Geospatial analysis of cardiovascular mortality before and during the COVID-19 pandemic in Peru: analysis of the national death registry to support emergency management in Peru.

Background: COVID-19 has led to significant global mortality, with Peru being among the countries most affected. While pre-existing comorbidities have been linked to most cases, the exact distribution of fatalities within the country remains unclear. We aimed to assess deaths attributed to cardiovascular diseases (CVD) before and during the COVID-19 pandemic across various regions and provinces in Peru. Methods: An observational georeferencing study was designed. Peru faced four waves of COVID-19 over three years, with variable impacts across its three regions (Coast, Highlands, and Jungle). Deaths related to cardiovascular diseases, such as heart failure (HF), arrhythmia, acute myocardial infarction (AMI), strokes, and acute coronary syndrome, were examined as primary variables. The study period spanned pre-pandemic years (2017-2019) and pandemic years (2020-2021), utilizing death data from the National Death Information System (SINADEF). The georeferencing analysis was conducted using ArcGIS v10.3. Results: A total of 28,197 deaths were recorded during the study period, with significant increases during the pandemic (2020-2021). Cardiovascular deaths were disproportionately higher during the pandemic, totaling 19,376 compared to 8,821 in the pre-pandemic period (p < 0.001). AMI and HF were the leading causes of mortality, showing significant increases from the pre-pandemic (5,573 and 2,584 deaths) to the pandemic period (12,579 and 5,628 deaths), respectively. Deaths due to CVD predominantly affected individuals aged over 60, with significant increases between the two study periods (7,245 vs. 16,497 deaths, p = 0.002). Geospatial analysis revealed regional disparities in CVD mortality, highlighting provinces like Lima and Callao as COVID-19 critical areas. The substantial increase in cardiovascular deaths during the COVID-19 pandemic in Peru showed distinctive patterns across regions and provinces. Conclusions: Geospatial analysis identified higher-risk areas and can guide specific interventions to mitigate the impact of future health crises. Understanding the dynamic relationship between pandemics and cardiovascular health is crucial for effective public health strategies.

The role of estrogen metabolites in human ovarian function.

Estrogens produced by the ovary play diverse roles in controlling physiological changes in the function of the female reproductive system. Although estradiol acts through classical nuclear receptors, its metabolites (EMs) act by alternative pathways. It has been postulated that EMs act through paracrine-autocrine pathways to regulate key processes involved in normal follicular growth, corpus luteum (CL) development, function, and regression. The present review describes recent advances in understanding the role of EMs in human ovarian physiology during the menstrual cycle, including their role in anovulatory disorders and their action in other target tissues.

A plain language summary of the long-term relugolix combination therapy study for uterine fibroids.

What is this summary about? This is a summary of a research study (known as a clinical trial) called the LIBERTY extension study. The LIBERTY extension study is a long-term study looking at how well a medicine called relugolix combination therapy worked in reducing blood loss during menstrual periods in women with uterine fibroids with heavy menstrual periods. Women were included in the extension study if they finished the 24-week LIBERTY 1 or LIBERTY 2 studies. Heavy menstrual periods were considered to be menstrual blood loss of about one-third of a cup of blood (80 ml) per cycle for two cycles or about two-thirds of a cup of blood (160 ml) during one cycle. The LIBERTY extension study also looked at whether relugolix combination therapy was safe to take for up to 1 year. What were the results? Out of 770 total women with uterine fibroids with heavy menstrual bleeding who took part in the LIBERTY 1 and LIBERTY 2 studies, 476 took part in the LIBERTY extension study. From the start of the LIBERTY 1 and LIBERTY 2 studies through the end of the LIBERTY extension: 163 women took relugolix combination therapy for 52 weeks 149 women took relugolix alone for 12 weeks followed by relugolix combination therapy for 40 weeks 164 women took placebo for 24 weeks followed by relugolix combination therapy for 28 weeks The LIBERTY extension study showed that most women in all three treatment groups responded to relugolix combination therapy by having less bleeding during their menstrual periods, having improved anemia symptoms, and having stable bone mineral loss. Side effects were similar across treatment groups, and the most common side effects were headaches and hot flushes. What do the results mean? Women with uterine fibroids with heavy menstrual bleeding taking relugolix combination therapy may have fewer uterine fibroid bleeding symptoms for up to 1 year of treatment. Clinical Trial Registration: NCT03049735 (ClinicalTrials.gov) (LIBERTY 1) Clinical Trial Registration: NCT03103087 (ClinicalTrials.gov) (LIBERTY 2) Clinical Trial Registration: NCT03412890 (ClinicalTrials.gov) (LIBERTY extension study).

