node).The cumulative (accumulated) percentage of UF recurrence within 7 years after surgery was 67.4±8 % with the maximum increase of recurrence frequency in the 2nd and 3rd years after surgery (up to 31.7 6 % and 51.2±7 %, respectively). After conservative myomectomy, pregnancy occurred in 11 (27.5 %) women, including 2 out of 5 persons with infertility before surgery, and 4 out of 9 patients who had miscarriage in anamnesis. The maximum number of pregnancies (5) occurred in the interval from 1 to 1.5 years after surgery. Pregnancy ended in timely delivery in 7 patients, spontaneous abortion – 3 (7.5 %), induced abortion – 1 (2.5 %). All 7 pregnant women were delivered by caesarean section.Conclusions. A retrospective analysis of long-term outcomes of organ-preserving surgical treatment of patients of reproductive age with uterine fibroids determined a high frequency of myoma recurrence after conservative myomectomy, reaching 67.4±8 % in7 years after the operation. The greatest increase in recurrence was observed in the 2nd and 3rd years after surgery. The statistically significant risk factors for the development of recurrence of the disease were the number of myomatous nodes and the patient’s age (30–40 years). The use of hormonal therapy (norethisterone or oral contraceptives) after surgery did not lead to a decrease in the rate of recurrence of uterine fibroids. And although conservative myomectomy made it possible to increase the frequency of pregnancy in operated patients, the level of reproductive losses after surgery remained high (36.3 %)., Цель исследования: изучение факторов риска и частоты рецидивов миомы матки (ММ) после консервативной миомэктомии. Материалы и методы. Проведен клинико-статистический ретроспективный анализ отдаленных результатов оперативного лечения 40 пациенток репродуктивного возраста (от 19 до 42 лет) с ММ по данным историй болезней, амбулаторных карт и данных анкетного/телефонного опроса. Все женщины имели отягощенный гинекологический и репродуктивный анамнез. В послеоперационный период пациентки получали гормональную терапию прогестагенами (в циклическом режиме) и оральными контрацептивами в течение 6–12 мес. Для диагностики рецидива заболевания каждые 3 мес на протяжении первых 3 лет проводили клинический осмотр, бимануальное обследование, трансвагинальную эхографию, далее – каждые полгода. Факт рецидива миомы констатировали при появлении, как минимум, одного миоматозного узла более 1 см в диаметре. Результаты. Удаленные результаты изучали у 36 больных из 40, перенесших консервативную миомэктомию. На момент оценки средний возраст пациенток после оперативного вмешательства составил 39,7±6,17 года, из них в активном репродуктивном возрасте находились 4 (11%) женщины, в позднем репродуктивном возрасте – 11 (33,3%), в пременопаузальном периоде – 10 (27,7%). Средний срок наблюдения составил 6,22±1,71 года. Рецидив ММ констатирован у 22 (55%) больных, 3 (7,5%) из которых нуждались в повторном оперативном вмешательстве (2 женщинам выполнена надвлагалищная ампутация матки, 1 – трансцервикальная резекция субмукозного узла). Кумулятивный (накопленный) процент рецидива ММ в течение 7 лет после операции составил 67,4±8% с максимальным приростом частоты рецидивов на 2-м и 3-м годах после операции (до 31,7±6% и 51,2±7% соответственно). После консервативной миомэктомии беременность наступила у 11 (27,5%) женщин, в том числе у 2 из 5, у которых диагностировано бесплодие до операции, и у 4 из 9, у которых фиксировали невынашивание беременности. Максимальное количество беременностей (5) наступило в интервале от 1 до 1,5 года после операции. Беременность закончилась своевременными родами у 7 пациенток, самопроизвольным абортом – у 3 (7,5%), искусственным абортом – у 1 (2,5%). Все 7 беременных были родоразрешены путем кесарева сечения. Заключение. Ретроспективный анализ отдаленных результатов органосохраняющего хирургического лечения пациенток репродуктивного возраста с миомой матки выявил высокую частоту рецидива миомы после консервативной миомэктомии, достигавшей 67,4±8% через 7 лет. Наибольший рост рецидивов наблюдался на 2-й и 3-й год после операции. Статистически значимыми факторами риска развития рецидива заболевания являлись количество миоматозных узлов и возраст пациентки в интервале 30–40 лет. Использование гормональной терапии (норэтистерона или оральных контрацептивов) после операции не привело к снижению частоты рецидивов миомы матки. И хотя консервативная миомэктомия позволила повысить частоту наступления беременности у оперированных пациенток, однако уровень репродуктивных потерь после операции оставался высоким (36,3%)., Мета дослідження: вивчення факторів ризику і частоти виникнення рецидивів міоми матки (ММ) за віддаленими результатами консервативної міомектомії.Матеріали та методи. Проведено клініко-статистичний ретроспективний аналіз віддалених результатів оперативного лікування 40 пацієнток репродуктивного віку (від 19 до 42 років) з ММ за даними історій хвороб, амбулаторних карт і даних анкетного/телефонного опитування. Усі жінки мали обтяжений гінекологічний і репродуктивний анамнез. У післяопераційний період пацієнтки отримували гормональну терапію прогестагенами (у циклічному режимі) і оральними контрацептивами протягом 6–12 міс. Для діагностики рецидиву захворювання кожні 3 міс протягом перших 3 років проводили клінічний огляд, бімануальне обстеження, трансвагінальну ехографію, надалі – кожні півроку. Факт рецидиву міоми констатували за появи, як мінімум, одного міоматозного вузла понад 1 см у діаметрі.Результати. Віддалені результати вивчали у 36 хворих з 40, які перенесли консервативну міомектомію. На момент оцінювання, середній вік пацієнток після оперативного втручання становив 39,7±6,17 року, з них в активному репродуктивному віці перебували 4 (11%) особи, у пізньому репродуктивному віці – 11 (33,3%), у пременопаузальному періоді – 10 (27,7%). Середній термін спостереження становив 6,22±1,71 року. Рецидив ММ констатовано у 22 (55%) хворих, 3 (7,5%) з яких потребували повторного оперативного втручання (2 жінкам виконано надпіхвову ампутацію матки, 1 – трансцервікальну резекцію субмукозного вузла). Кумулятивний (накопичений) відсоток рецидиву ММ протягом 7 років після операції становив 67,4±8% з максимальним підвищенням частоти рецидивів на 2-у і 3-у роках після операції (до 31,7±6% і 51,2±7% відповідно).Завагітніли після консервативної міомектомії 11 (27,5%) жінок, у тому числі 2 з 5, яким діагностовано безпліддя до операції, та 4 з 9, у яких фіксували невиношування вагітності. Максимальна кількість вагітностей (5) настала в інтервалі від 1 до 1,5 року після операції. Вагітність закінчилась своєчасними пологами у 7 пацієнток, мимовільним абортом – у 3 (7,5%), штучним абортом – в 1 (2,5%). Усі 7 вагітних були розроджені шляхом кесарева розтину.Заключення. Ретроспективний аналіз віддалених результатів органозберігального хірургічного лікування пацієнток репродуктивного віку з міомою матки виявив високу частоту рецидиву міоми після консервативної міомектомії, яка досягала 67,4±8% через 7 років. Найбільший приріст рецидивів спостерігався на 2-й і 3-й рік після операції. Статистично значущими факторами ризику розвитку рецидиву захворювання були кількість міоматозних вузлів і вік пацієнтки в інтервалі 30–40 років. Використання гормональної терапії (норетистерону або оральних контрацептивів) після операції не привело до зниження частоти рецидивів міоми матки. І хоча консервативна міомектомія дозволила підвищити частоту настання вагітності в оперованих пацієнток, однак рівень репродуктивних втрат після операції залишався високим (36,3%).

