Effects of different insulin sensitisers in the management of polycystic ovary syndrome: A systematic review and meta-analysis.

OBJECTIVE: Characteristic features of polycystic ovary syndrome (PCOS) include insulin resistance and an increased risk for type 2 diabetes. To promote improved insulin sensitivity, insulin sensitisers have been used in PCOS. However, direct comparisons across these agents are limited. This study compared the effects of metformin, rosiglitazone and pioglitazone in the management of PCOS to inform the 2023 International Evidence-based PCOS Guideline. DESIGN: Systematic review and meta-analysis of the literature. PATIENTS: Women with PCOS and treatment with insulin sensitisers. MEASUREMENTS: Hormonal and clinical outcomes, as well as side effects. RESULTS: Of 1660 publications identified, 13 randomised controlled trials were included. Metformin was superior in lowering weight (mean difference [MD]: -4.39, 95% confidence interval [CI]: -7.69 to -1.08 kg), body mass index (MD: -0.95, 95% CI: -1.41 to -0.49 kg/m2 ) and testosterone (MD: -0.10, 95% CI: -0.18 to -0.03 nmol/L) versus rosiglitazone, whereas there was no difference when comparing metformin to pioglitazone. Adding rosiglitazone or pioglitazone to metformin did not improve metabolic outcomes. However, rosiglitazone seemed superior to metformin in lowering lipid concentrations. CONCLUSIONS: Metformin should remain the first-line insulin sensitising treatment in adults with PCOS for the prevention and management of weight and metabolic features. The addition of thiazolidinediones appears to offer little benefit.

Dapagliflozin pharmacokinetics is similar between patients with heart failure with reduced ejection fraction and patients with type 2 diabetes mellitus.

Dapagliflozin was recently approved for use in adults with chronic heart failure with reduced ejection fraction (HFrEF) with/without type 2 diabetes mellitus (T2DM). The objectives of this analysis were to characterize dapagliflozin pharmacokinetics in patients with HFrEF and to compare dapagliflozin systemic exposure between adults with HFrEF with/without T2DM and adults with T2DM. A nonlinear mixed-effects modelling approach was applied; the population-pharmacokinetic model was developed using 9735 dapagliflozin plasma concentrations from 2744 patients. The final two-compartmental model adequately described the observed dapagliflozin concentrations, with a similar estimated apparent clearance compared with a previous estimate in patients with T2DM without HF and in healthy subjects (23.0 [95% CI: 22.6-23.9] L/h vs. 22.9 [95% CI: 22.1-23.7] L/h). The model-predicted median area under the dapagliflozin concentration-time profile was ≤1.2-fold higher in patients with HFrEF vs. those with T2DM without HFrEF, which is not considered clinically relevant. Dapagliflozin exposure was similar between patients with HFrEF with/without T2DM and T2DM patients without HFrEF.

International evidence-based guideline on assessment and management of PCOS-A Nordic perspective.

Polycystic ovary syndrome (PCOS) affects about 12% of women of reproductive age. In 2018, the first evidence-based guideline on assessment and management of PCOS was published, and an updated extended guideline was released in August 2023. These guidelines followed best practice and are endorsed by 39 organizations worldwide, making them the most robust source of evidence to guide clinical practice. In the 2023 guideline, diagnostic criteria have been further refined as polycystic ovary morphology can now be assessed with gynecological ultrasound or elevated anti-Müllerian hormone levels. A healthy lifestyle should be at the focus of care for all women with PCOS; however, with no specific diet or physical exercise recommended. The latest evidence on medical treatments and fertility management are reviewed, including special considerations regarding long-term follow-up of metabolic and psychiatric comorbidities and pregnancy in women with PCOS. Here we summarize the recommendations from a Nordic perspective.

A quantitative modeling framework to understand the physiology of the hypothalamic-pituitary-adrenal axis and interaction with cortisol replacement therapy.

