Increased cardiovascular and metabolic morbidity in patients with 21-hydroxylase deficiency : a Swedish population-based national cohort study

CONTEXT: Congenital adrenal hyperplasia (CAH) is lethal in its most severe forms if not treated with glucocorticoids. However, glucocorticoids may increase the risk of cardiovascular and metabolic morbidity. OBJECTIVE: This study aimed to study cardiovascular and metabolic morbidity in CAH. DESIGN, SETTING, AND PARTICIPANTS: Patients with CAH due to 21-hydroxylase deficiency (n = 588; >80% with known CYP21A2 mutations) were compared with controls matched for sex, year, and place of birth (n = 58 800). Data were obtained by linking national population-based registers. Subgroup analyses were performed regarding sex, clinical severity (salt wasting, simple virilizing, nonclassic), CYP21A2 genotype (null, I2 splice, I172N, P30L), and stratified by the introduction of neonatal screening, age groups, and nonobesity. MAIN OUTCOME MEASURES: To study cardiovascular and metabolic morbidity in CAH. RESULTS: In CAH, both any cardiovascular and metabolic disorders (OR [odds ratio], 3.9; 95% CI [confidence interval], 3.1-5.0), and cardiovascular disease (OR, 2.7; 95% CI, 1.9-3.9) were increased. Separate analyses of the individual diseases showed higher frequencies in CAH of hypertension, hyperlipidemia, atrial fibrillation, venous thromboembolism, obesity, diabetes (mainly type 2), obstructive sleep disorder, thyrotoxicosis, and hypothyroidism. Similar results were seen in the stratified groups. On the subgroup level, females were generally more affected (especially I172N and the nonclassic group), as were males with the null genotype. CONCLUSIONS: CAH was associated with excess cardiovascular and metabolic morbidity but the mechanism is not certain as the glucocorticoids were not assessed. Hypothyroidism and obesity may be an effect of close observation. However, more severe conditions were presumably detected equally in patients and controls. Screening for diabetes and other metabolic disorders that increase cardiovascular risk is important.Magn. Bergvalls FoundationKarolinska InstitutetStockholm County CouncilSwedish Research Council through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences, SIMSAM 340-2013-5867Manuscrip

A Phase II Prospective, Randomized, Double‐Blind , Placebo‐Controlled and Multicenter Clinical Trial to Assess the Safety of 0.005% Estriol Vaginal Gel in Hormone Receptor–Positive Postmenopausal Women With Early Stage Breast Cancer in Treatment With Aromatase Inhibitor in the Adjuvant Setting

Lessons learned: The levels of circulating follicle-stimulating hormone, luteinizing hormone, estriol, estradiol, and estrone remained unchanged after a 12-week treatment with 0.005% estriol vaginal gel in postmenopausal women receiving nonsteroidal aromatase inhibitors for hormone receptor-positive early breast cancer. These results support the safety of 0.005% estriol vaginal gel for the treatment of bothering symptoms of vulvovaginal atrophy in breast cancer survivors. The results provide clinicians with confidence in the use of this product in women who do not experience symptom relief with nonhormonal remedies. Background: Symptoms of vulvovaginal atrophy associated with treatment with nonsteroidal aromatase inhibitors (NSAIs) negatively impact patients' quality of life and may affect adherence to NSAIs. Vaginal estrogens effectively improve these symptoms, although their safe use in breast cancer survivors remains unclear. Methods: Postmenopausal women with hormone receptor-positive early breast cancer receiving NSAI and moderate-to-severe vaginal dryness were randomized to 0.005% estriol vaginal gel or placebo for 12 weeks. Circulating estrogens, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), were analyzed at baseline and at weeks 1, 3, 8, and 12. The primary safety outcome was the variation in serum FSH from baseline to week 12. Results: Sixty-one women (mean age, 59 years) enrolled in the study. Small oscillations were observed in FSH and LH, although they were always maintained within the postmenopausal range. No significant differences were found in the variation of FSH and LH between baseline and week 12 from the physiological variation observed before treatment. Women receiving 0.005% estriol vaginal gel had slightly increased estriol levels at weeks 1 and 3, with a subsequent reduction until normalizing at week 12; estradiol and estrone remained the below limit-of-quantitation in almost all samples. Conclusion: Ultralow-dose 0.005% estriol vaginal gel did not significantly influence estrogens, FSH, and LH levels in women with breast cancer receiving NSAI. A transient negligible absorption of estriol and a nonsignificant variation of FSH after 12 weeks were observed. These findings provide confidence for the safe use of 0.005% estriol vaginal gel in women with breast cancer with an indication for treatment with vaginal estrogens