The objective:a study of the risk factors and the frequency of recurrence of uterine fibroids (UF) after conservative myomectomy. Materials and methods.A clinical and statistical retrospective analysis of the long-term outcomes of surgical treatment of 40 patients in reproductive age (from 19 to 42 years) with UF was carried out based on the data of case histories, outpatient cards and data from a questionnaire/telephone survey. All women had a complicated gynecological and reproductive history. In the postoperative period, the patients received hormonal therapy with progestogens (in cyclic regime) and oral contraceptives for 6–12 months. For the diagnosis of UF recurrence, clinical examination, bimanual examination, transvaginal echography were performed every 3 months during the first 3 years, then every six months. The fact of UF recurrence was ascertained of the appearance at least of one myomatous node more than 1 cm in diameter. Results.The long-term results were studied in 36 out of 40 patients after conservative myomectomy. At the time of assessment, the average age of patients after surgery was 39.7±6.17 years, 4 (11 %) women of them were in active reproductive age, 11 (33.3 %) – late reproductive age, and 10 (27.7 %) – premenopausal period. The mean period of observations was 6.22±1.71 years. Recurrence of UF was diagnosed in 22 (55 %) patients, 3 (7.5 %) of them required repeated surgery (2 women after supravaginal amputation of the uterus, 1 – transcervical resection of the submucous node). The cumulative (accumulated) percentage of UF recurrence within 7 years after surgery was 67.4±8 % with the maximum increase of recurrence frequency in the 2nd and 3rd years after surgery (up to 31.7 6 % and 51.2±7 %, respectively). After conservative myomectomy, pregnancy occurred in 11 (27.5 %) women, including 2 out of 5 persons with infertility before surgery, and 4 out of 9 patients who had miscarriage in anamnesis. The maximum number of pregnancies (5) occurred in the interval from 1 to 1.5 years after surgery. Pregnancy ended in timely delivery in 7 patients, spontaneous abortion – 3 (7.5 %), induced abortion – 1 (2.5 %). All 7 pregnant women were delivered by caesarean section. Conclusions.A retrospective analysis of long-term outcomes of organ-preserving surgical treatment of patients of reproductive age with uterine fibroids determined a high frequency of myoma recurrence after conservative myomectomy, reaching 67.4±8 % in7 years after the operation. The greatest increase in recurrence was observed in the 2nd and 3rd years after surgery. The statistically significant risk factors for the development of recurrence of the disease were the number of myomatous nodes and the patient’s age (30–40 years). The use of hormonal therapy (norethisterone or oral contraceptives) after surgery did not lead to a decrease in the rate of recurrence of uterine fibroids. And although conservative myomectomy made it possible to increase the frequency of pregnancy in operated patients, the level of reproductive losses after surgery remained high (36.3 %).

The most recent studies of progesterone research provide remarkable insights into the physiological role and clinical importance of this hormone. Although the name progesterone itself means “promoting gestation”, this steroid hormone is far more than a gestational agent. Progesterone is recognized as a key physiological component of not only the menstrual cycle and pregnancy but also as an essential steroidogenic precursor of other gonadal and non-gonadal hormones such as aldosterone, cortisol, estradiol, and testosterone. Based on current findings, progesterone and novel progesterone-based drugs have many important functions, including contraception, treatment of dysfunctional uterine bleeding, immune response, and prevention of cancer. Considering the above, reproduction and life are not possible without progesterone; thus, a better understanding of this essential molecule could enable safe and effective use of this hormone in many clinical conditions.

Miaomiao Li*, Tao Guo*, Ran Cui, Ying Feng, Huimin Bai, Zhenyu ZhangDepartment of Obstetrics and Gynecology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of China*These authors contributed equally to this workObjectives: This study aimed to identify potential prognostic factors for patients with complex atypical hyperplasia (CAH) or early-stage endometrial cancer (EC) who received progestin therapy to spare fertility and, thus, improve the management of this patient group.Materials and methods: The PubMed, PMC, EMBASE, Web of Science, and Cochrane databases were searched for correlational studies published in English. Studies that evaluated the prognosis of patients with CAH or early-stage EC were pooled for a systematic review and meta-analysis.Results: In total, 31 eligible studies, including 8 prospective and 23 retrospective studies involving 1099 patients, were included in this analysis. The most commonly used progestin agents were medroxyprogesterone acetate (MPA, 47.0%) and megestrol acetate (MA, 25.5%). The total complete response (CR) rate was 75.8% (833/1099), and the median time to CR with first-line progestin therapy was 6 months. In total, 294 (26.8%) patients who achieved CR became pregnant spontaneously (28 cases) or through assisted reproductive technology (127 cases). During the median follow-up of 39 months, 245 (22.3%) women developed recurrence. Only one patient (0.09%) died of the disease. The meta-analysis showed that compared to a BMI

The development of the steroid hormones currently used in contraception and menopausal hormone replacement provides an interesting story in terms of brilliant research, international rivalry, major advances and sheer serendipity. This paper provides a historical perspective on the use of oestrogens and progestogens in clinical practice from the 1920s until the present day.

Background: The first objective of this review was to present, based on recent literature, the most frequently applied medical options (oral contraceptive pills (OCPs) and progestogens) for the management of symptomatic endometriosis, and evaluate their effectiveness in treating premenopausal women with endometriosis-associated pelvic pain, dysmenorrhea, non-menstrual pelvic pain and dyspareunia. The second objective was to review the concept of progesterone resistance and newly available treatment options. Methods: We reviewed the most relevant papers (n = 73) on the efficacy of OCPs and progestogens as medical therapy for endometriosis, as well as those on progesterone resistance and new medical alternatives (oral gonadotropin-releasing hormone (GnRH) antagonist). Eleven papers, essentially reviews, were selected and scrutinized from among 94 papers discussing the concept of progesterone resistance. Results: Having reviewed the most significant papers, we can confirm that OCPs and progestogens are effective in two-thirds of women suffering from endometriosis, but that other options are required in case of failure (in one-third of women due to progesterone resistance) or intolerance to these compounds. It is clear that there is a need for effective long-term oral treatment capable of managing endometriosis symptoms, while mitigating the impact of side effects. Biochemical, histological and clinical evidence show that estrogens play a critical role in the pathogenesis of endometriosis, so lowering levels of circulating estrogens should be considered an effective medical approach. The efficacy of three oral GnRH antagonists is discussed on the basis of published studies. Conclusion: There is a place for GnRH antagonists in the management of symptomatic endometriosis and clinical trials should be conducted, taking into account the different phenotypes in order to propose novel algorithms.

