Use Of Progestins Research Articles

A Retrospective Analysis of Progestogen Use in Transgender Women

Abstract Background: Many transgender women seek progestogens as part of their feminizing gender-affirming hormone treatment (GAHT), particularly to address breast development, body composition, mood stabilization, and changes in sexual desire and sleep. However, there are few studies that evaluate the role of progestogen use in feminizing GAHT. Reasons for initiating and continuing progestogen therapy have been mostly anecdotal to date, dependent on patient preference and provider practice style, and data about effects remain scarce. Objective: To characterize progestogen use patterns in transgender women at one academic center; identify reasons for initiation and continuation of its use; and determine perceived related benefits and adverse events. Methods: Retrospective analysis of transgender women prescribed feminizing GAHT at Stanford Health Care (SHC) between 2014-2020. Those using either combination estrogen + micronized progesterone or combination estrogen + medroxyprogesterone acetate (MPA) were included in our sample. Twenty-five consecutive charts were reviewed in detail for patterns of progestogen use, reasons for initiation and continuation, and its perceived effects. Results: 410 transgender women sought care at SHC between 2014-2020. Ninety-six patients (23%) were prescribed micronized progesterone and 15 patients (4%) MPA at some point in their care, in addition to estrogen use. Of the 25 patient charts reviewed in detail (median age 30 years, IQR 25-42), 32% (n = 8) had clear documentation in the medical record of why progestogen was started and 25% (n = 6) included a description of the patient’s perceived effects with progestogen therapy. The most common reason to start progestogen was improved breast development (20%, n = 5). Three individuals reported improved nipple/breast growth. Median duration of progestogen use was 34.4 months (IQR 22.3-47.4) with 22 out of 25 patients still on progestogen therapy at time of chart review. Median duration of estrogen use prior to initiation of progestogen use was 14.2 months (IQR 7.1-35.8). No cardiovascular or thromboembolic events were noted in the reviewed patients on progestogen therapy. Discussion: Over one in four transgender women seeking feminizing GAHT received a form of progestogen therapy as part of their overall GAHT. Most patients on progestogens lack documentation of why it was started or whether the patient seems to benefit from its addition. Given the continued paucity of data supporting or against progestogen use in feminizing GAHT, gender-affirming hormone providers may benefit from further education on how to counsel patients about progestogen use and how to assess for potential progestogen-associated effects over time. Finally, more consistent documentation in the electronic medical record will allow for more definitive conclusions regarding the benefits and risks of progestogen therapy in the future.

Identification of Genes and Pathways Differentially Expressed in Progestin Responsive Endometrial Cancer and Hyperplasia

One of the oldest and most common therapies for endometrial complex atypical hyperplasia (CAH) and low-stage, low-grade endometrioid endometrial carcinoma (EEC) is the use of progestins. Importantly, the use of progestins remains the only fertility-sparing treatment available. Despite frequent initial response to progestins, relapse rates are high (35-50%). Currently, there are no biomarkers available for predicting a woman’s likelihood of successful progestin therapy.Primary samples (n = 63) were obtained from a total of 31 patients with either CAH or EEC who underwent progestin therapy and were acquired pre- and post-treatment with progestins. Pathological review of the FFPE samples was performed to identify regions of high hyperplastic or neoplastic content for core punches and RNA extraction. RNA-seq was then performed on the FFPE RNA using the TruSeq RNA Exome approach, a method that uses targeted capture to improve sequencing from fragmented samples. Differential expression analysis was performed using two methods: DESeq2 a parametric method and Noiseq a non-parametric method. Both methods were used to obtain an overlapping subset of genes to reduce spurious results due to samples with outlier expression.Analysis of all samples identified 137 genes significantly associated with outcome. These 137 genes were largely increased in post-treatment samples from progestin responders and were highly enriched for progestogen and estrogen responsive genes, indicating a strong hormonal gene expression response to progestin therapy. Importantly, post-treatment samples from non-responding patients did not show this expression pattern, demonstrating that this set of genes may indicate successful hormone response in post-treatment samples. We also identified a 61 gene signature that remains high in non-responders after treatment compared to responders. Overall, we find that responders show a coordinated change in expression during progestin therapy that is missing from non-responders and this signature could be used in the early evaluation of progestin treatment success.Focusing solely on pre-treatment samples, we identified more variable expression differences across tumors, suggesting multiple reasons for progestin success/failure. We found that the combined expression of estrogen receptor alpha and progesterone receptor was predictive of progestin therapy success. In addition, non-responding tumors had increased expression of several immune-related genes that we are currently exploring. Overall, these results show that progestin therapy response could be predicted using gene expression signatures and that multiple factors may underlie progestin success/failure.