Suboptimal psychosocial outcomes in patients with congenital adrenal hyperplasia : epidemiological studies in a nonbiased national cohort in Sweden

Context: Congenital adrenal hyperplasia (CAH), CYP21A2 deficiency, results in cortisol and aldosterone deficiency and increased production of androgens, with a good genotype phenotype correlation. Objective: To study psychosocial outcomes in relation to clinical severity, CYP21A2 genotype, in men and women. Design: An epidemiological study with a matched cohort control design. Setting: All known CAH patients in Sweden. Participants: 588 patients, >95% with known severity of CAH; 100 controls per patient matched for sex, year and place of birth. Main outcome and measures: Proxies for quality of life were selected: level of education, employment, income, sick-leave, disability pension, marriage and children. Results: Women with salt-wasting (SW) CAH had completed primary education less often (OR 0.3), not explained by neonatal salt-crisis or hypoglycemia since the men did not differ from controls. Men and women in the less severe I172N genotype group were more likely to have an academic education (OR 1.8) SW women were more likely to have an income in the top 20 percentile (OR 2.0 ). Both men and women had more disability pension (OR 1.5) and sick leave (OR 1.7). The men more often had long lasting employment (OR 3.1). Men were more often (OR 1.6) while women were less often married (OR 0.7). Patients had children less often (OR 0.3). Conclusions: This study shows important outcome differences regarding education, employment, marriage and fertility depending on sex and severity of CAH. The mechanisms behind this and the increased risk for sick leave or disability pension in both men and women should be identified to improve medical and psychological care.The Swedish Research CouncilAccepte

Offered Support and Knowledge about the Menstrual Cycle in the Athletic Community: A Cross-Sectional Study of 1086 Female Athletes

Many female athletes perceive that symptoms related to the menstrual cycle such as dysmenorrhea, premenstrual symptoms, amenorrhea or side-effects of hormonal contraceptives negatively impact their training, performance, and general well-being. Knowledge and communication about female athletes’ health is therefore important in the sport community. The aims of this study were to explore the level of knowledge and communication about menstrual cycle issues and use of hormonal contraceptives in the athletic community and to describe the kinds of medical support offered to female athletes. A total of 1086 Swedish and Norwegian athletes from 57 different sports responded to a web-based questionnaire. Of these, 58% (n = 627) practiced team sports and 42% (n = 459) individual sports. Twenty-six percent (n = 278) of the athletes perceived their knowledge about female athlete health to be poor/very poor and the knowledge was most often acquired from medical staff. Fifty-three percent (n = 572) of the athletes perceived the knowledge acquired of their coaches as poor/very poor, even though a significantly (p < 0.001) higher proportion of athletes with a female coach (30%, n = 31) rated their coach’s knowledge as very good/good, compared to athletes with a male coach (5%, n = 31). Only 11% (n = 116) of the athletes discussed female health issues with their coach. The majority (81%, n = 842) of the athletes partly to strongly agreed that female athlete health is considered a taboo topic in the athletic community. Forty-seven percent (n = 510) of the athletes had access to a physiotherapist, while only three percent (n = 29) had access to a gynecologist. Low perceived knowledge, lack of communication and support demonstrate the need for a multi-professional medical team and enhanced educational efforts focused on female athlete health in the athletic community

Perceived impact of the menstrual cycle and hormonal contraceptives on physical exercise and performance in 1,086 athletes from 57 sports