Congenital adrenal hyperplasia (CAH) is characterized by impaired adrenal cortisol production. Hydrocortisone (synthetic cortisol) is the drug-of-choice for cortisol replacement therapy, aiming to mimic physiological cortisol circadian rhythm. The hypothalamic-pituitary-adrenal (HPA) axis controls cortisol production through the pituitary adrenocorticotropic hormone (ACTH) and feedback mechanisms. The aim of this study was to quantify key mechanisms involved in the HPA axis activity regulation and their interaction with hydrocortisone therapy. Data from 30 healthy volunteers was leveraged: Endogenous ACTH and cortisol concentrations without any intervention as well as cortisol concentrations measured after dexamethasone suppression and single dose administration of (i) 0.5-10 mg hydrocortisone as granules, (ii) 20 mg hydrocortisone as granules and intravenous bolus. A stepwise model development workflow was used: A newly developed model for endogenous ACTH and cortisol was merged with a refined hydrocortisone pharmacokinetic model. The joint model was used to simulate ACTH and cortisol trajectories in CAH patients with varying degrees of enzyme deficiency, with or without hydrocortisone administration, and healthy individuals. Time-dependent ACTH-driven endogenous cortisol production and cortisol-mediated feedback inhibition of ACTH secretion processes were quantified and implemented in the model. Comparison of simulated ACTH and cortisol trajectories between CAH patients and healthy individuals showed the importance of administering hydrocortisone before morning ACTH secretion peak time to suppress ACTH overproduction observed in untreated CAH patients. The developed framework allowed to gain insights on the physiological mechanisms of the HPA axis regulation, its perturbations in CAH and interaction with hydrocortisone administration, paving the way towards cortisol replacement therapy optimization.

Combined oral contraceptive pill compared with no medical treatment in the management of polycystic ovary syndrome: A systematic review.

OBJECTIVE: As part of the update of the International Evidence-Based Guidelines for the Assessment and Management of polycystic ovary syndrome (PCOS), a systematic review was performed to inform evidence-based recommendations. DESIGN: Systematic review. Only randomised controlled trial were included. PATIENTS: Women with PCOS; the use of combined oral contraceptive pills (COCP) was compared with no medical treatment. MEASUREMENTS: Outcomes were designed in collaboration with clinical experts, researchers, and consumers. Critical outcomes included hirsutism, irregular cycles, quality of life, body mass index (BMI), and weight. RESULTS: 1660 publications were identified, but only four studies were included. No studies could be combined for meta-analysis. COCP treatment improved cycle regularity compared with no medical treatment (100% vs. 0%, with low certainty of evidence). COCP showed no difference in improvement of hirsutism or BMI compared with placebo or lifestyle; a lower weight after COCP compared with no treatment (mean difference [MD] -8.0 (95% confidence interval, CI -11.67); -4.33 kg); and improvement in quality of life (MD 1.2 [95% CI 0.96]; 1.44), but these results were all very low certainty of evidence. CONCLUSION: Results show that COCP benefit cycle regulation, but other benefits or potential adverse effects were only identified with very low certainty of evidence. The COCP is frontline medical treatment in PCOS, but this is still based on established efficacy in the broader general population. Our results show that research in PCOS is seriously lacking and should be prioritised to capture core reproductive, metabolic and psychological outcomes important in PCOS.

Clinical practitioners' experiences of psychological treatment for autistic children and adolescents with school attendance problems: a qualitative study.

BACKGROUND: School attendance problems (SAPs) are common among children and adolescents with autism spectrum disorder (ASD). Currently, there is a lack of guidelines for treatment or interventions aimed at this group. METHOD: Twelve clinical practitioners were interviewed via in-depth interviews using a semi-structured question guide. Interviews were audiotaped, transcribed verbatim, and initially independently coded by two coders. The interviews were analyzed according to thematic analysis. RESULTS: The majority of the clinicians reported that it was common that children and adolescents with ASD at CAP had prolonged SAPs. A total of four themes and 22 sub-themes were identified in the analysis: the treatment situation; treatment goals at CAP; treatment interventions; and desired development. Insufficient adaptations in response to core impairment of ASD and lack of support in their daily life could be factors to the development of SAPs. Prolonged social isolation in combination with severe psychiatric comorbidities was reported as a treatment barrier. Also, insufficient collaboration between mental health care services, school and social services obstructed the return to school for this group of students. Favorable factors for positive treatment outcome were: early detection, accurate assessment and coordination between mental health care and schools and environmental adaptation at school as well as at home, parent support and sometimes change of school. Concerning useful therapeutic techniques, exposure from cognitive-behavioral treatment was reported. CONCLUSION: Children and adolescents with ASD with limited societal support tend to develop SAPs. Important factors that impact the outcome of treatment were the length of the absence from school and the severity of psychiatric comorbidities. Tailored and adapted interventions at school, parent support and mental health care are needed. Research about assessment and treatment for children and adolescents with ASD and SAPs is needed.