In Utero Exposure to 17α-Hydroxyprogesterone Caproate May Contribute to Increasing Incidence Rates of Early-Onset Cancer

Background: 17α-hydroxyprogesterone caproate (17-OHPC) is a synthetic progestogen introduced in the 1950s to treat habitual and threatened abortion in pregnant women. Although 17-OHPC is still available (tradename Makena), little is known about its effects on health of adult offspring, and questions concerning safety and effectiveness remain. For example, progestogens have been implicated in cancer, and trends in the use of 17-OHPC in early pregnancy during the 1950s and 60s parallel increasing incidence rates of certain cancers in young adults, such as early-onset colorectal cancer, born during that time. Methods: We examined the effect of 17-OHPC exposure in utero on risk of cancer in adult offspring in the Child Health and Development Studies, a cohort of women receiving prenatal care between June 1959 and September 1966, with deliveries through June 1967 (n=18,751 live births excluding neonatal deaths among 14,507 mothers). Diagnosed conditions and prescribed medications were abstracted from mothers’ medical records beginning 6 months prior to pregnancy through delivery. We identified mothers who received 17-OHPC (tradenames Delalutin and Proluton) in early pregnancy, defined as day 1 - 140 of gestation. Incident cancers diagnosed in offspring through 2018 were ascertained by linkage with the California Cancer Registry. Results: Among 18,751 live births, 954 cancers were diagnosed at ages 18 - 58 years. The most frequent cancers were breast (20.9%), cervical (10.9%), colorectal (7.1%), and prostate (5.9%) cancer and melanoma (9.2%). Although few mothers (n=181, 1.0%) received 17-OHPC in early pregnancy, in utero exposure was more common in offspring diagnosed with cancer (n=18, 1.9%) compared to those without cancer (n=163, 0.9%). Conditions indicating 17-OHPC included threatened abortion (54.0%), amnionitis (9.4%), and incompetent cervix (3.0%). 17-OHPC increased risk of any cancer in offspring (OR 2.08, 95% CI 1.27, 3.40), with particularly striking associations for colorectal (OR 4.78, 95% CI 1.49, 15.41) and prostate (OR 3.83, 95% CI 0.93, 15.83) cancer. There was no association between conditions indicating 17-OHPC and risk of any cancer in offspring (threatened abortion: n=1,891 mothers, OR 1.07, 95% CI 0.87, 1.32), or with use of other progestogens within 6 months prior to pregnancy (medroxyprogesterone acetate: n=50 mothers, OR 0.38, 95% CI 0.05, 2.76). Conclusions: Findings support susceptibility of multiple organ systems to endocrine disruption during early development and risk of cancer decades later - and may partly explain increasing rates of early-onset colorectal cancer. Even before mechanisms of carcinogenesis are elucidated, caution using 17-OHPC and other endocrine-active pharmaceuticals in early pregnancy is warranted, especially in the absence of a clear short-term benefit, and given the possible effect on risk of cancer in adult offspring.

Cancer Progress and Priorities: Breast Cancer.

Breast cancer is the most commonly diagnosed invasive cancer among women both globally and within the United States and the number one cause of cancer-related deaths among women globally ([1, 2][1]). Less than 1% of diagnosed breast cancers occur in men ([2][2]) and, therefore, male breast cancer is

68. Hemorrhagic shock due to ruptured hepatic adenoma secondary to oral norethindrone acetate in a patient with type 3 von Willebrand disease: a case report

