Association of growth from birth until middle age with sex hormone parameters and reproductive function in the Northern Finland Birth cohort 1966

Abstract Obesity predisposes people to numerous morbidities and less well-known reproductive problems. In women, obesity increases the risk of infertility and polycystic ovary syndrome (PCOS). In men, obesity impairs reproductive health and is associated with testosterone (T) deficiency. Since the above-mentioned problems affect a significant proportion of the population, this study focuses on the association between early risk factors and reproductive problems, providing a great opportunity to identify the sensitive time periods for preventive actions. The aim of this study was to assess the impact of prenatal factors, birth weight (BW), and BMI, from birth until middle age, on sex hormone levels and reproductive function in both women and men. The study populations (women and men with impaired reproductive function, women with PCOS and men with low T at age 31) were derived from the Northern Finland Birth Cohort 1966 with additional data from the Finnish Medical Birth Register. Multiple confounding factors, such as socioeconomic and lifestyle factors, marital status, attempts to have children, and adult obesity, could be considered. The results revealed that in girls, obesity in mid-childhood and especially in puberty — and in boys, low BMI in early childhood — predicted impaired reproductive function, as well as an increased risk of childlessness regardless of confounding factors. In boys, overweight and obesity in early childhood was associated with a decreased risk of infertility, but BMI from mid-childhood onwards did not affect their subsequent reproductive function. Both women with PCOS and men with low T at age 31 already had higher weight gain from childhood onwards; their weight gain began earlier, and their BMIs remained higher until age 46. In boys, maternal obesity was associated significantly with later T deficiency, suggesting that metabolic factors during pregnancy affect boys’ endocrine function later in life. Lower BW and prematurity in girls were associated with PCOS later in life. Given the well-known health risks related to obesity and the steadily rising prevalence of maternal obesity, the study results emphasize the importance of preventing obesity, maintaining an optimal growth during childhood, and preventing maternal obesity, as all these factors affect reproductive health later in life.Tiivistelmä Lihavuus aiheuttaa monien sairauksien lisäksi myös merkittäviä lisääntymisterveyden ongelmia ja lisää riskiä lapsettomuudelle. Lihavuus lisää naisilla munasarjojen monirakkulaoireyhtymän (PCOS) ja miehillä mieshormonivajeen riskiä. Nämä ongelmat koskettavat merkittävää osaa väestöstä. Tämä tutkimus antaa mahdollisuuden tunnistaa varhaisten riskitekijöiden yhteyksiä lisääntymisterveyden ongelmiin ja siten löytää keinoja oikea-aikaisiin ennaltaehkäiseviin toimiin. Tässä tutkimuksessa arvioitiin raskauden aikaisten tekijöiden, syntymäpainon ja painoindeksin (BMI) kehityksen vaikutusta hormonaalisiin muuttujiin ja lisääntymisterveyteen sekä naisilla että miehillä keski-ikään saakka. Tutkimuspopulaatiot (lapsettomuudesta kärsivät naiset ja miehet, PCOS-naiset sekä miehet, joilla todettiin mieshormonivaje 31-vuotiaana) koostuivat Pohjois-Suomen syntymäkohortista 1966, johon yhdistettiin Terveyden ja hyvinvoinninlaitoksen syntymärekisterin tietoja. Tutkimusaineisto mahdollisti useiden sekoittavien tekijöiden, kuten sosioekonomisen aseman, elintapojen, siviilisäädyn, lapsitoiveen ja aikuisiän lihavuuden, huomioimisen analyyseissa. Tutkimuksessa havaittiin, että keskilapsuuden ja murrosiän lihavuus tytöillä ja varhaislapsuuden matala BMI pojilla olivat yhteydessä lapsettomuusongelmiin ja riskiin jäädä myöhemmin lapsettomaksi siviilisäädystä riippumatta. Toisaalta poikien ylipaino ja lihavuus varhaislapsuudessa, mutta ei enää sen jälkeen, vähensivät lapsettomuusongelmien riskiä. Sekä PCOS-naisilla että 31-vuotiaana mieshormonivajeesta kärsivillä miehillä todettiin suurempi painon kertyminen jo varhaislapsuudessa, ja BMI pysyi korkeampana kuin kontrolleilla aina keski-ikään saakka. Pojilla äidin lihavuus liittyi merkittävästi itsenäisenä riskitekijänä myöhempään mieshormonivajeeseen viitaten siihen, että raskauden aikaiset aineenvaihdunnalliset tekijät vaikuttavat merkittävästi myöhempään hormonaalisen toimintaan. Tytöillä matalampi syntymäpaino ja ennenaikaisuus lisäsivät riskiä PCOS:lle. Tämän tutkimuksen tulokset korostavat synnyttäjien ylipainon ja lapsuusiän lihavuuden ehkäisemisen sekä optimaalisen kasvun tukemisen tärkeyttä, varsinkin kun otetaan huomioon lihavuuteen liittyvät muut terveysriskit ja synnyttäjien ylipainon jatkuva lisääntyminen, koska nämä kaikki vaikuttavat myöhempään lisääntymisterveyteen