Risk of induced abortions in childhood cancer survivors.

BACKGROUND: The relative probability of pregnancy and parenthood in cancer survivors is reduced. Studies have shown that cancer survivors are concerned about the health of their offspring and the recurrence of their own cancer. This could lead to an increased risk of induced abortion. The aim of this study was to examine whether pregnancies of childhood cancer survivors (CCSs) who were 0 to 14 years old at diagnosis in 1971-2012 were more likely to result in induced abortions in comparison with population controls. METHODS: Data from Finnish registries for cancer, births, and induced abortions were merged to identify 420 first pregnancies of CCSs and 2508 first pregnancies of age-matched population controls in 1987-2013. Poisson regression and logistic regression modeling were used to estimate incidence rates and relative risks (RRs) with 95% confidence intervals (CIs) of first pregnancies and induced abortions in CCSs in comparison with population controls. RESULTS: The risk of first pregnancy was reduced in CCSs in comparison with population controls (RR, 0.72; 95% CI, 0.64-0.80), whereas the risk of a first pregnancy resulting in an induced abortion was similar in CCSs and population controls (RR, 1.01; 95% CI, 0.77-1.33). In subanalyses stratifying by decade of diagnosis and cancer treatment, the risk of induced abortion was similar in CCSs and population controls. CONCLUSIONS: Female CCSs do not have an overall increased risk of induced abortions. The reduced probability of pregnancy among CCSs highlights the continued need for interventions to preserve fertility at the time of a cancer diagnosis.

Use of fertility drugs in early-onset female cancer survivors-A Finnish register-based study on 8,929 survivors.

Advances in multimodality cancer treatments have increased the risk of long-term complications in early-onset cancer survivors. For female cancer survivors, these include diminished reproductive function, often resulting in a narrowed fertile window. The aim of our study was to evaluate the use of fertility treatments in cancer survivors (aged 0-39 years at diagnosis) compared to siblings. Data from Finnish registers on cancer, birth and prescribed medications were merged to identify 8,929 survivors and 9,495 siblings without previous deliveries. Fertility drug purchases from 1993 to 2012 at the age of 16-41 years were included. A Poisson regression model was used to estimate incidence rate ratios (IRRs) for the use of fertility drugs, adjusting for age and calendar time at fertility drug purchase. Fertility treatments were more common in survivors compared to siblings, as 6.1% of survivors compared to 3.8% of siblings had bought fertility drugs (IRR 1.43, 95% confidence interval [CI] 1.25-1.65). A subclassification of fertility treatments into ovulation inductions and assisted reproductive technology (ART), showed increased use of ART (IRR 2.41, 95% CI 1.97-2.96), whereas the use of ovulation induction was similar in survivors and siblings. Analyses by calendar time periods showed the use of ART to be significantly higher in the most recent decade, from 2003 onwards. We conclude that cancer survivors have an increased risk for subfertility, which is why fertility counseling is important. However, our results mirror a more active approach among clinicians towards fertility treatments in cancer survivors during the most recent years.

Risk factors for preterm delivery among early onset cancer survivors: A Finnish register-based study.

Previous studies have shown an elevated risk for preterm delivery among early onset cancer survivors. Whether the preterm delivery starts spontaneously, due to possible uterine damage because of cancer treatment, or is induced due to maternal conditions is unclear. Our aim was to assess pregnancy related conditions in female cancer survivors possibly underlying the elevated risk for preterm labor. Nationwide cancer and birth registries were merged to identify 1,753 first deliveries of cancer survivors (diagnosed below 40 years of age) and 5,123 first deliveries of matched female comparison subjects between January 1991 and December 2013. Conditional logistic regression models were used to estimate the risk for pregnancy related conditions adjusting for maternal age, gestational age and smoking. We found an overall increased risk for hospitalization during pregnancy (OR 1.45, 95% CI 1.25-1.68), intrahepatic cholestasis (OR 2.86, 95% CI 1.09-7.49), fear of childbirth (OR 2.25, 95% CI 1.31-3.85) and mental disorders and diseases of the nervous system complicating pregnancy and labor (OR 5.89, 95% CI 2.31-15.00). Among survivors, 129 (7.4%) delivered preterm compared to 268 (5.2%) comparisons subjects (p = 0.004). We found a statistically significant increased risk for preterm delivery among cancer survivors with vaginal bleeding (OR 1.35, 95% CI 1.07-1.71) and pre-eclampsia (1.35, 95% CI 1.06-1.72) compared to comparison subjects with the same condition. Health professionals treating these women should be aware of these risks. In general, however, our results are reassuring when it comes to pregnancies among cancer survivors.