<h3>Background</h3> Patients with von Willebrand's disease (vWD) often require menstrual suppression in order to avoid episodes of heavy bleeding. While multiple hormone-based options are appropriate for these patients, specific side effects and clinical considerations based on the type and severity of vWD need further study. We discuss refinement of treatment options for menorrhagia for an adolescent with type 3 vWD who presented with a complication likely related to chronic progestin exposure. <h3>Case</h3> Patient C.D. was diagnosed with type 3 vWD in infancy and presented at 11 years-old for management of menorrhagia with a goal of amenorrhea. She was initially started on oral norethindrone acetate alone 3 times daily, which was continued for years to control breakthrough bleeding while receiving injectable progestins followed by the etonorgestrel-releasing implant. At 15 years-old, C.D. presented to the emergency room after 1 day of severe abdominal pain. She was found to be hypotensive with peritoneal signs on exam. CT demonstrated multiple hepatic masses, the largest being 9 cm with active contrast extravasation suggesting a bleeding adenoma with associated hemoperitoneum. She underwent an emergent right hepatic lobe embolization by interventional radiology. She recovered in the pediatric ICU with stabilization of her bleeding. The etiology of her hepatic adenomas was suspected to be chronic progestin use. After department discussions with hematology and gynecology, the oral norethindrone acetate was discontinued during her hospital course and she experienced withdrawal bleeding. On hospital day 13, the patient's contraceptive implant was removed and a levonorgestrel-releasing IUD was placed, which expelled 2 days later in the setting of heavy vaginal bleeding. C.D. received depot-medroxyprogesterone and was discharged home on daily recombinant VWF. At 1-month follow-up, the patient was amenorrheic and had stable hepatic masses on repeat imaging. The patient was maintained on injectable progestins with plans to trial a progestin IUD in the future. <h3>Comments</h3> Hepatic adenoma is a known complication of estrogen-containing medications and a rare side effect from peripheral conversion of oral progestins. A few case reports have shown regression of hepatic adenomas after cessation of progestin therapy. Furthermore, menses suppression for patients with severe vWD is critical to avoid menorrhagia. Patients with type 3 vWD particularly have limited pharmacologic options for preventing heavy menses. Through this case report, we discuss the management options for menstrual suppression and control of menorrhagia in patients with severe vWD with consideration of potential morbid side effects, and explore areas of further research of treatment regimens.

Abstract PO019: Identification of differentially expressed genes in primary samples of endometrial hyperplasia and endometrioid endometrial carcinoma responsive to progestin therapy

Abstract One of the oldest and most common therapies for endometrial complex atypical hyperplasia (CAH) and low-stage, low-grade endometrioid endometrial carcinoma (EEC) is the use of progestins. Importantly, the use of progestins remains the only fertility-sparing treatment available. Despite frequent initial response to progestins, relapse rates are high (35-50%). This study aims to identify gene expression signatures indicative of the likelihood of successful progestin therapy. Primary samples (n = 63) were obtained from a total of 31 patients with either CAH or EEC who underwent progestin therapy. Samples were acquired pre- and post-treatment with progestins. Pathological review of the FFPE samples was performed to identify regions of high hyperplastic or neoplastic content for core punches and RNA extraction. RNA-seq was then performed on the FFPE RNA using the TruSeq RNA Exome approach (Illumina), a method that uses targeted capture to improve sequencing from fragmented samples. Differential expression (DE) analysis was performed using two methods: DESeq2 a parametric method and Noiseq a non-parametric method. Both methods were used to obtain an overlapping subset of DE genes to reduce spurious results due to samples with outlier expression. Gene set enrichment was performed using ENRICHR. Analysis of all samples using DESeq2 identified 843 genes significantly associated with outcome, while Noiseq identified 318 genes, with an overlap between the two methods of 137. These 137 genes were largely increased in post-treatment samples from progestin responders and were enriched for the DSigDB terms “progesterone”, “medroxyprogesterone acetate”, and “estradiol”, indicating a strong hormonal gene expression response to progestin therapy. Importantly, post-treatment samples from non-responding patients did not show this expression pattern, demonstrating that this set of genes may indicate successful hormone response in post-treatment samples. Additionally, a small gene signature (61 genes) was specifically decreased in post-treatment responders compared to all other groups. This gene set is enriched for the GO molecular function “enhancer binding”, BioPlanet 2019 sets “BMP signaling pathway in stem cells” and “Signaling events mediated by the hedgehog family”. The genes in this set may be related to failure on progestin therapies and surprisingly include both ESR1 (estrogen receptor a) and PGR (progesterone receptor). Analysis of RNA-seq data from our cohort of CAH and EEC samples identified a 137 gene signature post-progestin treatment that indicate successful clinical response. We also identified a 61 gene signature that remains high in non-responders after treatment compared to responders. Overall, we find that responders show a coordinated change in expression during progestin therapy that is missing from non-responders and this signature could be used in the early evaluation of progestin treatment success. Citation Format: Craig M. Rush, Jeffery M. Vahrenkamp, Kathryn Szczotka, Mark K. Dodson, Elke A. Jarboe, Andrew P. Soisson, Jay Gertz. Identification of differentially expressed genes in primary samples of endometrial hyperplasia and endometrioid endometrial carcinoma responsive to progestin therapy [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO019.

