Hyperandrogenism, menstrual irregularities and polycystic ovary syndrome:impact on female reproductive and metabolic health from early adulthood until menopause

Abstract Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of women of reproductive age, affecting 5–18% of them. Menstrual irregularities, hyperandrogenemia and obesity are key features in PCOS and they are suggested to be the most important metabolic risks linked to PCOS, but their respective roles are still under debate. Anti-Müllerian hormone (AMH) is involved in sexual differentiation and follicle growth and its level is increased in women with PCOS. The aims of this project were to clarify the significance of menstrual irregularities, hyperandrogenemia and serum levels of AMH in adolescence as predictive factors of the syndrome and to investigate the respective roles of obesity and hyperandrogenism as metabolic risk factors in women with PCOS from adolescence to late adulthood. The study populations were the Northern Finland Birth Cohort 1986 (N=3373 women) and a Nordic population including 1553 women with PCOS and 448 controls. At the age of 16 years, women with menstrual irregularities were more hyperandrogenic compared with women with normal menstrual cycles. Serum AMH levels correlated positively with those of testosterone at this age. They were higher in adolescents with menstrual irregularities compared with those with regular cycles and in women with hirsutism or PCOS at the age of 26 years. However, AMH was not a good marker of metabolic abnormalities in adolescence or a reliable tool to predict PCOS in later life. Androgen levels were higher in women with PCOS throughout life compared with controls. The parameters that best predicted PCOS at all ages were the free androgen index, and androstenedione. Women with PCOS exhibited increased abdominal obesity, altered insulin metabolism, worse lipid profiles and higher blood pressure from early adulthood until menopause compared with controls. The highest prevalence of metabolic syndrome was detected in obese and hyperandrogenic women with PCOS. In conclusion, irregular menstrual cycles, identified by a simple question at adolescence, represent a good marker of hyperandrogenemia, later metabolic risks and development of PCOS. Due to the persistence of hyperandrogenism and metabolic alterations, the treatment of PCOS should be focused on prevention and treatment of these problems as early as in adolescence in order to decrease future morbidity.Tiivistelmä Monirakkulainen munasarjaoireyhtymä (polycystic ovary syndrome, PCOS) on lisääntymisikäisten naisten tavallisin (5-18%) hormonaalinen häiriö. Kuukautishäiriöt, mieshormoniylimäärä eli hyperandrogenismi ja lihavuus kuuluvat oireyhtymään oleellisesti ja niiden ajatellaan olevan tärkeimmät PCOS:aan liittyvät metaboliset riskitekijät, vaikkakin niiden tarkat roolit ovat epäselvät. Anti-Müllerian hormoni (AMH) vaikuttaa sukupuolen kehitykseen sikiöaikana sekä munarakkuloiden kypsymiseen hedelmällisessä iässä ja sen pitoisuus on suurentunut PCOS-naisilla. Tämän väitöskirjan tavoitteena oli selvittää kuukautishäiriöiden, hyperandrogenismin ja AMH-pitoisuuden ennustearvoa PCOS-oireyhtymälle, sekä arvioida lihavuuden ja hyperandrogenismin vaikutusta metabolisiin riskitekijöihin PCOS-naisilla läpi elämän. Tutkimusaineistoina olivat Pohjois-Suomen syntymäkohortti 1986 (N=3373 naista) sekä pohjoismaalainen yhteistyöaineisto, jossa oli 1553 PCOS-naista ja 448 kontrollia. 16-vuotiaiden kuukautishäiriöistä kärsivien naisten mieshormonipitoisuuksien todettiin olevan korkeammat kuin naisilla, joilla kuukautiskierto oli säännöllinen. AMH-tasot korreloituivat positiivisesti testosteronin kanssa 16-vuotiaana, ja pitoisuus oli koholla naisilla, joilla todettiin kuukautishäiriö. AMH-tasot 16-vuotiaana olivat myös korkeampia naisilla, joilla oli 26-vuotiaana PCOS tai hirsutismi. Kuitenkaan AMH-pitoisuus 16-vuotiaana ei korreloinut metabolisten riskitekijöiden kanssa eikä se ollut luotettava parametri ennustamaan PCOS:n kehittymistä. Mieshormonitasot olivat korkeammat PCOS-naisilla läpi elämän verrattuna kontrolleihin. Vapaan mieshormonin indeksit ja androstendioni olivat parhaat parametrit erottamaan PCOS-naiset kontrolleista. PCOS-naisilla todettiin olevan enemmän vyötärölihavuutta, huonompi veren rasvaprofiili ja korkeampi verenpaine varhaisaikuisuudesta menopaussiin saakka. Lihavilla hyperandrogeenisilla naisilla todettiin suurin metabolisen oireyhtymän esiintyvyys. Yksinkertaisella kysymyksellä selvitetyt kuukautishäiriöt nuoruusiässä todettiin olevan yhteydessä hyperandrogenismiin sekä myöhempiin metabolisiin riskeihin ja PCOS:n kehittymiseen. Jotta pystyttäisiin vähentämään myöhempää sairastavuutta ja kuolleisuutta PCOS-naisilla, oireyhtymän hoidon tulisi keskittyä ennaltaehkäisemään ja hoitamaan lihavuutta, hyperandrogenismia ja metabolisia riskejä jo varhaisaikuisuudessa