The circadian rhythm of corticosteroid-binding globulin has little impact on cortisol exposure after hydrocortisone dosing.

CONTEXT: Optimization of hydrocortisone replacement therapy is important to prevent under- and over dosing. Hydrocortisone pharmacokinetics is complex as circulating cortisol is protein bound mainly to corticosteroid-binding globulin (CBG) that has a circadian rhythm. OBJECTIVE: A detailed analysis of the CBG circadian rhythm and its impact on cortisol exposure after hydrocortisone administration. DESIGN AND METHODS: CBG was measured over 24 hours in 14 healthy individuals and, employing a modelling and simulation approach using a semi-mechanistic hydrocortisone pharmacokinetic model, we evaluated the impact on cortisol exposure (area under concentration-time curve and maximum concentration of total cortisol) of hydrocortisone administration at different clock times and of the changing CBG concentrations. RESULTS: The circadian rhythm of CBG was well described with two cosine terms added to the baseline of CBG: baseline CBG was 21.8 µg/mL and interindividual variability 11.9%; the amplitude for the 24 and 12 hours cosine functions were relatively small (24 hours: 5.53%, 12 hours: 2.87%) and highest and lowest CBG were measured at 18:00 and 02:00, respectively. In simulations, the lowest cortisol exposure was observed after administration of hydrocortisone at 23:00-02:00, whereas the highest was observed at 15:00-18:00. The differences between the highest and lowest exposure were minor (≤12.2%), also regarding the free cortisol concentration and free fraction (≤11.7%). CONCLUSIONS: Corticosteroid-binding globulin has a circadian rhythm but the difference in cortisol exposure is ≤12.2% between times of highest and lowest CBG concentrations; therefore, hydrocortisone dose adjustment based on time of dosing to adjust for the CBG concentrations is unlikely to be of clinical benefit.

Model-based characterization of the relationship between dapagliflozin systemic exposure and HbA1c response in patients with type 1 diabetes mellitus.

AIMS: To quantitatively describe the relationship between dapagliflozin systemic exposure and HbA1c response among patients with type 1 diabetes mellitus (T1DM) and assess the potential impact of covariate effects. MATERIALS AND METHODS: Individual longitudinal HbA1c data from two phase 3 studies in patients with T1DM (24-week treatment with once-daily dapagliflozin 5 or 10 mg or placebo, with adjustable insulin) were analyzed using a non-linear mixed effect modeling approach. Area under the concentration curve was used to measure dapagliflozin systemic exposure. Baseline HbA1c, estimated glomerular filtration rate, reduction in total insulin dose, baseline glucose concentrations, age, sex, race (Asian vs. non-Asian), and insulin administration method (multiple daily injections vs. insulin pump) were assessed as covariates. RESULTS: A maximum effect (Emax ) model identified a positive exposure-response relationship. Model-predicted placebo-corrected HbA1c reductions after 24 weeks for dapagliflozin 5- and 10-mg doses were - 0.42% [95% confidence interval (CI) -0.47 to -0.36) and - 0.45% (95% CI -0.50 to -0.40), respectively; baseline HbA1c was ~8.4%. This was in good agreement with actual observations from both studies. Baseline HbA1c was a significant covariate: patients with higher baseline HbA1c were predicted to have greater HbA1c reductions. CONCLUSIONS: The relationship between dapagliflozin systemic exposure and HbA1c response was successfully described in patients with T1DM. None of the tested covariates affected the efficacy of dapagliflozin to a clinically relevant extent. Therefore, no dose adjustment of dapagliflozin is required in patients with T1DM based on the tested covariates. ClinicalTrials.gov, NCT02268214; NCT02460978.

Subsequent risk of cancer among women with a history of placental abruption.