Clinical Use of Progestins and Their Mechanisms of Action: Present and Future (Review).

This review summarizes the current opinions on the mechanisms of action of nuclear, mitochondrial, and membrane progesterone receptors. The main aspects of the pharmacological action of progestins have been studied. Data on the clinical use of gestagens by nosological groups are presented. Particular attention is paid to progesterone, megestrol acetate, medroxyprogesterone acetate due to broadening of their spectrum of action. The possibilities of using gestagens as neuroprotectors, immunomodulators, and chemosensitizers are considered.

Systematic Review and Meta-Analysis of Hormone Replacement Therapy

To survey and assess investigations of HRT for forestalling intellectual decrease and dementia in solid postmenopausal ladies Studies of perception were not consolidated quantitatively on account of heterogeneous examination plan. Ladies suggestive from menopause had upgrades in verbal memory, carefulness, thinking, and engine speed, however no improvement of other psychological capacities. For the most part, no advantages were seen in asymptomatic ladies. A meta-investigation of observational examinations recommended that HRT was related with a diminished danger of dementia (outline chances proportion, certainty span). Notwithstanding, potential predispositions and absence of control for potential confounders limit translation of these examinations. Studies didn't contain sufficient data to survey satisfactorily the impacts of progestin use, different estrogen arrangements or portions, or length of treatment. In ladies with menopausal indications, HRT may have explicit psychological impacts, and future examinations should focus on these impacts. The meta-examination tracked down a diminished danger of dementia in HRT clients however most investigations had significant methodological impediments.

Analysis of the causes of unsuccessful hormonal treatment of non-atypical endometrial hyperplasia in premenopousal women

Annotation. Non-atypical endometrial hyperplasia (NEH), despite of benign morphology, may be insensitive to the hormonal treatment and has a tendency to recurrence and progression to atypia in some cases. The study purpose was the investigation of different type of progestins treatment results and comparison of progesterone receptors (PGR) and Е-cadherin expression in the sensitive NEH(+) and resistant NEH(–) to progestin treatment type of NEH. Prospective study of three groups of women with histologically confirmed NEH, who took different progestins during 6 months was done: І group – 96 women, who took micronized progesterone orally 200 mg per day continually, ІІ group – 161 women, who took dydrogesterone 20 mg per day continually, ІІІ group – 54 women, who were inserted LNG-IUD 52 mg. Control histopathological investigations of the endometrial samplings at 3 and 6 months were done. Expression of PGR and Е-cadherin by immunohistochemistry were investigated in the start samples of endometrium for all 63 NEH(–) women, 48 NEH(+) women and 20 control samples of normal proliferative and secretory endometrium. In the result of the study only nonsignificant and unreliable differences between different progestins efficacy were found. It was 75% normal endometrium samples till 6 months for micronized progesterone, 81.4% for dydrogesterone and 83.3% for LNG-IUD. Data analysis of PGR expression in the NEH(–) endometrium has shown significantly less week expression as for glandular cells (50.82±0.73), as for stromal cells (47.34±0.82) in comparison to the NEH(+) endometrial samples (glandular – 183.7±3.1; stroma 166.4±2.3; р&lt;0.05) and normal proliferative (193.2±8.5 і 178.7±6.3 respectively; р&lt;0.05) and secretory (140.2±4,4 і 116.6±3,1 respectively; р&lt;0.05) endometrium. Е-cadherin expression in the glandular endometrial cells NEH(–) mostly was negative (86.4%) and 13.6% cells only demonstrated its week expression. NEH(+) women cells predominantly showed a positive reaction. It was often enough week (49.2%) and moderate (34.4%), but only in the 16.4% samples were negative. Thus, the use of progestogens for the treatment of NEH in women with low expression of PGR and negative expression of E-cadherin in the endometrium is inappropriate. Investigations of PGR та Е-cadherin expression in the endometrium of women with NEH before starting treatment may provide an opportunity to predict negative result in advance and chose alternative therapeutical approach.

Use of oral progestogen in women with threatened miscarriage in the first trimester: a randomized double-blind controlled trial.