Background Limb deficiencies associated with amniotic bands comprise a wide range of congenital anomalies. The association of maternal medication and the risk of amniotic band sequence (ABS) has not yet been addressed. Methods This nationwide population-based case-control study used national registers on congenital anomalies, births and induced abortions, cross-linked with information on maternal prescription medicine use obtained from the registers on Reimbursed Drug Purchases and Medical Special Reimbursements. All cases with congenital limb deficiency associated with amniotic bands born between 1996 and 2008 were included in the study. Five controls without limb deficiency matched for residency and time of conception were randomly selected from the Medical Birth Register. Results In total, 106 children with limb deficiency associated with ABS were identified and compared with 530 matched controls. Young maternal age (less than 25 y) increased the risk of limb deficiencies [odds ratio=1.72; 95% confidence interval (CI): 1.06, 2.80]. Primiparity was also associated with increased risk [adjusted odds ratio (aOR)=2.42; 95% CI: 1.52, 3.88]. After adjusting for maternal age, pregestational diabetes, and parity, maternal use of beta-blockers (adjusted OR=24.2; 95% CI: 2.57, 228) and progestogens (adjusted OR=3.79; 95% CI: 1.38, 10.4) during the first trimester of pregnancy significantly increased the risk of limb deficiencies associated with amniotic bands. Conclusions Primiparity significantly increased the risk of limb defects associated with amniotic bands. Also, a novel association on increased risk of ABS with maternal use of progestogens or beta-blockers during the first trimester of pregnancy was observed. Level of evidence Level III.

Background In a recently published multicenter randomized controlled trial, we demonstrated that progestogens are not effective as maintenance tocolysis. Objective This study was aimed to evaluate if previous finding may be affected by positive urine culture and/or vaginal swab. Study Design We performed a secondary analysis of the PROTECT trial (NCT01178788). Women with singleton pregnancy between 22 and 31 6/7 weeks' gestation, admitted for threatened preterm labor were considered. At admission, we collected urine culture and vaginal swabs. At discharge, women with a cervical length ≤25 mm were randomized to vaginal progesterone or 17α-hydroxyprogesterone caproate or observation group. We used Chi-square statistics, considering 97.5% CI (confidence interval) and p-value less than 0.025 for significance. Results Urine culture and vaginal swabs were collected in 232 out of 235 patients included in the primary analysis. Overall, 31 out of 232 women (13.4%) had positive urine culture and 60 out of 232 (25.9%) had positive vaginal swab. In women with negative urine culture, a higher rate of preterm birth was found in vaginal progesterone group (27/69, 39.7%) respect with controls (14/68, 20.6%; relative risk [RR] = 1.90; 97.5% CI: 1.01–3.57; p = 0.018). Conclusion Among women with negative urine culture, the rate of preterm birth

Background Exposure to per-/polyfluoroalkyl substances (PFASs) can disrupt endocrine hormones in humans. Prior studies have focused on the harmful effects of the two traditional per-/polyfluoroalkyl substances (PFASs), perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA). Other PFASs, used as the replacements of PFOS and PFOA, are widely and increasingly detected in humans. Whether these replacements influence glucocorticoids and progestogens in newborns remains unknown. Objective To investigate the associations between exposures of PFOS, PFOA and their replacements and glucocorticoids and progestogens in newborns. Methods We measured the concentrations of 13 PFASs, 3 glucocorticoids (11-deoxycortisol, cortisol and cortisone) and 2 progestogens [progesterone, 17-hydroxyprogesterone (17OHP)] in the cord sera of 374 neonates in a birth cohort from Wuhan, China, between 2013 and 2014. We evaluated the associations of each PFAS with glucocorticoids and progestogens using multiple linear regression models, and multiple comparisons were additionally corrected via false discovery rates (FDR). Results Out of the 13 PFASs, 9 were detected in over 95% of cord sera. The Chinese specific PFOS replacement − 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA, trade name F-53B) was positively associated with 13.13% change in cortisol in girls (95% CI = 4.47%, 22.52%, for each IQR increase in 6:2 Cl-PFESA). Seven PFASs had positive associations with the precursor of cortisol, namely 11-deoxycortisol (percent change ranged from 6.41% to 11.24%, for each IQR increase in PFASs). Perfluorobutane sulfonate (PFBS) in cord sera was positively associated with progesterone in the linear model, whereas PFOS and perfluorohexane sulfonate (PFHxS) levels were associated with progesterone in the quartile models. No PFASs were related to 17OHP or cortisone. Conclusions In this study, PFOS, PFOA and/or their replacements were positively associated with progesterone, cortisol and 11-deoxycortisol in newborns. These results suggested that not only PFOS and PFOA, but also other PFASs have potential impacts on glucocorticoids and progestogens in newborns.

Object: Is it possible to use different progestins cotreatment with human menopausal gonadotrophin (hMG) in women with advanced endometriosis but normal ovulation during controlled ovarian hyperstimulation (COH) in vitro fertilization (IVF)? Whether different progestins treatments can be an alternative choice for women with severe endometriosis in considering IVF/ICSI treatment remains unknown? Design: Non-inferiority randomized clinical trial. Setting: Tertiary-care academic medical center. Population: Four hundred and fifty infertile patients with severe endometriosis undergoing IVF/ICSI between May 2016 and March 2017. Methods: Four hundred and fifty infertile patients with severe endometriosis undergoing IVF/ICSI were randomized to: medroxyprogesterone acetate +hMG; dydrogesterone +hMG; and progesterone +hMG. Ovulation was induced with a gonadotropin-releasing hormone agonist (GnRH-a) and chorionic gonadotropin (hCG). Viable embryos were cryopreserved for later transfer. Main Outcome Measures: The primary endpoint outcome was the number of oocytes retrieved. Secondary indicators included the incidence of a premature surge in luteinizing hormone (LH), the number of viable embryos, and clinical pregnancy outcomes. Results: The number of oocytes retrieved was higher in the medroxyprogesterone acetate +hMG group than the two other groups (9.3 ± 5.7 vs. 8.0 ± 4.5 vs. 7.8 ± 5.2, P = 0.021). LH levels were suppressed after a 6-day progestin treatment in the medroxyprogesterone acetate +hMG and dydrogesterone +hMG groups, but there was a rebound of LH values in the progesterone +hMG group. No premature LH surge and ovarian hyperstimulation syndrome (OHSS) occurred. No significant differences among the three groups were observed in fertilization and pregnancy outcomes. Conclusion: It is mandatory to point out that our conclusions are valid for patients with ovarian advanced endometriosis but normal ovarian functions. These results suggest three different progestins protocols are equivalent in terms of pregnancy outcomes for women with advanced endometriosis. PPOS protocol can be an alternative choice for women with severe endometriosis and normal ovarian reserve in IVF/ICSI treatment. These methods could be tested with other populations of women with endometriosis. Clinical Trial Registration: www.ClinicalTrials.gov, identifier:ChiCTR-OIN-16008529. Trial registration date: 2014-05-25. Date of first patient enrollment: May 2016.