BACKGROUND: Placentation is characterized by extensive cell proliferation and neovascularization, which is similar to the processes observed in the development of cancer. Nonetheless, little is known about the relation between abnormal placentation, such as placental abruption, and cancer. MATERIAL AND METHODS: Data on women with placental abruption in a singleton pregnancy between 1971 and 2005 (n = 7804) were collected from the Finnish Hospital Discharge Registry and the Finnish Medical Birth Registry. The cohort was then linked with the Finnish Cancer Registry records until the end of 2013. Standardized incidence ratios (SIRs) were calculated for different cancers by dividing the observed numbers of cancers by those expected. The expected numbers were based on national cancer incidence rates. RESULTS: During follow-up, 597 cancers were found among women with a history of placental abruption. The overall risk of cancer was not increased (SIR 0.95, 95% CI 0.88-1.02). However, the history of placental abruption was associated with an increased risk of lung cancer (SIR 1.51, 95% CI 1.05-2.10) and thyroid cancer (SIR 1.47, 95% CI 1.04-2.02). A decreased risk was found for breast cancer (SIR 0.85, 95% CI 0.75-0.96). The risk of rectal cancer was also decreased, although these numbers were small (SIR 0.49, 95% CI 0.20-1.01). CONCLUSIONS: Overall, the risk of lung cancer was increased, and the risk of breast cancer decreased, in women with a history of placental abruption. These observations can be explained to some extent by risk factors or risk markers for placental abruption. The increased risk of thyroid cancer may be explained by surveillance bias.

Fertility treatments among female cancer survivors giving birth - a Finnish register-based study.

BACKGROUND: Long-term survival rates for most types of childhood cancers have improved dramatically over the past decades. However, because of advances in multimodality treatments, cancer survivors nowadays more often face long-term complications, including diminished gonadal and reproductive function. The aim of this study was to identify whether the use of fertility treatments among early onset (0-34 years) cancer survivors giving birth differed from that among siblings giving birth and to identify the subgroups of cancer survivors that were most likely to require fertility treatments. MATERIAL AND METHODS: Nationwide cancer and birth registries were merged to identify 1974 post-diagnosis deliveries of cancer survivors and 6107 deliveries of female siblings in 2004-2013. Unconditional multivariate logistic regression models were used to estimate the risk for different fertility treatments namely assisted reproductive technology, intrauterine insemination and ovulation induction. We adjusted for maternal age, year of delivery, parity and smoking. RESULTS: We found overall significantly increased odds for use of any fertility treatments in survivors compared to siblings (OR 1.84, 95% CI 1.18-2.86). As time from cancer treatment increased, the odds for need of fertility treatments increased, being highest at 11 to 15 years post cancer treatment (OR 2.88, 95% CI 1.13-7.30). Survivors diagnosed at ages 25-34 years had the highest odds for use of fertility treatments compared to siblings (OR 2.31, 95% CI 1.01-5.32). CONCLUSIONS: Our study supports previous findings indicating that cancer survivors have an increased risk for subfertility. Survivors diagnosed in their childhood had the lowest risk for fertility treatment and seemed to get pregnant with less extensive fertility treatments than survivors diagnosed as adults. Time elapsed from cancer treatment played a central role, increasing the need for fertility treatments compared to siblings, suggesting that cancer therapies might lead to diminished ovarian reserve.

Mortality and causes of death among women with a history of placental abruption.

INTRODUCTION: Women with a history of placental abruption have an increased later morbidity, but not much is known of the later mortality. MATERIAL AND METHODS: Data on women with placental abruption (index cohort) between 1969 and 2005 (n = 7805) were collected from the Finnish Hospital Discharge Register and the Finnish Medical Birth Register. A matched reference cohort consisted of women without placental abruption (n = 23 523). The causes of death were retrieved from the Cause-of-Death Register. Cause-specific mortality was compared by hazard ratios (HR). Standardized mortality ratios were calculated to compare both cohorts with the general female population. The main outcome measure was subsequent mortality. RESULTS: By the end of 2013 there were 395 deaths in the index cohort and 863 deaths in the reference cohort. The overall mortality was increased in the index cohort compared with the reference cohort [HR 1.39, 95% confidence interval (CI) 1.24-1.57]. The index cohort had an increased risk of death from respiratory tract malignancies (HR 1.72, 95% CI 1.05-2.82), alcohol-related causes (HR 1.84, 95% CI 1.25-2.72), and external causes (HR 1.63, 95% CI 1.19-2.22), especially suicide (HR 1.71, 95% CI 1.07-2.74). The mortality from cardiovascular diseases did not differ. The standardized mortality ratio was increased in the index cohort compared with the general Finnish female population (HR 1.13, 95% CI 1.02-1.24), especially for respiratory tract malignancies (HR 1.79, 95% CI 1.16-2.64). The index cohort women tended to die younger than referent women (p < 0.001). CONCLUSIONS: Overall mortality among women with a history of placental abruption is increased. These women tend to die younger than referent women do.