Will use of oral progestogen in women with threatened miscarriage in the first trimester reduce the miscarriage rate when compared with placebo? Use of oral progestogen in women with threatened miscarriage in the first trimester did not reduce miscarriage before 20 weeks when compared with placebo. Miscarriage is a common complication of pregnancy and occurs in 15-20% of clinically recognized pregnancies. Use of vaginal progestogens is not effective in reducing miscarriage but there is still no good evidence to support use of oral progestogen for the treatment of threatened miscarriage. This was a randomized double-blind controlled trial. A total of 406 women presenting with threatened miscarriage in the first trimester were recruited from 30 March 2016 to May 2018. Women attending Early Pregnancy Assessment Clinics because of vaginal bleeding during the first trimester were recruited and randomly assigned to use dydrogesterone 40 mg orally, followed by 10 mg orally three times a day or placebo until 12 completed weeks of gestation or 1 week after the bleeding stopped, whichever was later. The primary outcome was the miscarriage rate before 20 weeks of gestation. The two groups of women had comparable age, BMI, number of previous miscarriages, gestation and ultrasound findings at presentation. The miscarriage rate before 20 weeks of gestation was similar in both groups, being 12.8% (26/203) in the progestogen group and 14.3% (29/203) in the placebo group (relative risk 0.897, 95% CI 0.548-1.467; P = 0.772). The live birth rate was 81.3% in the progestogen group versus 83.3% in the placebo group (P = 0.697). No significant differences were found between the two groups in terms of obstetric outcomes and side effects. The primary outcome was the miscarriage rate, rather than the live birth rate. Women were recruited from Early Pregnancy Assessment Clinics and those with heavy vaginal bleeding might be admitted into wards directly instead of attending Early Pregnancy Assessment Clinic. The severity of vaginal bleeding was subjectively graded by women themselves. The sample size was not adequate to demonstrate a smaller difference in the miscarriage rate between the progestogen and placebo groups. We did not exclude women with multiple pregnancy, which increased the risk of miscarriage although there was only one set of twin pregnancy in the placebo group. Use of oral progestogen is not recommended in women with threatened miscarriage in the first trimester. This study was funded by the Health and Medical Research Fund, HKSAR (reference number 12132341). All authors declared no conflict of interest. ClinicalTrials.gov with an identifier NCT02128685. 1 May 2014. 30 March 2016.

Oral contraceptive use by formulation and endometrial cancer risk among women born in 1947\u20131964: The Nurses\u2019 Health Study II, a prospective cohort study

Oral contraceptives (OCs) have been associated with long-term lower endometrial cancer risk; relatively little is known about associations with more recent OC formulations and associations with longer-term risk. A total of 107,069 women from the Nurses’ Health Study II recalled OC use from age 13 to baseline (1989); biennial questionnaires updated data on OC use until 2009. OCs were classified by estrogen and progestin type, dose, and potency based on reported brand. 864 incident endometrial cancer cases were identified through 2017. Multivariable Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals [95% CI] for the association of OC use with endometrial cancer risk. OC use was associated with lower endometrial cancer risk (ever use, HR 0.77 [95% CI 0.65–0.91]; >10 years of use, 0.43 [0.32–0.58] vs. never OC use). Inverse associations for duration were evident regardless of time since last use. Longer durations (> 5 years) of ethinyl estradiol (0.52 [0.41–0.67]) and second-generation progestins (0.43 [0.30–0.61]), both versus never use, were more strongly associated with lower risk than mestranol (0.66 [0.50–0.88], p-het = 0.01) and first-generation progestins (0.62 [0.49–0.78], p-het = 0.03). Inverse associations were generally observed for cross-classified cumulative average estrogen and progestin dose and potency (< vs. ≥ median; ever use vs. never OC use), with the exception of high estrogen and low progestin dose. OCs were associated with lower endometrial cancer risk, independent of time since last use. Use of ethinyl estradiol and second-generation progestins were more strongly inversely associated with risk compared with older formulations.

Sex steroids and autoimmune rheumatic diseases: state of the art.

In autoimmune rheumatic diseases, oestrogens can stimulate certain immune responses (including effects on B cells and innate immunity), but can also have dose-related anti-inflammatory effects on T cells, macrophages and other immune cells. By contrast, androgens and progesterone have predominantly immunosuppressive and anti-inflammatory effects. Hormone replacement therapies and oral contraception (and also pregnancy) enhance or decrease the severity of autoimmune rheumatic diseases at a genetic or epigenetic level. Serum androgen concentrations are often low in men and in women with autoimmune rheumatic diseases, suggesting that androgen-like compounds might be a promising therapeutic approach. However, androgen-to-oestrogen conversion (known as intracrinology) is enhanced in inflamed tissues, such as those present in patients with autoimmune rheumatic diseases. In addition, it is becoming evident that the gut microbiota differs between the sexes (known as the microgenderome) and leads to sex-dependent genetic and epigenetic changes in gastrointestinal inflammation, systemic immunity and, potentially, susceptibility to autoimmune or inflammatory rheumatic diseases. Future clinical research needs to focus on the therapeutic use of androgens and progestins or their downstream signalling cascades and on new oestrogenic compounds such as tissue-selective oestrogen complex to modulate altered immune responses.