Progesterone is well known for its numerous endocrinologic roles in pregnancy but is also endowed with fascinating immunomodulatory capabilities. It can downregulate the induction of inflammatory reactions, the activation of immune cells and the production of cytokines, which are critical mediators of immune responses. These features appear to be critical to the success of pregnancy, given the ability of maternal immune reactivity to interfere with pregnancy and to contribute to several pregnancy complications. This review summarizes the contribution of maternal immune effectors in general, and cytokines in particular, to pregnancy complications such as recurrent miscarriage, pre-eclampsia and preterm labor; it describes the promise offered by supplementation with progesterone and the oral progestogen dydrogesterone, as well as the progesterone-induced blocking factor in the prevention and/or treatment of these serious complications.

El objetivo del presente trabajo fue evaluar el efecto del tratamiento con Altrenogest sobre la aparición de celo y el tamaño de la camada en cerdas primíparas. Setenta y dos hembras (Landrace x Yorkshire) con un peso promedio de 155 ± 5 kg se asignaron aleatoriamente en dos grupos: GT = grupo tratamiento (n=36), al cual se le aplicó un protocolo de sincronización de celo con Altrenogest durante 18 días (20 mg/día) sobre el alimento y GC = grupo control (n=36). Se registró la concentración de los celos del grupo tratamiento para medir la eficacia del progestágeno. El número de lechones nacidos vivos (LNV), muertos (LNM) y totales (LNT) fue registrado en ambos grupos para su comparación a través de un ANOVA, usando el software estadístico INFOSTAT. No se encontraron diferencias significativas para el número de LNM y LNT, mientras que el número de LNV se vio favorecido por el tratamiento (p

BackgroundAn indirect comparison meta-analysis published in 2013 reported that both vaginal progesterone and cerclage are equally efficacious for preventing preterm birth and adverse perinatal outcomes in women with a singleton gestation, previous spontaneous preterm birth and a sonographic short cervix. The efficacy of vaginal progesterone has been disputed after publication of the OPPTIMUM study.ObjectiveTo compare the efficacy of vaginal progesterone and cerclage in preventing preterm birth and adverse perinatal outcomes in women with a singleton gestation, previous spontaneous preterm birth and a midtrimester sonographic short cervix.Data SourcesMEDLINE, EMBASE, LILACS, and CINAHL (from their inception to March 2018); Cochrane databases, bibliographies, and conference proceedings.Study Eligibility CriteriaRandomized controlled trials comparing vaginal progesterone with placebo/no treatment or cerclage with no cerclage in women with a singleton gestation, previous spontaneous preterm birth and a sonographic cervical length Study Appraisal and Synthesis MethodsUpdated systematic review and adjusted indirect comparison meta-analysis of vaginal progesterone versus cerclage using placebo/no cerclage as the common comparator. The primary outcomes were preterm birth ResultsFive trials comparing vaginal progesterone versus placebo (265 women) and 5 comparing cerclage versus no cerclage (504 women) were included. Vaginal progesterone, compared with placebo, significantly reduced the risk of preterm birth ConclusionsVaginal progesterone and cerclage are equally effective for preventing preterm birth and improving perinatal outcomes in women with a singleton gestation, previous spontaneous preterm birth, and a midtrimester sonographic short cervix. The choice of treatment will depend on adverse events and cost-effectiveness of interventions, and patient/physician’s preferences.

Ovarian sex steroids can modulate new vessel formation and development, and the clarification of the underlying mechanism will provide insight into neovascularization-related physiological changes and pathological conditions. Unlike estrogen, which mainly promotes neovascularization through activating classic post-receptor signaling pathways, progesterone (P4) regulates a variety of downstream factors with angiogenic or antiangiogenic effects, exerting various influences on neovascularization. Furthermore, diverse progestins, the synthetic progesterone receptor (PR) agonists structurally related to P4, have been used in numerous studies, which could contribute to unequal actions. As a result, there have been many conflicting observations in the past, making it difficult for researchers to define the exact role of progestogens (PR agonists including naturally occurring P4 and synthetic progestins). This review summarizes available evidence for progestogen-mediated neovascularization under physiological and pathological circumstances, and attempts to elaborate their functional characteristics and regulatory patterns from a comprehensive perspective.

The safety of progestogens as a class has drawn much attention after the publication of data from the Women’s Health Initiative (WHI) trial, particularly with respect to cardiovascular disease. Depending on the chemical structure, pharmacokinetics, receptor affinity and potency of action, progestogens have a divergent range of properties that may translate to very different clinical effects. The purpose of this review is to describe the role of varied progestogens in hormone replacement therapy (HRT), especially focusing on blood lipids, which are the most important parameters for assessing cardiovascular disease risk.

Objective To assess the efficacy of vaginal progesterone for the prevention of preterm birth and neonatal morbidity and mortality in asymptomatic women with a twin gestation and a sonographic short cervix (cervical length ≤ 25 mm) in the mid-trimester. Methods This was an updated systematic review and meta-analysis of individual patient data (IPD) from randomized controlled trials comparing vaginal progesterone with placebo/no treatment in women with a twin gestation and a mid-trimester sonographic cervical length ≤ 25 mm. MEDLINE, EMBASE, POPLINE, CINAHL and LILACS (all from inception to 31 December 2016), the Cochrane Central Register of Controlled Trials, Research Registers of ongoing trials, Google Scholar, conference proceedings and reference lists of identified studies were searched. The primary outcome measure was preterm birth < 33 weeks' gestation. Two reviewers independently selected studies, assessed the risk of bias and extracted the data. Pooled relative risks (RRs) with 95% confidence intervals (CI) were calculated. Results IPD were available for 303 women (159 assigned to vaginal progesterone and 144 assigned to placebo/no treatment) and their 606 fetuses/infants from six randomized controlled trials. One study, which included women with a cervical length between 20 and 25 mm, provided 74% of the total sample size of the IPD meta-analysis. Vaginal progesterone, compared with placebo/no treatment, was associated with a statistically significant reduction in the risk of preterm birth < 33 weeks' gestation (31.4% vs 43.1%; RR, 0.69 (95% CI, 0.51–0.93); moderate-quality evidence). Moreover, vaginal progesterone administration was associated with a significant decrease in the risk of preterm birth < 35, < 34, < 32 and < 30 weeks' gestation (RRs ranging from 0.47 to 0.83), neonatal death (RR, 0.53 (95% CI, 0.35–0.81)), respiratory distress syndrome (RR, 0.70 (95% CI, 0.56–0.89)), composite neonatal morbidity and mortality (RR, 0.61 (95% CI, 0.34–0.98)), use of mechanical ventilation (RR, 0.54 (95% CI, 0.36–0.81)) and birth weight < 1500 g (RR, 0.53 (95% CI, 0.35–0.80)) (all moderate-quality evidence). There were no significant differences in neurodevelopmental outcomes at 4–5 years of age between the vaginal progesterone and placebo groups. Conclusion Administration of vaginal progesterone to asymptomatic women with a twin gestation and a sonographic short cervix in the mid-trimester reduces the risk of preterm birth occurring at < 30 to < 35 gestational weeks, neonatal mortality and some measures of neonatal morbidity, without any demonstrable deleterious effects on childhood neurodevelopment. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