A plain language summary of the safety of relugolix combination therapy and improvement in symptoms in women with uterine fibroids from the LIBERTY 1 and LIBERTY 2 studies.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of research studies (known as clinical trials) called LIBERTY 1 and LIBERTY 2. The LIBERTY 1 and LIBERTY 2 studies looked at how well a medication called relugolix combination therapy worked to reduce heavy bleeding at the time of menstruation compared with placebo. The studies also looked at what side effects were reported in women with uterine fibroids and heavy menstrual bleeding. WHAT WERE THE RESULTS?: Researchers looked at 388 adult women in the LIBERTY 1 study and 382 adult women in the LIBERTY 2 study. All women had heavy menstrual bleeding with uterine fibroids before the start of the LIBERTY 1 and LIBERTY 2 studies. The women were given one of three treatments during the studies: relugolix combination therapy or placebo for 24 weeks, or delayed relugolix combination therapy (relugolix alone for the first 12 weeks, then relugolix combination therapy for the last 12 weeks of the studies). More women taking relugolix combination therapy in the LIBERTY 1 study (73%) and LIBERTY 2 study (71%) had menstrual blood loss of less than one-third of a cup (80 mL) and had reduction of at least 50% less blood loss during their last menstrual period after 24 weeks of taking the medicine compared with placebo (LIBERTY 1: 19% and LIBERTY 2: 15%). The women taking relugolix combination therapy also had less pain than those taking placebo. Side effects were similar across treatment groups. Headaches and hot flushes were the most common side effects. WHAT DO THE RESULTS MEAN?: More women with uterine fibroids taking relugolix combination therapy for 24 weeks were likely to have fewer uterine fibroid symptoms than women receiving placebo. Clinical Trial Registration: NCT03049735 (LIBERTY 1); NCT03103087 (LIBERTY 2).

Long-term Relugolix Combination Therapy for Symptomatic Uterine Leiomyomas.

OBJECTIVE: In the LIBERTY 1 and LIBERTY 2 placebo-controlled trials, once-daily relugolix combination therapy reduced menstrual blood loss volume and pain in women with heavy menstrual bleeding associated with uterine leiomyomas and was well tolerated, with preservation of bone mineral density (BMD) through 24 weeks. Here we report the long-term efficacy and safety of relugolix combination therapy treatment for up to 52 weeks. METHODS: Women with uterine leiomyoma-associated heavy menstrual bleeding who completed any treatment arm in either the LIBERTY 1 or LIBERTY 2 trial were eligible to enroll in a 28-week long-term extension study. All participants received once-daily relugolix combination therapy (40 mg relugolix, estradiol 1 mg, norethindrone acetate 0.5 mg) in the extension study. The primary efficacy endpoint was the proportion of women who achieved or maintained a menstrual blood loss volume of less than 80 mL and a 50% or greater reduction in menstrual blood loss volume from LIBERTY study baseline to the last 35 days of treatment (defined as responders ). Analyses were conducted for all three randomized treatment groups from pivotal studies. RESULTS: Overall, 477 women enrolled, 476 were treated, and 363 (76.1%) completed 52 weeks. Among patients treated with relugolix combination therapy through 52 weeks (n=163), sustained improvement in heavy menstrual bleeding was observed in 87.7% (responders). The least squares mean menstrual blood loss volume reduction was 89.9%, with 70.6% of patients achieving amenorrhea. At week 52, 59.0% of patients with anemia at baseline had improvements in hemoglobin concentration of greater than 2 g/dL. Distress due to uterine leiomyoma-associated symptoms measured by the BPD (Bleeding and Pelvic Discomfort) scale score was reduced by 51.3 points. Sustained reductions in uterine and uterine leiomyoma volume were observed. Bone mineral density was preserved through week 52. CONCLUSION: Improvements in heavy menstrual bleeding and anemia and reduction of uterine leiomyoma-associated symptom burden were sustained through up to 52 weeks of treatment with relugolix combination therapy in women with uterine leiomyomas. No new safety concerns were identified, and BMD was maintained. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT03049735; NCT03103087; NCT03412890. FUNDING SOURCE: Myovant Sciences GmbH.

Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy.