Laparoscopically guided transversus abdominis plane block versus local wound analgesia in laparoscopic surgery for peritoneal endometriosis:study protocol for a prospective randomized controlled double-blinded LTAP-trial

Abstract Background: Ultrasound-guided transversus abdominis plane block (TAP) performed by anesthesiologist has been shown to be an effective and safe analgesia method in abdominal surgery, reducing postoperative opioid consumption. Recently, there has been growing interest to insert TAP under laparoscopic vision (LTAP) by surgeon. LTAP has been used in laparoscopic gastrointestinal surgery, but studies on LTAP in gynecologic laparoscopic surgery are sparse and inconsistent. The purpose of this study is to compare the efficacy of LTAP and local wound analgesia in laparoscopic surgery due to suspected or diagnosed superficial peritoneal endometriosis. Methods: The LTAP-trial is a prospective randomized controlled double-blinded study comparing the efficacy and safety of LTAP with local wound analgesia in laparoscopic endometriosis surgery. Patients are randomized to receive LTAP with levobupivacaine and wound infiltration with placebo or wound infiltration with levobupivacaine and LTAP with placebo. The primary outcome is postoperative opioid consumption measured by patient-controlled analgesia (PCA) pump. Secondly, subjective postoperative pain up to 24 h postoperatively will be measured by Numeric Rating Scale (NRS). Additional outcome measures are factors related to recovery and length of stay in the hospital as well as a 6-month follow-up survey regarding pain (NRS) and endometriosis-related wellbeing (endometriosis-related health profile, EHP-30) after surgery. A total of 46 patients will be randomized in a proportion of 1:1. Discussion: Patients with peritoneal endometriosis are often prone to severe postoperative pain that may prohibit their enhanced recovery after laparoscopy. Thus, there is a need for effective postoperative pain management with minimal side-effects. This study focusing on laparoscopically inserted transversus abdominis plane block may provide new insight in dealing with postoperative pain after laparoscopic endometriosis surgery as well as after other gynecologic surgery

Obesity represses CYP2R1, the vitamin D 25‐hydroxylase, in the liver and extrahepatic tissues

Abstract Low plasma level of 25‐hydroxyvitamin D (25‐OH‐D), namely vitamin D deficiency, is associated with obesity and weight loss improves 25‐OH‐D status. However, the mechanism behind obesity‐induced vitamin D deficiency remains unclear. Here, we report that obesity suppresses the expression of cytochrome P450 (CYP) 2R1, the main vitamin D 25‐hydroxylase, in both mice and humans. In humans, weight loss induced by gastric bypass surgery increased the expression of CYP2R1 in the s.c. adipose tissue suggesting recovery after the obesity‐induced suppression. At the same time, CYP27B1, the vitamin D 1α‐hydroxylase, was repressed by the weight loss. In a mouse (C57BL/6N) model of diet‐induced obesity, the plasma 25‐OH‐D was decreased. In accordance, the CYP2R1 expression was strongly repressed in the liver. Moreover, obesity repressed the expression of CYP2R1 in several extrahepatic tissues, the kidney, brown adipose tissue, and testis, but not in the white adipose tissue. Obesity had a similar effect in both male and female mice. In mice, obesity repressed expression of the vitamin D receptor in brown adipose tissue. Obesity also upregulated the expression of the vitamin D receptor and CYP24A1 in the s.c. adipose tissue of a subset of mice; however, no effect was observed in the human s.c. adipose tissue. In summary, we show that obesity affects CYP2R1 expression both in the mouse and human tissues. We suggest that in mouse the CYP2R1 repression in the liver plays an important role in obesity‐induced vitamin D deficiency. Currently, it is unclear whether the CYP2R1 downregulation in extrahepatic tissues could contribute to the obesity‐induced low plasma 25‐OH‐D, however, this phenomenon may affect at least the local 25‐OH‐D concentrations

Long-term results of a prospective randomized trial comparing tension-free vaginal tape versus transobturator tape in stress urinary incontinence