Climacteric status is associated with sexual dysfunction at the age of 46:a population-based study

Abstract Objectives: Increasing age and menopausal transition increase the risk of sexual dysfunction. Sexual dysfunction is common in women experiencing menopause before the age of 40 years, whereas evidence on sexual function in women experiencing menopause in their mid-40s is scarce. We aimed to investigate sexual function in 46-year-old women in relation to their menopausal status. Methods: This study cross-sectionally evaluated sexual function of women in a prospective population-based Northern Finland Birth Cohort 1966 (NFBC1966). A 46-year follow-up study of NFBC1966 included a broad questionnaire evaluating health, lifestyle, and life situation, as well as menstrual history and sexual function, and blood sampling analysis including follicle stimulating hormone and free androgen index (FAI). The participants were divided into two groups by their menopause status, defined by follicle-stimulating hormone and menstrual history. We performed logistic regression models in which parameters of sexual function were dependent factors and climacteric status, self-reported health, FAI, relationship status, smoking, and education level were independent variables. Results: The study population included 2,661 women. In regression models, more advanced climacteric status was associated with higher frequency and difficulty level of low sexual desire and vaginal dryness (odds ratios with 95% confidence intervals: 2.80 [2.12‐3.71], 3.22 [2.43‐4.27], 3.83 [2.82‐5.20], 3.75 [2.75‐5.12], respectively), lower frequency of sexual thoughts (1.34 [1.02‐1.75]), and higher frequency of problems with intercourse (2.35 [1.51‐3.66]). Lower FAI and poorer health were associated with impaired sexual function. Conclusions: The current study suggests that women experiencing menopausal transition in their mid-40s are at risk of impaired sexual function

Low testosterone at age 31 associates with maternal obesity and higher body mass index from childhood until age 46:a birth cohort study