BACKGROUND: Uterine fibroids are a common cause of heavy menstrual bleeding and pain. Treatment with the combination of relugolix (an oral gonadotropin-releasing hormone-receptor antagonist), estradiol, and norethindrone acetate, administered once daily, may have efficacy in women with uterine fibroids and heavy bleeding while avoiding hypoestrogenic effects. METHODS: We conducted two replicate international, double-blind, 24-week, phase 3 trials involving women with fibroid-associated heavy menstrual bleeding. Participants were randomly assigned in a 1:1:1 ratio to receive once-daily placebo, relugolix combination therapy (40 mg of relugolix, 1 mg of estradiol, and 0.5 mg of norethindrone acetate), or delayed relugolix combination therapy (40 mg of relugolix monotherapy, followed by relugolix combination therapy, each for 12 weeks). The primary efficacy end point in each trial was the percentage of participants with a response (volume of menstrual blood loss <80 ml and a ≥50% reduction in volume from baseline) in the relugolix combination therapy group, as compared with the placebo group. Key secondary end points were amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, fibroid volume, and uterine volume. Safety and bone mineral density were assessed. RESULTS: A total of 388 women in trial L1 and 382 in trial L2 underwent randomization. A total of 73% of the participants in the relugolix combination therapy group in trial L1 and 71% of those in trial L2 had a response (primary end point), as compared with 19% and 15%, respectively, of those in the placebo groups (P<0.001 for both comparisons). Both relugolix combination therapy groups had significant improvements, as compared with the placebo groups, in six of seven key secondary end points, including measures of menstrual blood loss (including amenorrhea), pain, distress from bleeding and pelvic discomfort, anemia, and uterine volume, but not fibroid volume. The incidence of adverse events was similar with relugolix combination therapy and placebo. Bone mineral density was similar with relugolix combination therapy and placebo but decreased with relugolix monotherapy. CONCLUSIONS: Once-daily relugolix combination therapy resulted in a significant reduction in menstrual bleeding, as compared with placebo, and preserved bone mineral density in women with uterine fibroids. (Funded by Myovant Sciences; LIBERTY 1 [L1] and LIBERTY 2 [L2] ClinicalTrials.gov numbers, NCT03049735 and NCT03103087, respectively.).

Significance of pro-angiogenic estrogen metabolites in normal follicular development and follicular growth arrest in polycystic ovary syndrome.