Female athletes train and compete under the potential influence of hormonal fluctuations during the menstrual cycle or during use of various hormonal contraceptives. Dysmenorrhea and premenstrual symptoms are common in the general population, as well as side effects of hormonal contraceptives. More detailed knowledge concerning prevalence and perceived impact of these symptoms on training and performance in different sports is required. The aim of the study was to 1) characterize perceptions of training and performance during the menstrual cycle phases and by hormonal contraceptive use in a large population of female athletes; 2) explore whether symptoms experienced are related to perceived performance; and 3) examine potential differences in these factors between athletes at different levels of performance. The study was based on self-reported data from 1,086 athletes from 57 sports at different performance levels via a web-based questionnaire. Thirty-seven percent (n = 407) of the athletes did not use hormonal contraceptives. In this group, menstrual cycle related symptoms were common across all athlete levels, particularly dysmenorrhea (74%, n = 300) and premenstrual symptoms (78%, n = 318), which also influenced perceived performance of aerobic fitness, muscle strength, mental sharpness, balance, and sleep quality. Sixty-three percent (n = 679) of the athletes used various hormonal contraceptives and 40% (n = 272) perceived a variety of side-effects. Physical performance was experienced equally independent of time-point of the pill-chart except for the period of inactive pills, which was associated with more negative impact. Nonetheless, only 18% (n = 191) of the athletes considered menstrual cycle or hormonal contraceptive issues when planning their training or competitions. These results indicate that greater focus is needed to identify and effectively treat different menstrual cycle and hormonal contraceptive related symptoms on an individual level

Women with polycystic ovary syndrome present with altered endometrial expression of stanniocalcin-1

Stanniocalcin-1 (STC-1) is a pro-survival factor that protects tissues against stressors, such as hypoxia and inflammation. STC-1 is co-expressed with the endometrial receptivity markers, and recently endometrial STC-1 was reported to be dysregulated in endometriosis, a condition linked with endometrial progesterone resistance and inflammation. These features are also common in the endometrium in women with polycystic ovary syndrome (PCOS), the most common endocrine disorder in women. Given that women with PCOS present with subfertility, pregnancy complications, and increased risk for endometrial cancer, we investigated endometrial STC-1 expression in affected women. Endometrial biopsy samples were obtained from women with PCOS and controls, including samples from overweight/obese women with PCOS before and after a 3-month lifestyle intervention. A total of 98 PCOS and 85 control samples were used in immunohistochemistry, reverse-transcription polymerase chain reaction, or in vitro cell culture. STC-1 expression was analyzed at different cycle phases and in endometrial stromal cells (eSCs) after steroid hormone exposure. The eSCs were also challenged with 8-bromo-cAMP and hypoxia for STC-1 expression. The findings indicate that STC-1 expression is not steroid hormone mediated although secretory-phase STC-1 expression was blunted in PCOS. Lower expression seems to be related to attenuated STC-1 response to stressors in PCOS eSCs, shown as downregulation of protein kinase A activity. The 3-month lifestyle intervention did not restore STC-1 expression in PCOS endometrium. More studies are warranted to further elucidate the mechanisms behind the altered endometrial STC-1 expression and rescue mechanism in the PCOS endometrium. Summary sentence Endometrial expression of STC-1 in the secretory phase is blunted in women with PCOS, suggesting impaired protection against stress.Peer reviewe

Normo- and hyperandrogenic women with polycystic ovary syndrome exhibit an adverse metabolic profile through life