Progestins for pituitary suppression during ovarian stimulation for ART: a comprehensive and systematic review including meta-analyses.

Progestins are capable of suppressing endogenous LH secretion from the pituitary. Progestins can be used orally and are less expensive than GnRH analogues. However, early endometrial exposure to progestin precludes a fresh embryo transfer (ET), but the advent of vitrification and increasing number of oocyte cryopreservation cycles allow more opportunities for using progestins for pituitary suppression. This review summarizes: the mechanism of pituitary suppression by progestins; the effectiveness of progestins when compared with GnRH analogues and with each other; the effect of progestins on oocyte and embryo developmental potential and euploidy status; and the cost-effectiveness aspects of progestin primed stimulation. Future research priorities are also identified. The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via PubMed, the Web of Science and Scopus were screened with a combination of keywords related to ART, progesterone, GnRH analogue and ovarian stimulation, in various combinations. The search period was from the date of inception of each database until 1 April 2020. Only full text papers published in English were included. Overall, the duration of stimulation, gonadotrophin consumption and oocyte yield were similar with progestins and GnRH analogues. However, sensitivity analyses suggested that progestins were associated with significantly lower gonadotrophin consumption than the long GnRH agonist protocol (mean difference (MD) = -648, 95% CI = -746 to -550 IU) and significantly higher gonadotrophin consumption than the short GnRH agonist protocol (MD = 433, 95% CI = 311 to 555 IU). Overall, live birth, ongoing and clinical pregnancy rates per ET were similar with progestins and GnRH analogues. However, when progestins were compared with GnRH agonists, sensitivity analyses including women with polycystic ovary syndrome (risk ratio (RR) = 1.27, 95% CI = 1.06 to 1.53) and short GnRH agonist protocols (RR = 1.14, 95% CI = 1.02 to 1.28) showed significantly higher clinical pregnancy rates with progestins. However, the quality of evidence is low. Studies comparing medroxyprogesterone acetate, dydrogesterone and micronized progesterone suggested similar ovarian response and pregnancy outcomes. The euploidy status of embryos from progestin primed cycles was similar to that of embryos from conventional stimulation cycles. Available information is reassuring regarding obstetric and neonatal outcomes with the use of progestins. Despite the lower cost of progestins than GnRH analogues, the mandatory cryopreservation of all embryos followed by a deferred transfer may increase cost per live birth with progestins as compared to an ART cycle culminating in a fresh ET. Progestins can present an effective option for women who do not contemplate a fresh ET, e.g. fertility preservation, anticipated hyper responders, preimplantation genetic testing, oocyte donors, double stimulation cycles.

Risk Factors and Prevalence of Limb Deficiencies Associated With Amniotic Band Sequence: A Population-based Case-control Study.

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. 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. 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. 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 III.

Cultura da secreção intrauterina de cadelas durante a ovariohisterectomia para escolha empírica de antimicrobianos

Pyometra occurs mainly in older animals; however, the use of progestogens contributes for the younger females to be affected as well. Its treatment consists of fluid therapy, antibiotic therapy and ovariohysterectomy, and the choice of antimicrobial, generally, is based on the knowledge of the agents most commonly isolated in this type of infection and to which active principles they are sensitive. Nevertheless, it is known that over time bacteria acquire natural resistance to antibiotics and that this resistance is usually accelerated by their indiscriminate use. In that sense, studies that update which antimicrobials are efficient to fight bacterial infections are important and necessary, especially, because when diagnosing an animal with pyometra, the antibiotic therapy should be initiated immediately and the choice of the active principle, at least, in the first moment, is empirical. Therefore, the objective of this work was to determine the microbiological profile, through culture and antibiogram, of the intrauterine content of bitches submitted to elective ovary hysterectomy, thus contributing to a more conscious and effective empirical choice in the treatment of these infections.