Fertility counselling and fertility preservation among early onset female cancer patients-A Finnish register-based study.

INTRODUCTION: Advances in multimodality cancer treatments have increased long-term survival rates for early onset cancer patients, with 5-year survival rates reaching 80% in Northern Europe. According to recent recommendations, clinicians should, as early as possible, inform cancer patients about the impact that cancer treatment may have on their fertility. Still, there is limited published data on fertility counselling (FC) and fertility preservation (FP) for cancer patients. METHODS: This register-based study used hospital records to identify female cancer patients in the hospital district (n = 192) who received FC at the age of 16-42 years between 2011 and 2019. RESULTS: Altogether, 97 (50.5%) cancer patients were eligible for FP. Of these, 55 (56.7%) underwent FP, whereas 42 (43.3%) declined. Women undergoing FP were recommended cancer treatments with a higher risk of infertility (p = 0.01), and women with breast cancer were more prone to undergo FP than women with lymphoma (p = 0.043). In FP treatment cycles, the mean number of oocytes retrieved (13.9 ± 7.7 vs. 12.0 ± 6.5, p = 0.04) and transferrable embryos (4.7 ± 2.9 vs. 3.7 ± 2.8, p = 0.002) was higher among cancer patients compared to age-matched comparisons with male or tubal factor infertility. The total mean gonadotropin dose used was higher among cancer patients (2243 ± 963 IU vs. 1679 ± 765 IU, p < 0.001). CONCLUSION: We conclude that a good ovarian response during FP can be achieved in female cancer patients.

Utility of Serum Anti-Müllerian Hormone Measurement as Part of Polycystic Ovary Syndrome Diagnosis.

The 2023 international evidence-based guideline update for the assessment and management of polycystic ovary syndrome (PCOS) recommends using the Rotterdam criteria for the diagnosis of PCOS. The updated guideline has evidence-based recommendation for the diagnosis, and it now also includes serum anti-Müllerian hormone (AMH) measurement as an alternative tool for gynecological ultrasound to diagnose polycystic ovary morphology (PCOM). The aim of this new recommendation was to facilitate PCOS diagnostic workup in primary care and other disciplines, as currently most diagnosing is done in gynecology and infertility clinics. Here, we review factors affecting AMH levels as well as the utility of AMH in PCOS diagnosis. We identified relevant studies that report different cut-offs for AMH to diagnose PCOM as part of PCOS diagnosis. There are, however, some limitations when using AMH that should be acknowledged. These include physiological aspects like age, ethnicity, and obesity and iatrogenic causes like hormonal medication and ovarian surgery. Also reference ranges are different depending on AMH assay used. As a summary, we conclude that AMH is a usable tool in PCOM diagnostics, but it does not have a single cut-off. Therefore, further studies are needed to establish age and assay-based reference ranges.

Metformin and Combined Oral Contraceptive Pills in the Management of Polycystic Ovary Syndrome: A Systematic Review and Meta-analysis.

CONTEXT: Polycystic ovary syndrome (PCOS) affects more than 1 in 10 women. OBJECTIVE: As part of the 2023 International PCOS Guidelines update, comparisons between combined oral contraceptive pills (COCP), metformin, and combination treatment were evaluated. DATA SOURCES: Ovid Medline, Embase, PsycINFO, All EBM, and CINAHL were searched. STUDY SELECTION: Women with PCOS included in randomized controlled trials (RCTs). DATA EXTRACTION: We calculated mean differences and 95% CIs regarding anthropometrics, metabolic, and hyperandrogenic outcomes. Meta-analyses and quality assessment using GRADE were performed. DATA SYNTHESIS: The search identified 1660 publications; 36 RCTs were included. For hirsutism, no differences were seen when comparing metformin vs COCP, nor when comparing COCP vs combination treatment with metformin and COCP. Metformin was inferior on free androgen index (FAI) (7.08; 95% CI 4.81, 9.36), sex hormone binding globulin (SHBG) (-118.61 nmol/L; 95% CI -174.46, -62.75) and testosterone (0.48 nmol/L; 95% CI 0.32, 0.64) compared with COCP. COCP was inferior for FAI (0.58; 95% CI 0.36, 0.80) and SHBG (-16.61 nmol/L; 95% CI -28.51, -4.71) compared with combination treatment, whereas testosterone did not differ. Metformin lowered insulin (-27.12 pmol/L; 95% CI -40.65, -13.59) and triglycerides (-0.15 mmol/L; 95% CI -0.29, -0.01) compared with COCP. COCP was inferior for insulin (17.03 pmol/L; 95% CI 7.79, 26.26) and insulin resistance (0.44; 95% CI 0.17, 0.70) compared with combination treatment. CONCLUSIONS: The choice of metformin or COCP treatment should be based on symptoms, noting some biochemical benefits from combination treatment targeting both major endocrine disturbances seen in PCOS (hyperinsulinemia and hyperandrogenism).