STUDY QUESTION: Do alterations in pro- and anti-angiogenic estrogen metabolites in follicular fluid (FF) contribute to the follicular growth arrest and anovulation associated with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: FF of PCOS women with anovulation have reduced levels of pro-angiogenic estrogen metabolites (EMs) and vascular endothelial growth factor (VEGF) compared to that of fertile women with regular menstrual cycles, but exogenous gonadotropins increase the pro-angiogenic EMs and VEGF levels in PCOS women. WHAT IS KNOWN ALREADY: PCOS is characterized by the arrest of follicular development that leads to chronic anovulation. Follicular arrest is generally associated with elevated plasma levels of luteinizing hormone (LH), androgens and anti-Mullerian hormone (AMH). There is also reduced angiogenesis in the follicles of PCOS women compared to those of normal cycling women. It is known that angiogenesis is a critical factor during follicular development. We and other investigators have explored the role of EMs in ovarian angiogenesis, particularly in human corpus luteum function, showing that 4-hydroxyestrone (4-OHE1) and 16-ketoestradiol (16-kE2) have pro-angiogenic effects while 2-methoxyestradiol (2-ME2) and 2-methoxyestrone (2-ME1) have anti-angiogenic effects. Additionally, 2-hydroxyestradiol (2-OHE2), which is produced in the ovary, has proliferative and pro-angiogenic properties. We hypothesized that EMs could be involved in angiogenesis necessary for ovarian follicular development in fertile women, and that dysregulation of these factors may contribute to follicular arrest in PCOS. The relationship between EMs, VEGF and AMH in the pathophysiology of follicular arrest in PCOS has not been previously studied at a follicular level in anovulatory women without ovulation induction. STUDY DESIGN, SIZE, DURATION: This is a comparative experimental study of serum and FF collected from different sized follicles (antral ˂10 mm and dominant ˃16 mm) of women with and without ovarian stimulation. The study included women with regular menstrual cycles who were proven to be fertile (n = 20) and PCOS women with follicular arrest who were candidates for ovarian drilling (n = 17), as well as other patients requiring ovarian stimulation, i.e. control women undergoing IVF for male factor infertility (n = 12) and PCOS women undergoing IVF (n = 17). In vitro studies were carried out on granulosa-lutein cells (GCs) obtained from subsets of women undergoing IVF for male factor infertility (n = 6) and PCOS women undergoing IVF (n = 6). GCs were maintained in culture for up to 6 days. PARTICIPANTS/MATERIALS, SETTING, METHODS: Intrafollicular estradiol, estrone and EMs concentrations were determined by high performance liquid chromatography-mass spectrometry. Testosterone in serum was measured by RIA, and LH, FSH and sex hormone-binding globulin in serum were measured with IRMA kits. AMH was determined in serum and FF by enzyme linked immunosorbant assay (ELISA). VEGF levels were measured in FF and conditioned medium by ELISA. Conditioned medium were obtained from cultured GCs. The angiogenic potential was assessed by in vitro angiogenic assays. MAIN RESULTS AND THE ROLE OF CHANCE: Pro-angiogenic EMs (4-OHE1, 16-kE2 and 2-OHE2) and VEGF were lower in FF of antral follicles of PCOS women with follicular arrest compared those of fertile women with ovulatory cycles (P < 0.05). In contrast, higher concentrations of AMH were found in FF of antral follicles from PCOS women with follicular arrest compared to those of fertile women with ovulatory cycles (P < 0.05). Exogenous gonadotropins used in IVF increased pro-angiogenic EMs and VEGF production in PCOS women, reaching similar profiles compared to control women receiving gonadotropins in their IVF treatment for male factor infertility. The pro-angiogenic EM 2-OHE2 increased the angiogenic potential and VEGF levels of GCs from PCOS women compared to the basal condition (P < 0.05). These findings suggest that there is a role for pro-angiogenic EMs in the control of follicular VEGF production. LIMITATIONS, REASONS FOR CAUTION: The limitations include the possibility that in vitro analysis of GCs might not reflect the in vivo mechanisms involved in the pro-angiogenic action of 2-OHE2 since GCs obtained at the time of oocyte retrieval belong to a very early stage of the luteal phase and might not be representative of GCs during follicular growth. Therefore, our findings do not conclusively rule out the possibility that other in vivo mechanisms also account for defective angiogenesis observed in PCOS. WIDER IMPLICATIONS OF THE FINDINGS: The present study highlights the significance of EMs, angiogenic factors and AMH and their interaction in the pathophysiology of follicular development in PCOS. This study provides new insights into the role of pro-angiogenic factors in follicular arrest in PCOS. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by CONICYT/FONDECYT 1140693 and NIH grant R01HD083323. All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Anti-Müllerian hormone in type 2 and gestational diabetes during the second half of pregnancy: relationship with sexual steroid levels and metabolic parameters.

Hyperandrogenemia and hyperinsulinemia are observed in women with diabetes during pregnancy. The effect of diabetes on anti-Müllerian hormone (AMH) levels during pregnancy is unclear. The aim of this study was to determine the AMH levels in women with type 2 diabetes (T2D) and gestational diabetes (GD) compared to healthy (C) pregnant women during the second half of gestation. A prospective study of 69 pregnant women with T2D (N: 21), GD (N: 24) and C (N: 24) were followed up during the second half of pregnancy. Clinical assessments and blood samples were collected at 26.7 (25-27.8); 34 (32-34.9) and 37.5 (37-40) weeks of gestation. AMH, sexual steroids, insulin, homeostatic model assessment of insulin resistance, HbA1c levels were measured. AMH levels were similar between T2D, GD and C (p = .07). A decline of AMH levels during the second half of gestation was observed in the three groups (p < .0001). AMH levels were negatively associated with age (p < .001). A positive association between AMH and testosterone (p < .05) was found in all groups. A progressive decline of AMH levels is observed in diabetic and healthy women during the second half of pregnancy. Testosterone levels are an independent factor that influences AMH levels during pregnancy. However, AMH levels are not affected by the presence of diabetes during gestation.

The use of long-acting reversible contraceptives in Latin America and the Caribbean: current landscape and recommendations.