Considerations for Providing Pediatric Gender-Affirmative Care During the COVID-19 Pandemic

Considerations for Providing Pediatric Gender-Affirmative Care During the COVID-19 Pandemic

THE VALUE OF THE EXPRESSION OF PROGESTERONE RECEPTORS (PR-A AND PR-B) AS PREDICTORS OF RECURRENCE OF ENDOMETRIAL HYPERPLASIA AFTER THERAPY WITH PROGESTINS

The aim of the study. Improving diagnostics and predicting the effectiveness of pathogenetic treatment with progestins of endometrial hyperplasia without atypia, based on the study of the expression of progesterone receptors (PR-A and PR-B) and their ratio in endometrial tissues.Materials and methods. A prospective study was performed in 40 patients of reproductive age with abnormal uterine bleeding, who were diagnosed with endometrial hyperplasia without atypia based on histological examination of endometrial tissue. The control group consisted of 15 patients in whom after treatment there were histological changes to the endometrium of the secretory type. Material for morphological and immunohistochemical studies was obtained by scraping the uterine cavity. The study of progesterone receptors (PRA and PR-B) was performed by immunohistochemistry in the laboratory of immunohistochemistry DDMA. All patients received treatment with micronized progesterone at a dose of 400 mg / day continuously for 6 months. To determine the effect of progestin use, a control study was performed by scraping the uterine cavity after 6 months and the effectiveness of treatment was determined by histological changes of the endometrium.Research results. The treatment showed that 74% of women had histological normalization of the ratio of stromal and epithelial component, 18.7% were diagnosed with simple atypical endometrial hyperplasia (PNGE). Complex atypical endometrial hyperplasia (CNGE) was diagnosed in 7.3% of women. Prior to treatment, low PR-A expression in the endometrial glands (P = 0.013) and stroma (P 1 ratio (19%; P <0.001). According to a study of women with no effect from the therapy, in contrast to women with effective therapy, there was a decrease in the expression of progesterone receptors by 65%, which has a statistically significant relationship with recurrence of endometrial hyperplasia. Conclusions. Treatment of endometrial hyperplasia without atypia with progesterone drugs will be 74% ineffective with low expression of progesterone receptors in endometrial cells. immunohistochemical expression of PR-A and PR-B and their ratio in the stroma and glands during endometrial biopsy before progestin therapy is a valuable prognostic factor for recurrence of endometrial hyperplasia. Therefore, when deciding on the appointment of progestins for the treatment of endometrial hyperplasia without atypia, it is recommended to study the expression of receptors in the endometrium.

Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women’s Health Initiative Randomized Clinical Trials

The influence of menopausal hormone therapy on breast cancer remains unsettled with discordant findings from observational studies and randomized clinical trials. To assess the association of prior randomized use of estrogen plus progestin or prior randomized use of estrogen alone with breast cancer incidence and mortality in the Women's Health Initiative clinical trials. Long-term follow-up of 2 placebo-controlled randomized clinical trials that involved 27 347 postmenopausal women aged 50 through 79 years with no prior breast cancer and negative baseline screening mammogram. Women were enrolled at 40 US centers from 1993 to 1998 with follow-up through December 31, 2017. In the trial involving 16 608 women with a uterus, 8506 were randomized to receive 0.625 mg/d of conjugated equine estrogen (CEE) plus 2.5 mg/d of medroxyprogesterone acetate (MPA) and 8102, placebo. In the trial involving 10 739 women with prior hysterectomy, 5310 were randomized to receive 0.625 mg/d of CEE alone and 5429, placebo. The CEE-plus-MPA trial was stopped in 2002 after 5.6 years' median intervention duration, and the CEE-only trial was stopped in 2004 after 7.2 years' median intervention duration. The primary outcome was breast cancer incidence (protocol prespecified primary monitoring outcome for harm) and secondary outcomes were deaths from breast cancer and deaths after breast cancer. Among 27 347 postmenopausal women who were randomized in both trials (baseline mean [SD] age, 63.4 years [7.2 years]), after more than 20 years of median cumulative follow-up, mortality information was available for more than 98%. CEE alone compared with placebo among 10 739 women with a prior hysterectomy was associated with statistically significantly lower breast cancer incidence with 238 cases (annualized rate, 0.30%) vs 296 cases (annualized rate, 0.37%; hazard ratio [HR], 0.78; 95% CI, 0.65-0.93; P = .005) and was associated with statistically significantly lower breast cancer mortality with 30 deaths (annualized mortality rate, 0.031%) vs 46 deaths (annualized mortality rate, 0.046%; HR, 0.60; 95% CI, 0.37-0.97; P = .04). In contrast, CEE plus MPA compared with placebo among 16 608 women with a uterus was associated with statistically significantly higher breast cancer incidence with 584 cases (annualized rate, 0.45%) vs 447 cases (annualized rate, 0.36%; HR, 1.28; 95% CI, 1.13-1.45; P < .001) and no significant difference in breast cancer mortality with 71 deaths (annualized mortality rate, 0.045%) vs 53 deaths (annualized mortality rate, 0.035%; HR, 1.35; 95% CI, 0.94-1.95; P= .11). In this long-term follow-up study of 2 randomized trials, prior randomized use of CEE alone, compared with placebo, among women who had a previous hysterectomy, was significantly associated with lower breast cancer incidence and lower breast cancer mortality, whereas prior randomized use of CEE plus MPA, compared with placebo, among women who had an intact uterus, was significantly associated with a higher breast cancer incidence but no significant difference in breast cancer mortality.