Evaluation of the Pharmacokinetics of Dapagliflozin in Patients With Chronic Kidney Disease With or Without Type 2 Diabetes Mellitus.

Evidence shows that sodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, can delay the progressive decline of kidney function in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). We used a population pharmacokinetics (popPK) model to characterize the pharmacokinetics of dapagliflozin in patients with CKD and compare dapagliflozin systemic exposure in different populations, such as CKD with or without T2DM and T2DM without CKD. A 2-compartmental popPK model was developed from a previous popPK model. The final popPK model was based on 9715 dapagliflozin plasma concentrations from 3055 patients included in clinical studies involving adults with CKD with or without T2DM, adults with T2DM, healthy subjects, and pediatric patients with T2DM. Overall, the apparent clearance for patients treated with dapagliflozin was 21.6 L/h, similar to previous estimates in adults with T2DM and healthy subjects (22.9 L/h). Model-derived area under the plasma concentration-time curve (AUC) was not meaningfully different between patients with CKD with and without T2DM. Median AUC was 1.6-fold higher in adult patients with CKD with T2DM compared with adult patients with T2DM without CKD. Compared with patients with normal kidney function (estimated glomerular filtration rate ≥90 mL/min/1.73 m2 ), median AUC was 2.4-fold higher in patients with CKD (with/without T2DM) with estimated glomerular filtration rate 15-29 mL/min/1.73 m2 owing to decreased renal clearance of dapagliflozin. A higher AUC was observed in patients with a higher age or lower body weight but was not considered clinically relevant. This popPK model adequately described dapagliflozin pharmacokinetics and found that systemic exposure in patients with CKD was consistent, irrespective of T2DM status.

Different kinds of oral contraceptive pills in polycystic ovary syndrome: a systematic review and meta-analysis.

OBJECTIVE: To compare between different combined oral contraceptive pills (COCPs) as part of the update of the International Evidence-Based Guidelines on the Assessment and Management of polycystic ovary syndrome (PCOS). DESIGN: A systematic review and meta-analysis was performed, Prospero CRD42022345640. METHODS: MEDLINE, EMBASE, All EBM, CINAHL, and PsycINFO was searched on July, 8, 2022, for studies including women with PCOS, comparing 2 different COCPs in randomized controlled trials. RESULTS: A total of 1660 studies were identified, and 19 randomized controlled trials (RCTs) were included.Fourth-generation COCP resulted in lower body mass index (BMI) (mean difference [MD] 1.17 kg/m2 [95% confidence interval {CI} 0.33; 2.02]) and testosterone (MD 0.60 nmol/L [95% CI 0.13; 1.07]) compared with third-generation agents, but no difference was seen in hirsutism.Ethinyl estradiol (EE)/cyproterone acetate (CPA) was better in reducing hirsutism as well as biochemical hyperandrogenism (testosterone [MD 0.38 nmol/L {95% CI 0.33-0.43}]) and BMI (MD 0.62 kg/m2 [95% CI 0.05-1.20]) compared with conventional COCPs.There was no difference in hirsutism between high and low EE doses. No evidence regarding natural estrogens in COCP was identified. CONCLUSION: With current evidence, combined regimens containing an antiandrogen (EE/CPA) may be better compared with conventional COCPs in reducing hyperandrogenism, but EE/CPA will not be recommended as a first-line COCP treatment by the pending PCOS guideline update, due to higher venous thrombotic events (VTE) risk in the general population. Later-generation progestins offer theoretical benefits, but better evidence on clinical outcomes is needed in women with PCOS. TRIAL REGISTRATION: The protocol for the systematic review was registered prospectively in Prospero, CRD42022345640.