Objective: To compare the metabolic profiles of normo- and hyperandrogenic women with polycystic ovary syndrome (PCOS) with those of control women at different ages during reproductive life. Design: Case-control study. Setting: Not applicable. Patient(s): In all, 1,550 women with normoandrogenic (n = 686) or hyperandrogenic (n = 842) PCOS and 447 control women were divided into three age groups: 39 years). Interventions(s): None. Main Outcome Measure(s): Body mass index (BMI), waist circumference, blood pressure, glucose, insulin, cholesterol, lipoproteins, triglycerides and high-sensitivity C-reactive protein. Result(s): Both normo- and hyperandrogenic women with PCOS were more obese, especially abdominally. They had increased serum levels of insulin (fasting and in oral glucose tolerance tests), triglycerides, low-density lipoprotein, and total cholesterol, higher blood pressure, and lower high-density lipoprotein levels independently from BMI compared with the control population as early as from young adulthood until menopause. The prevalence of metabolic syndrome was two-to fivefold higher in women with PCOS compared with control women, depending on age and phenotype, and the highest prevalence was observed in hyperandrogenic women with PCOS at late reproductive age. Conclusion(s): When evaluating metabolic risks in women with PCOS, androgenic status, especially abdominal obesity and age, should be taken into account, which would allow tailored management of the syndrome from early adulthood on. (C) 2016 by American Society for Reproductive Medicine.Peer reviewe

Higher blood pressure in normal weight women with PCOS compared to controls

Objective: Obesity is considered to be the strongest predictive factor for cardio-metabolic risk in women with polycystic ovary syndrome (PCOS). The aim of the study was to compare blood pressure (BP) in normal weight women with PCOS and controls matched for age and BMI. Methods: From a Nordic cross-sectional base of 2615 individuals of Nordic ethnicity, we studied a sub cohort of 793 normal weight women with BMI = 140/90 mmHg was 11.1% (57/ 512) in women with PCOS vs 1.8% (5/281) in controls, P = 35 years the prevalence of BP >= 140/90 mmHg was comparable in women with PCOS and controls (12.7% vs 9.8%, P = 0.6). Using multiple regression analyses, the strongest association with BP was found for age, waist circumference, and total cholesterol in women with PCOS. Conclusions: Normal weight women with PCOS have higher BP than controls. BP and metabolic screening are relevant also in young normal weight women with PCOS.Peer reviewe

Comparison of selected exercise training modalities in the management of PCOS: a systematic review and meta-analysis to inform evidence-based guidelines

Summary: Background: Polycystic ovary syndrome (PCOS) is a common endocrine condition in women of reproductive age that often presents with reproductive, metabolic, and psychological symptoms. While exercise is part of the management of PCOS, it is unclear which form of exercise may be most effective and for which outcomes. Aim: In order to inform the updated 2023 International evidence-based guideline for the assessment and management of polycystic ovary syndrome, this systematic review aimed to determine the exercise modality that provides the greatest improvement in anthropometric, metabolic, hormonal/reproductive, and psychological outcomes in adult women with PCOS. Methods: Five databases were searched from inception to July 2022. Studies eligible for inclusion consisted of those in a PCOS population, that compared two exercise modalities, and reported at least one anthropometric, metabolic, hormonal/reproductive, and/or psychological outcome. Screening, data extraction, and methodological quality assessments were conducted by two independent reviewers. Methodological quality assessment was performed using the Cochrane Risk of Bias tool and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines were used to determine the certainty of evidence. Meta-analysis was performed utilising Comprehensive Meta-Analysis software, Version 3. Results: Of the 4739 records identified, five unique studies were eligible for inclusion in the systematic review and meta-analysis, comprising a total of 216 individuals. Meta-analyses comparing high-intensity interval training (HIIT) to moderate-intensity continuous training (MICT) on anthropometric, metabolic, and hormonal/reproductive parameters found no statistically significant differences in outcomes between groups, and the certainty of evidence was graded as low or very low. Results from single studies showed that HIIT was more effective than MICT for menstrual regularity (odds ratio [95% confidence interval] ​= ​7.875 [1.105, 56.125], p ​= ​0.039, very low certainty). HIIT vs resistance training, and diet ​+ ​MICT vs diet ​+ ​MICT ​+ ​resistance training were examined by a single study each, and no statistically significant differences were found for any outcome, with the certainty of evidence ranked as very low. Conclusion: To date, there are insufficient RCTs comparing exercise modalities in individuals with PCOS to establish with certainty whether one form of exercise is superior to another for the management of PCOS