Postoperative hormonal treatment for prevention of endometrioma recurrence after ovarian cystectomy: a systematic review and network meta-analysis.

BackgroundThe efficacy of hormonal regimens for the prevention of endometrioma recurrence in women who have undergone conservative surgery is still controversial.ObjectiveTo compare the efficacy of different hormonal regimens in this context and to rank them.Search strategyMEDLINE and Scopus databases were searched through January 2020.Selection criteriaRandomised controlled trials (RCTs) or cohorts, comparing the effect of any pair of interventions (i.e. cyclic oral contraceptives [OC], continuous OC, gonadotropin‐releasing hormone agonist [GnRHa], dienogest [DNG], levonorgestrel‐releasing intrauterine system [LNG‐IUS] and expectant management) on endometrioma recurrence were selected.Data collection and analysisData were independently extracted by two reviewers. Relative treatment effects were estimated using network meta‐analysis (NMA) and ranked in descending order.Main resultsSix RCTs (675 patients) and 16 cohorts (3089 patients) were included. NMA of the RCTs involving expectant management, cyclic OC, continuous OC, GnRHa and GnRHa + LNG‐IUS, showed that all hormonal regimens had a nonsignificant lower risk of endometrioma recurrence compared with expectant management. NMA of the cohorts involving expectant, cyclic OC, continuous OC, GnRHa, DNG, LNG‐IUS, GnRHa + OC, and GnRHa + LNG‐IUS indicated that LNG‐IUS, DNG, continuous OC, GnRHa + OC and cyclic OC had a significantly lower risk of endometrioma recurrence than expectant management. LNG‐IUS was ranked highest, followed by DNG and GnRHa + LNG‐IUS. Long‐term use of hormonal treatment either OC or progestin had a significantly lower risk of endometrioma recurrence than expectant treatment.ConclusionIn the NMA of RCTs, there was no evidence supporting hormonal treatment for postoperative prevention of endometrioma recurrence. This was at odds with the cohort evidence, which found the protective effect of OC and progestin regimens, especially long‐term treatment. Large‐scale RCTs of these agents are still required.Tweetable abstractHormonal regimens given as long‐term treatment tend to reduce risk of endometrioma recurrence after conservative surgery.

Fertility-sparing treatment in early endometrial cancer: current state and future strategies.

Endometrial cancer (EC) is the fifth most common cancer in women worldwide. Global estimates show rising incidence rates in both developed and developing countries. Most women are diagnosed postmenopausal, but 14–25% of patients are premenopausal and 5% are under 40 years of age. Established risk factors include age and hyperestrogenic status associated with nulliparity, obesity, and metabolic syndrome. Standard treatment for EC, which involves total hysterectomy and bilateral salpingo-oophorectomy, has excellent survival outcomes, particularly for low-grade endometrioid tumors. However, it leads to permanent loss of fertility among women who wish to preserve their reproductive potential. With current trends of reproductive-age women delaying childbearing, rising EC incidence rates, and a growing epidemic of obesity, particularly in developed countries, research on conservative non-surgical treatment approaches remains a top priority. Fertility-sparing treatment predominantly involves the use of oral progestins and levonorgestrel-releasing intrauterine devices, which have been shown to be feasible and safe in women with early stage EC and minimal or no myometrial invasion. However, data on the efficacy and safety of conservative management strategies are primarily based on retrospective studies. Randomized clinical trials in younger women and high-risk obese patients are currently underway. Here, we have presented a comprehensive review of the current literature on conservative, fertility-sparing approaches, defining the optimal candidates and evaluating tumor characteristics, reproductive and oncologic outcomes, and ongoing clinical trials. We have also summarized current guidelines and recommendations based on the published literature.