The article tells about the use of a combined contraceptive preparation containing the novel progestogen - dienogest - in conservative antirecurrent treatment of endometriosis. According to current concepts, endometriosis is a chronical dishormonal, immunodependent, multifactorial, genetically determined disease which manifests itself in the growth and presence of endometrioid heterotopias in the uterus. While accurate diagnosis and ablation of heterotopias require surgery, for subsequent treatment, doctor's toolkit offers a multitude of medicines the effects of which are on the whole described by the following: fight against manifestations of endometriosis, inhibition of the progression of the process, reduction of the disease recurrence, and improving the quality of life of patients. Pharmacotherapy of endometriosis should be effective and safe. Dienogest demonstrated properties comparable to those of gonadotropin-releasing hormone agonists, especially for early clinical manifestations of endometriosis. The combined contraceptive containing ethinylestradiol and dienogest is best suited for long-term (several months) treatment of endometriosis under a cyclic or continuous regimen.

The hypothesis of a hormonal dependence of cutaneous melanoma has been debated in the literature over past decades. Within this context, it is critical to increase our knowledge on the influence of exogenous hormone use on the risk of this cancer.The aim of this project was to explore the influence of hormonal treatments (oral contraceptives, fertility drugs, premenopausal use of progestogens, and menopause hormone therapy) on the risk of cutaneous melanoma in women.The project was mainly based on the large E3N (Étude épidémiologique auprès de femmes de l’Éducation Nationale) prospective cohort, which included about 100,000 women aged 40-65 years at inclusion in 1990. The cohort collected data on pigmentary phenotype, sun exposure, hormonal treatment use, and medical data including cutaneous melanomas, which were ascertained through pathology reports (761 incident cases between 1990 and 2011). Additional information on sun exposure, available for a portion of the E3N cohort, was used. These detailed data were collected as part of the E3N-SunExp case-control study launched in 2008.Analyses were extended to the EPIC consortium (European Prospective Investigation into Cancer and Nutrition), which includes about 334 500 women and 1,734 incident melanoma cases.The results arising from this project show modest associations between exogenous hormone use and melanoma risk and suggest no strong direct influence of hormones on melanoma development. However, results suggest intentional UV exposure behaviors in exogenous hormone users, which opens new perspectives for future investigations in this field.; L’hypothèse de l’hormono-dépendance du mélanome cutané est en débat dans la littérature depuis de nombreuses années. Dans ce contexte, il est essentiel de mieux connaître l’influence potentielle de la prise de traitements hormonaux sur le risque de ce cancer.L’objectif de ce projet de thèse était d’étudier l’influence de la prise de traitements hormonaux (contraceptifs oraux, traitements de l’infertilité, progestatifs pris seuls avant la ménopause et traitements hormonaux de la ménopause) sur le risque de mélanome cutané chez les femmes.Le projet a été conduit principalement à partir de la cohorte prospective E3N (Étude épidémiologique auprès de femmes de l’Éducation nationale) portant sur environ100 000 femmes âgées de 40 à 65 ans à l’inclusion en 1990. L’étude E3N inclut des données détaillées sur le profil pigmentaire, l’exposition solaire et la prise de traitements hormonaux des participantes, ainsi que sur la survenue éventuelle de mélanome cutané, dont les cas ont été confirmés par histologie (761 cas confirmés entre 1990 et 2011). Des données complémentaires sur l’exposition solaire, disponibles pour une fraction de la cohorte E3N, ont également été utilisées. Ces données détaillées sont issues de l’enquête cas-témoin nichée E3N-SunExp menée en 2008. Les analyses ont ensuite été étendues au consortium de cohortes européennes prospectives EPIC (European Prospective Investigation into Cancer and Nutrition), sur près de 334 500 femmes parmi lesquelles 1 734 cas de mélanomes incidents ont été diagnostiqués.Les résultats mettent en évidence des associations modestes entre la prise de traitements hormonaux et le risque de mélanome et ne soutiennent pas l’hypothèse de l’hormono-dépendance de ce cancer. Cependant, ils suggèrent un comportement d’exposition intentionnelle aux UV chez leurs utilisatrices, ce qui ouvre une nouvelle perspective pour les recherches futures dans ce domaine.