Abstract Introduction and hypothesis: This study was aimed at investigating the long-term effectiveness of minimally invasive mid-urethral sling (MUS) surgery and at comparing the outcomes between retropubic (tension-free vaginal tape, TVT) and transobturator tape (TOT) methods in the treatment of stress urinary incontinence (SUI) and mixed urinary incontinence (MUI) with a predominant stress component in a long-term follow-up of a randomized controlled trial. Methods: This work is a long-term follow-up study of a previous prospective randomized trial conducted in the Department of Obstetrics and Gynecology at Oulu University Hospital between January 2004 and November 2006. The original 100 patients were randomized into the TVT (n=50) or TOT (n=50) group. The median follow-up time was 16 years, and the subjective outcomes were evaluated using internationally standardized and validated questionnaires. Results: Long-term follow-up data were obtained from 34 TVT patients and 38 TOT patients. At 16 years after MUS surgery, the UISS significantly decreased from a preoperative score in the TVT (11.88 vs 5.00, p<0.001) and TOT (11.05 vs 4.95, p<0.001) groups, showing a good long-term success of the MUS surgery in both groups. In comparing the TVT and TOT procedures, the subjective cure rates did not differ significantly between the study groups in long-term follow-up according to validated questionnaires. Conclusion: Midurethral sling surgery had good long-term outcomes in the treatment of SUI and MUI with a predominant stress component. The subjective outcomes of the TVT and TOT procedures were similar after a 16-year follow-up

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

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

Abstract 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. SCT-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-Br-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

IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 4: Prediction accuracy and software comparisons with improved data and modelling strategies

Oral drug absorption is a complex process depending on many factors, including the physicochemical properties of the drug, formulation characteristics and their interplay with gastrointestinal physiology and biology. Physiological-based pharmacokinetic (PBPK) models integrate all available information on gastro-intestinal system with drug and formulation data to predict oral drug absorption. The latter together with in vitro-in vivo extrapolation and other preclinical data on drug disposition can be used to predict plasma concentration-time profiles in silico. Despite recent successes of PBPK in many areas of drug development, an improvement in their utility for evaluating oral absorption is much needed. Current status of predictive performance, within the confinement of commonly available in vitro data on drugs and formulations alongside systems information, were tested using 3 PBPK software packages (GI-Sim (ver.4.1), Simcyp® Simulator (ver.15.0.86.0), and GastroPlusTM (ver.9.0.00xx)). This was part of the Innovative Medicines Initiative (IMI) Oral Biopharmaceutics Tools (OrBiTo) project. Fifty eight active pharmaceutical ingredients (APIs) were qualified from the OrBiTo database to be part of the investigation based on a priori set criteria on availability of minimum necessary information to allow modelling exercise. The set entailed over 200 human clinical studies with over 700 study arms. These were simulated using input parameters which had been harmonised by a panel of experts across different software packages prior to conduct of any simulation. Overall prediction performance and software packages comparison were evaluated based on performance indicators (Fold error (FE), Average fold error (AFE) and absolute average fold error (AAFE)) of pharmacokinetic (PK) parameters. On average, PK parameters (Area Under the Concentration-time curve (AUC0-tlast), Maximal concentration (Cmax), half-life (t1/2)) were predicted with AFE values between 1.11 and 1.97. Variability in FEs of these PK parameters was relatively high with AAFE values ranging from 2.08 to 2.74. Around half of the simulations were within the 2-fold error for AUC0-tlast and around 90% of the simulations were within 10-fold error for AUC0-tlast. Oral bioavailability (Foral) predictions, which were limited to 19 APIs having intravenous (i.v.) human data, showed AFE and AAFE of values 1.37 and 1.75 respectively. Across different APIs, AFE of AUC0-tlast predictions were between 0.22 and 22.76 with 70% of the APIs showing an AFE &gt; 1. When compared across different formulations and routes of administration, AUC0-tlast for oral controlled release and i.v. administration were better predicted than that for oral immediate release formulations. Average predictive performance did not clearly differ between software packages but some APIs showed a high level of variability in predictive performance across different software packages. This variability could be related to several factors such as compound specific properties, the quality and availability of information, and errors in scaling from in vitro and preclinical in vivo data to human in vivo behaviour which will be explored further. Results were compared with previous similar exercise when the input data selection was carried by the modeller rather than a panel of experts on each in vitro test. Overall, average predictive performance was increased as reflected in smaller AAFE value of 2.8 as compared to AAFE value of 3.8 in case of previous exercise.QC 20200930</p