Abstract Background: Low testosterone (T) levels in men associate with increased risks of obesity, type 2 diabetes, metabolic syndrome, and cardiovascular diseases. However, most studies are cross-sectional with follow-up-time < 10 years, and data on early growth are limited. Objective: To compare prenatal factors and body mass index (BMI) development from birth to age 46 in relation to low T at age 31. Materials and methods: Men with low T (T < 12.1 nmol/L, n = 132) and men with normal T at age 31 (n = 2561) were derived from the Northern Finland Birth Cohort 1966. Prenatal factors, longitudinal weight and height data from birth to age 14, and cross-sectional weight and height data at ages 31 and 46, and waist-hip-ratio (WHR) and T levels at age 31 were analyzed. Longitudinal modeling and timing of adiposity rebound (AR, second BMI rise at age 5–7 years) were calculated from fitted BMI curves. Results were adjusted for mother’s pre-pregnancy BMI and smoking status, birth weight for gestational age, alcohol consumption, education level, smoking status, and WHR at age 31. Results: Neither gestational age nor birth weight was associated with low T at age 31; however, maternal obesity during gestation was more prevalent among men with low T (9.8% vs. 3.5%, adjusted aOR: 2.43 [1.19−4.98]). Men with low T had earlier AR (5.28 vs. 5.82, aOR: 0.73 [0.56−0.94]) and higher BMI (p < 0.001) from AR onward until age 46. Men with both early AR and low T had the highest BMI from AR onward. Conclusions: In men, maternal obesity and early weight gain associate with lower T levels at age 31, independently of adulthood abdominal obesity. Given the well-known health risks related to obesity, and the rising prevalence of maternal obesity, the results of the present study emphasize the importance of preventing obesity that may also affect the later reproductive health of the offspring

Critical evaluation of deep neural networks for wrist fracture detection

Abstract Wrist Fracture is the most common type of fracture with a high incidence rate. Conventional radiography (i.e. X-ray imaging) is used for wrist fracture detection routinely, but occasionally fracture delineation poses issues and an additional confirmation by computed tomography (CT) is needed for diagnosis. Recent advances in the field of Deep Learning (DL), a subfield of Artificial Intelligence (AI), have shown that wrist fracture detection can be automated using Convolutional Neural Networks. However, previous studies did not pay close attention to the difficult cases which can only be confirmed via CT imaging. In this study, we have developed and analyzed a state-of-the-art DL-based pipeline for wrist (distal radius) fracture detection—DeepWrist, and evaluated it against one general population test set, and one challenging test set comprising only cases requiring confirmation by CT. Our results reveal that a typical state-of-the-art approach, such as DeepWrist, while having a near-perfect performance on the general independent test set, has a substantially lower performance on the challenging test set—average precision of 0.99 (0.99–0.99) versus 0.64 (0.46–0.83), respectively. Similarly, the area under the ROC curve was of 0.99 (0.98–0.99) versus 0.84 (0.72–0.93), respectively. Our findings highlight the importance of a meticulous analysis of DL-based models before clinical use, and unearth the need for more challenging settings for testing medical AI systems

Polycystic ovary syndrome and leukocyte telomere length:cross-sectional and longitudinal changes

Abstract Objective: Telomeres are DNA–protein complexes that protect chromosome ends from DNA damage and are surrogate biomarkers of cellular aging. Current evidence, almost entirely from cross-sectional observations, supports negative associations between leukocyte telomere length (LTL) and adverse lifestyle factors and cardiometabolic risk factors. Polycystic ovary syndrome (PCOS), the most common gynecological endocrine disorder, is associated with inflammation and oxidative stress, both factors associated with accelerated telomere attrition. We therefore hypothesized that LTL would be shorter and decrease more rapidly in women with PCOS in comparison to a control population. Design: This is a population-based cohort study comprising women of Northern Finland Birth Cohort 1966, with clinical examinations at ages 31 and 46. The sample included self-reported PCOS (age 31, n = 190; age 46, n = 207) and referent women (age 31, n = 1054; age 46, n = 1324) with data on LTL. Methods: The association between LTL and PCOS at ages 31 and 46 was analyzed by linear regression models adjusted for BMI, smoking, alcohol consumption and socioeconomic status at the corresponding age. Results: Women with PCOS had similar mean LTL at ages 31 and 46 (P > 0.4 for both). The mean LTL change between ages 31 and 46 did not differ between groups (P = 0.19). However, we observed a significant LTL attrition between ages 31 and 46 in the reference population (P < 0.001), but not in women with PCOS (P = 0.96). Conclusions: This finding may suggest a difference in the LTL attrition rate in women with PCOS, an unexpected finding that might affect their risk of age-related disease. Further research is needed to clarify the underlying mechanisms