The hypothesis of a hormonal dependence of cutaneous melanoma has been debated in the literature over past decades. Within this context, it is critical to increase our knowledge on the influence of exogenous hormone use on the risk of this cancer.The aim of this project was to explore the influence of hormonal treatments (oral contraceptives, fertility drugs, premenopausal use of progestogens, and menopause hormone therapy) on the risk of cutaneous melanoma in women.The project was mainly based on the large E3N (Étude épidémiologique auprès de femmes de l’Éducation Nationale) prospective cohort, which included about 100,000 women aged 40-65 years at inclusion in 1990. The cohort collected data on pigmentary phenotype, sun exposure, hormonal treatment use, and medical data including cutaneous melanomas, which were ascertained through pathology reports (761 incident cases between 1990 and 2011). Additional information on sun exposure, available for a portion of the E3N cohort, was used. These detailed data were collected as part of the E3N-SunExp case-control study launched in 2008.Analyses were extended to the EPIC consortium (European Prospective Investigation into Cancer and Nutrition), which includes about 334 500 women and 1,734 incident melanoma cases.The results arising from this project show modest associations between exogenous hormone use and melanoma risk and suggest no strong direct influence of hormones on melanoma development. However, results suggest intentional UV exposure behaviors in exogenous hormone users, which opens new perspectives for future investigations in this field.; L’hypothèse de l’hormono-dépendance du mélanome cutané est en débat dans la littérature depuis de nombreuses années. Dans ce contexte, il est essentiel de mieux connaître l’influence potentielle de la prise de traitements hormonaux sur le risque de ce cancer.L’objectif de ce projet de thèse était d’étudier l’influence de la prise de traitements hormonaux (contraceptifs oraux, traitements de l’infertilité, progestatifs pris seuls avant la ménopause et traitements hormonaux de la ménopause) sur le risque de mélanome cutané chez les femmes.Le projet a été conduit principalement à partir de la cohorte prospective E3N (Étude épidémiologique auprès de femmes de l’Éducation nationale) portant sur environ100 000 femmes âgées de 40 à 65 ans à l’inclusion en 1990. L’étude E3N inclut des données détaillées sur le profil pigmentaire, l’exposition solaire et la prise de traitements hormonaux des participantes, ainsi que sur la survenue éventuelle de mélanome cutané, dont les cas ont été confirmés par histologie (761 cas confirmés entre 1990 et 2011). Des données complémentaires sur l’exposition solaire, disponibles pour une fraction de la cohorte E3N, ont également été utilisées. Ces données détaillées sont issues de l’enquête cas-témoin nichée E3N-SunExp menée en 2008. Les analyses ont ensuite été étendues au consortium de cohortes européennes prospectives EPIC (European Prospective Investigation into Cancer and Nutrition), sur près de 334 500 femmes parmi lesquelles 1 734 cas de mélanomes incidents ont été diagnostiqués.Les résultats mettent en évidence des associations modestes entre la prise de traitements hormonaux et le risque de mélanome et ne soutiennent pas l’hypothèse de l’hormono-dépendance de ce cancer. Cependant, ils suggèrent un comportement d’exposition intentionnelle aux UV chez leurs utilisatrices, ce qui ouvre une nouvelle perspective pour les recherches futures dans ce domaine.

Object: Is it possible to use different progestins cotreatment with human menopausal gonadotrophin (hMG) in women with advanced endometriosis but normal ovulation during controlled ovarian hyperstimulation (COH) in vitro fertilization (IVF)? Whether different progestins treatments can be an alternative choice for women with severe endometriosis in considering IVF/ICSI treatment remains unknown? Design: Non-inferiority randomized clinical trial. Setting: Tertiary-care academic medical center. Population: Four hundred and fifty infertile patients with severe endometriosis undergoing IVF/ICSI between May 2016 and March 2017. Methods: Four hundred and fifty infertile patients with severe endometriosis undergoing IVF/ICSI were randomized to: medroxyprogesterone acetate +hMG; dydrogesterone +hMG; and progesterone +hMG. Ovulation was induced with a gonadotropin-releasing hormone agonist (GnRH-a) and chorionic gonadotropin (hCG). Viable embryos were cryopreserved for later transfer. Main Outcome Measures: The primary endpoint outcome was the number of oocytes retrieved. Secondary indicators included the incidence of a premature surge in luteinizing hormone (LH), the number of viable embryos, and clinical pregnancy outcomes. Results: The number of oocytes retrieved was higher in the medroxyprogesterone acetate +hMG group than the two other groups (9.3 ± 5.7 vs. 8.0 ± 4.5 vs. 7.8 ± 5.2, P = 0.021). LH levels were suppressed after a 6-day progestin treatment in the medroxyprogesterone acetate +hMG and dydrogesterone +hMG groups, but there was a rebound of LH values in the progesterone +hMG group. No premature LH surge and ovarian hyperstimulation syndrome (OHSS) occurred. No significant differences among the three groups were observed in fertilization and pregnancy outcomes. Conclusion: It is mandatory to point out that our conclusions are valid for patients with ovarian advanced endometriosis but normal ovarian functions. These results suggest three different progestins protocols are equivalent in terms of pregnancy outcomes for women with advanced endometriosis. PPOS protocol can be an alternative choice for women with severe endometriosis and normal ovarian reserve in IVF/ICSI treatment. These methods could be tested with other populations of women with endometriosis. Clinical Trial Registration: www.ClinicalTrials.gov, identifier:ChiCTR-OIN-16008529. Trial registration date: 2014-05-25. Date of first patient enrollment: May 2016

Simple Summary Young women treated for breast cancer may experience early menopause, which can negatively impact quality of life. The usual treatment for early menopause is hormone replacement. For hormone-sensitive breast cancers, however, hormones are not given as they can adversely affect the prognosis. In the case of triple-negative breast cancers (TNBC), which do not express the estrogen receptor (ER) and progesterone receptor (PR), research has not been able to show whether hormone replacement is safe yet. Theoretically, however, there are many possible mechanisms by which female hormones can have an effect on TNBC. We therefore reviewed the clinical and preclinical data investigating possible (in)direct effects of estrogens and progestogens on the course of TNBC. The ultimate aim is to provide practical recommendation on how best to treat chemotherapy-induced early menopause in TNBC patients. Abstract Triple-negative breast cancers (TNBC) occur more frequently in younger women and do not express estrogen receptor (ER) nor progesterone receptor (PR), and are therefore often considered hormone-insensitive. Treatment of premenopausal TNBC patients almost always includes chemotherapy, which may lead to premature ovarian insufficiency (POI) and can severely impact quality of life. Hormone replacement therapy (HRT) is contraindicated for patients with a history of hormone-sensitive breast cancer, but the data on safety for TNBC patients is inconclusive, with a few randomized trials showing increased risk-ratios with wide confidence intervals for recurrence after HRT. Here, we review the literature on alternative pathways from the classical ER/PR. We find that for both estrogens and progestogens, potential alternatives exist for exerting their effects on TNBC, ranging from receptor conversion, to alternative receptors capable of binding estrogens, as well as paracrine pathways, such as RANK/RANKL, which can cause progestogens to indirectly stimulate growth and metastasis of TNBC. Finally, HRT may also influence other hormones, such as androgens, and their effects on TNBCs expressing androgen receptors (AR). Concluding, the assumption that TNBC is completely hormone-insensitive is incorrect. However, the direction of the effects of the alternative pathways is not always clear, and will need to be investigated further.

Background Postpartum women need effective contraception. Concerns have been raised that use of progestogen-only contraceptives (POCs) may affect breastfeeding performance and infant health outcomes. Objectives We investigated the clinical outcomes of breastfeeding duration, initiation of supplemental feeding and weaning, as well as infant outcomes including infant growth, health and development among breastfeeding women using POCs compared with breastfeeding women not using POCs. Search strategy We searched the PubMed database for all articles published from database inception through December 2014. Selection criteria We included primary research studies of breastfeeding women of any age or parity who received POCs, including progestogen-only pills, injectables, implants or hormonal intrauterine devices (IUDs). The main outcomes were breastfeeding performance (as measured by initiation, continuation, frequency and exclusivity of breastfeeding) and infant health (as measured by growth, development or adverse health effects). Results Forty-nine articles reporting on 47 different studies were identified that investigated the use of POCs in breastfeeding women and reported clinically relevant outcomes of infant growth, health or breastfeeding performance. Studies ranged from poor to fair methodological quality and generally failed to show negative effects of the use of POCs on breastfeeding outcomes or on infant growth or development. One randomized controlled trial (RCT) raises concerns that immediate insertion of the levonorgestrel IUD postpartum may be associated with poorer breastfeeding performance when compared with delayed insertion, although two other RCTs evaluating early etonogestrel implants compared with delayed initiation of implants or depot medroxyprogesterone acetate failed to find such an association. Conclusion The preponderance of evidence fails to demonstrate adverse breastfeeding outcomes or negative health outcomes in infants such as restricted growth, health problems or impaired development. Evidence newly added to this review was largely consistent with previous evidence.

Objective To evaluate the efficacy of vaginal progesterone administration for preventing preterm birth and perinatal morbidity and mortality in asymptomatic women with a singleton gestation and a mid‐trimester sonographic cervical length (CL) ≤ 25 mm. Methods This was an updated systematic review and meta‐analysis of randomized controlled trials comparing the use of vaginal progesterone to placebo/no treatment in women with a singleton gestation and a mid‐trimester sonographic CL ≤ 25 mm. Electronic databases, from their inception to May 2016, bibliographies and conference proceedings were searched. The primary outcome measure was preterm birth ≤ 34 weeks of gestation or fetal death. Two reviewers independently selected studies, assessed the risk of bias and extracted the data. Pooled relative risks (RRs) with 95% confidence intervals (CI) were calculated. Results Five trials involving 974 women were included. A meta‐analysis, including data from the OPPTIMUM study, showed that vaginal progesterone significantly decreased the risk of preterm birth ≤ 34 weeks of gestation or fetal death compared to placebo (18.1% vs 27.5%; RR, 0.66 (95% CI, 0.52–0.83); P = 0.0005; five studies; 974 women). Meta‐analyses of data from four trials (723 women) showed that vaginal progesterone administration was associated with a statistically significant reduction in the risk of preterm birth occurring at, This article has been selected for Journal Club. Click here to view slides and discussion points.

Endometriosis, with more than centenary history, remains a challenge in our day. One of the more common options is adenomyosis, the share of which amounts to 80%. The aim of the study was to evaluate the clinical effectiveness and tolerance to resolve with chronic pelvic pain syndrome of adenomyosis the use of progestogen-new generation dienogest in a dose of 2 mg for 6 months. The study included 44 (n=44) women of reproductive age with a diagnosis of adenomyosis with chronic pelvic pain syndrome of various degrees of severity, whose average age was on average 36 yo 2 years who received therapy with dienogest in a daily dose of 2 mg for 6 months. The results showed high therapeuticefficiency dienogest in the treatment of pelvic pain caused by adenomyosis.

BACKGROUND: Preterm birth complicates almost all triplet pregnancies and no preventive strategy has proven effective. OBJECTIVE: To determine, using individual patient data (IPD) meta-analysis, whether the outcome of triplet pregnancy is affected by prophylactic administration of 17-hydroxyprogesterone caproate (17OHPc). SEARCH STRATEGY: We searched literature databases, trial registries and references in published articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) of progestogens versus control that included women with triplet pregnancies. DATA COLLECTION AND ANALYSIS: Investigators from identified RCTs collaborated on the protocol and contributed their IPD. The primary outcome was a composite measure of adverse perinatal outcome. The secondary outcome was the rate of birth before 32 weeks of gestation. Other pre-specified outcomes included randomisation-to-delivery interval and rates of birth at

Postmenopausal women using continuous combined estrogen/progestin therapy are likely to have irregular bleedings or spotting. Up to now, their causes remain unclear. Most investigators believe that a potential mechanism of abnormal bleedings during menopausal hormonal therapy could be a change in the ratio of pro- and anti-angiogenic factors, namely, of vascular endothelial growth factor to thrombospondin-1; alterations in metalloproteinases and their tissue inhibitors; changes in a tissue factor that is a mediator of endometrial hemostasis; as well as an increased number of endometrial leukocytes with predominance of uterine natural killer cells. As long as no link between bleeding discharge during continuous combined hormonal treatment and any of these actors has been established, each and every of them is the subject of in vivo and in vitro investigations. At present, there are no herapeutic methods to correct this complication of hormonal treatment. Patient monitoring to exclude neoplastic abnormalities in endometrium are of paramount importance.

Steroid hormones have been in use for more than a half a century as contraceptive agents, and only now are researchers elucidating the biochemical mechanisms of action and non-target effects. Progesterone and synthetic progestins, critical for women's health in the US and internationally, appear to have important effects on immune functioning and other diverse systems. Apart from the contraceptive world is a separate field that is devoted to understanding progesterone in other contexts. Based on research following a development timeline parallel to hormonal contraception, progesterone and 17-hydroxyprogesterone caproate are now administered to prevent preterm birth in high-risk pregnant women. Preterm birth researchers are similarly working to determine the precise biochemical actions and immunological effects of progesterone. Progesterone research in both areas could benefit from increased collaboration and bringing these two bodies of literature together. Progesterone, through actions on various hormone receptors, has lifelong importance in different organ systems and researchers have much to learn about this molecule from the combination of existing literatures, and from future studies that build on this combined knowledge base.

Synthetic progestins are emerging contaminants of the aquatic environment with endocrine disrupting potential. The main aim of the present study was to investigate the effects of the synthetic progestins gestodene, and drospirenone on sex differentiation in common carp (Cyprinus carpio) by histological analysis. To gain insights into the mechanisms behind the observations from the in vivo experiment on sex differentiation, we analyzed expression of genes involved in hypothalamus–pituitary–gonad (HPG) and hypothalamus–pituitary–thyroid (HPT) axes, histology of hepatopancreas, and in vitro bioassays. Carp were continuously exposed to concentrations of 2 ng/L of single progestins (gestodene or drospirenone) or to their mixture at concentration 2 ng/L of each. The exposure started 24 h after fertilization of eggs and concluded 160 days post-hatching. Our results showed that exposure of common carp to a binary mixture of drospirenone and gestodene caused increased incidence of intersex (32%) when compared to clean water and solvent control groups (both 3%). Intersex most probably was induced by a combination of multiple modes of action of the studied substances, namely anti-gonadotropic activity, interference with androgen receptor, and potentially also with HPT axis or estrogen receptor.

Objectives: This study aimed to identify potential prognostic factors for patients with complex atypical hyperplasia (CAH) or early-stage endometrial cancer (EC) who received progestin therapy to spare fertility and, thus, improve the management of this patient group. Materials and methods: The PubMed, PMC, EMBASE, Web of Science, and Cochrane databases were searched for correlational studies published in English. Studies that evaluated the prognosis of patients with CAH or early-stage EC were pooled for a systematic review and meta-analysis. Results: In total, 31 eligible studies, including 8 prospective and 23 retrospective studies involving 1099 patients, were included in this analysis. The most commonly used progestin agents were medroxyprogesterone acetate (MPA, 47.0%) and megestrol acetate (MA, 25.5%). The total complete response (CR) rate was 75.8% (833/1099), and the median time to CR with first-line progestin therapy was 6 months. In total, 294 (26.8%) patients who achieved CR became pregnant spontaneously (28 cases) or through assisted reproductive technology (127 cases). During the median follow-up of 39 months, 245 (22.3%) women developed recurrence. Only one patient (0.09%) died of the disease. The meta-analysis showed that compared to a BMI

Sex differences in hypothalamic-pituitary-adrenal (HPA) axis activity are well established in rodents. In addition to glucocorticoids, stress also stimulates the secretion of progesterone and deoxycorticosterone (DOC) from the adrenal gland. Neuroactive steroid metabolites of these precursors can modulate HPA axis function; however, it is not known whether levels of these steroids differ between male and females following stress. In the present study, we aimed to establish whether neuroactive steroid concentrations in the brain display sex- and/or region-specific differences under basal conditions and following exposure to acute stress. Brains were collected from male and female rats killed under nonstress conditions or following exposure to forced swimming. Liquid chromatography-mass spectrometry was used to quantify eight steroids: corticosterone, DOC, dihydrodeoxycorticosterone (DHDOC), pregnenolone, progesterone, dihydroprogesterone (DHP), allopregnanolone and testosterone in plasma, and in five brain regions (frontal cortex, hypothalamus, hippocampus, amygdala and brainstem). Corticosterone, DOC and progesterone concentrations were significantly greater in the plasma and brain of both sexes following stress; however, the responses in plasma were greater in females compared to males. This sex difference was also observed in the majority of brain regions for DOC and progesterone but not for corticosterone. Despite observing no stress-induced changes in circulating concentrations of pregnenolone, DHDOC or DHP, concentrations were significantly greater in the brain and this effect was more pronounced in females than males. Basal plasma and brain concentrations of allopregnanolone were significantly higher in females; moreover, stress had a greater impact on central allopregnanolone concentrations in females. Stress had no effect on circulating or brain concentrations of testosterone in males. These data indicate the existence of sex and regional differences in the generation of neuroactive steroids in the brain following acute stress, especially for the 5α-reduced steroids, and further suggest a sex-specific expression of steroidogenic enzymes in the brain. Thus, differential neurosteroidogenesis may contribute to sex differences in HPA axis responses to stress.

Introduction Progestogens are widely used for the conservative treatment of endometrial hyperplasia and early endometrial cancer. Nevertheless, they do not achieve the regression in all cases. Although several immunohistochemical markers have been assessed to predict the response to treatment, their usefulness is still unclear. We aimed to analyze the usefulness of each immunohistochemical marker studied in predicting the response to progestogens in endometrial hyperplasia and early endometrial cancer. Material and methods Electronic databases were searched for relevant articles from January 2000 to June 2018. All studies assessing the association of immunohistochemical markers with the outcome of the progestogen-based therapy in endometrial hyperplasia and early endometrial cancer were included. The expression of immunohistochemical markers in pretreatment phase and changes of expression during the follow-up were evaluated in relation to response to therapy and relapse. Results Twenty-seven studies with 1360 women were included in the systematic review; 43 immunohistochemical markers were assessed. The most studied predictive markers in the pretreatment phase were progesterone and estrogen receptors, although with conflicting results; their isoforms, and in particular progesterone receptor B, appeared more promising. Further studies are needed to confirm the usefulness of mismatch repair proteins, Dusp6, GRP78 and PTEN combined with other molecules such as phospho-AKT or phospho-mTOR. In the follow-up phase, Nrf2 and survivin showed the stronger evidence; a role may also be played by Bcl2 and Ki67. Further studies are necessary for Fas, NCoR, AKR1C1, HE4, PAX2 and SPAG9. Conclusions Several immunohistochemical markers might be helpful in predicting the response to conservative treatment of endometrial hyperplasia and early endometrial cancer on pretreatment and follow-up specimens. Further studies are needed to confirm their usefulness and possibly integrate them in a predictive immunohistochemical panel.

To evaluate the response of the “male effect” and “temporary weaning” on the synchronization of post-partum ovarian activity in Pelibuey ewes, an experiment was carried out using 78 Pelibuey ewes with suckling lambs. The ewes were separated from their offspring for 48 hours and randomly assigned to one of four treatments derived from the arrangement of two factors, “male effect” and “temporary weaning”, each at two levels. Treatments were: T1 (n = 20) control ewes, without “male effect” and without “temporary weaning”); T2 (n = 19) ewes without “male effect” and with “temporary weaning”; T3 (n = 20) ewes with “male effect” and without “temporary weaning”; and T4 (n = 19), ewes with “male effect” and with “temporary weaning”. The response to oestrus, return to oestrus, gestation rate and lambing rate were analysed using logistic regression. The onset of oestrus was analysed using survival curves. No significant differences were found for lambing rate and prolificacy among treatments. “Temporary weaning” (T2) and “male effect” (T3) did not influence the response to oestrus, rate and duration of return to oestrus, or gestation rate and fertility, and was similar to the control group (T1). The interaction of “male effect” with “temporary weaning” (T4) increased the response to oestrus, reduced the rate and duration of return to oestrus, and the gestation rate, but increased fertility. Synchronizing post-partum ovarian activity with “male effect” and “temporary weaning” reduces the onset of oestrus and the rate of return to oestrus, but increases the response to oestrus and fecundity in Pelibuey ewes.Keywords: Biostimulation, progestogens, prolificacy, prostaglandins, suckling

Endometriosis is a benign gynecological condition that is estimated to affect 10% of women in the general population and appears to be increasing in incidence. It is an estrogen-dependent inflammatory disease, and is primarily characterized by dysmenorrhea, deep dyspareunia, chronic pelvic pain, and variable effects on fertility. The symptoms may greatly affect quality of life, and symptom control may be the primary aim of initial management, while contraceptive effect is often secondary. It is estimated that 30%-50% of women with endometriosis have an infertility problem, so a considerable number of endometriosis sufferers will require effective, planned contraception to maximize "protection of fertility" and prevent progression of the endometriotic condition. Ideally, this contraception should also provide symptom relief and improvement of physical, mental, and social well-being. At the present time, long-term progestogens appear to be the most effective choice for meeting all of these requirements, but other options need to be considered. It is becoming increasingly recognized that hormonal contraceptive systems are necessary for prevention of disease recurrence following surgical treatment of endometriosis. The personal preferences of the woman are an integral part of the final contraceptive choice. This article discusses the advantages and disadvantages of the contraceptive options available to women with endometriosis.