STUDY QUESTION: Can the high rate and associated burden of unintended pregnancy (UP) and adolescent pregnancy in Latin America and the Caribbean (LAC) be reduced through wider access to and use of long-acting reversible contraceptive (LARC) methods? SUMMARY ANSWER: Studies show that impoved access to and use of LARC methods is an effective tool for reducing the high rates of UP, unsafe abortion and abortion-related complications, and maternal deaths (as well as reducing their social and financial burden), and we have provided recommendations to help achieve this in LAC. WHAT IS KNOWN ALREADY: LAC comprises 46 countries with 650 million inhabitants, and shows large disparities in socioeconomic development, access to health services and attention to sexual and reproductive health rights. The exercise of these rights and universal access to sexual and reproductive health (SRH) programmes is a key strategy for improving maternal health by reducing the number of UPs, the rate of women's and child mortality and morbidity, and the number of unsafe abortions. The implementation of SRH programmes in the region has contributed to a decrease in pregnancy rates of more than 50% over 40 years. However, despite this progress, the numbers of UP and adolescent pregnancies are still among the highest worldwide, which can be attributed in large part to the low prevalence of use of LARC methods. STUDY DESIGN SIZE DURATION: This is a position paper with the objective of reviewing the magnitude and burden of UP in LAC, as well as available LARC methods and barriers to their access, with the goal of increasing knowledge and awareness among healthcare professionals (HCP), policymakers and the general public about the potential to reduce UP rates through the increased use of LARC. PARTICIPANTS/MATERIALS SETTING METHOD: We searched the electronic databases of PubMed and EMBASE to identify studies published up to May 2017. We also searched for websites regarding LAC, LARC methods, and UP including, for example, those from the United Nations, the World Health Organization, Pan American Health Organization, the Alan Guttmacher Institute and the United States Agency for International Development. Studies were included if they investigated mainly UP and their consequences as well as the use of LARC methods in the region. During 3 days of meetings, the importance of the studies identified and the appropriateness of inclusion were discussed. MAIN RESULTS AND THE ROLE OF CHANCE: LAC is not one unit and shows great ethnic diversity as well as economic and cultural differences among the various countries. These differences must be taken into account when developing policies related to disseminating information and combatting misinformation regarding the use of LARC among different audiences, such as adolescents and young women, nulligravidas, indigenous populations and women with disabilities. Furthermore, only some governments have made efforts to increase accessibility to LARC methods, and there is a need to implement training programmes for HCPs, launch education campaigns for the general public, increase access and review the cost-benefit analyses specific to LARC, which have already demonstrated that the upfront cost of LARC is less than the cummulative expense of short-term contraceptives. Recommendations to achieve these goals are presented. LIMITATIONS REASONS FOR CAUTION: Knowledge and awareness of the contraceptive method itself and of the mix of individual countries in the region is essential to the development of specific strategies and actions, tailored to each particular country situation, aimed at increasing access to modern contraceptive methods, especially LARC. WIDER IMPLICATIONS OF THE FINDINGS: Healthcare systems in LAC should consider LARC as a primary option for decreasing UP and adolescent pregnancy. Disseminating information, increasing awareness of their efficacy, removing barriers and improving access to LARC methods are the urgent actions recommended for government, academia, professional organizations, insurance companies and policymakers in order to address this major public health problem in LAC. STUDY FUNDING/COMPETING INTERESTS: This manuscript was supported by a grant from the Americas Health Foundation (AHF), a 501(c)3 nonprofit organization dedicated to improving healthcare throughout the Latin American Region. LB and IM received additional support from the São Paulo Research Foundation (FAPESP) award # 2015/20504-9. The authors declare no conflict of interest.

New Diagnostic Criteria of Polycystic Ovarian Morphology for Adolescents: Impact on Prevalence and Hormonal Profile.

BACKGROUND: The ultrasonographic criteria used to identify polycystic ovarian morphology (PCOM) during adolescence have changed over time. Recently, a Worldwide Pediatric Consensus (PedC) defined PCOM using stricter criteria than the previous recommendations of the Rotterdam Consensus (RC) and Androgen Excess-Polycystic Ovarian Syndrome Society (AES/PCOS) criteria. The aim of this study was to determine the prevalence of PCOM in healthy adolescents according to the 3 reported diagnostic criteria and compare the hormonal profile in females with and without PCOM based on the PedC criteria. METHODS: Nonobese adolescents (n = 102) with regular menstrual cycles were studied. Transabdominal ultrasound and hormonal profiles were assessed during the follicular phase. PCOM was defined on the basis of the 3 published criteria. RESULTS: On the basis of the PedC, RC, and AES/PCOS criteria, PCOM was diagnosed in 13, 34, and 24% of adolescents, respectively. Adolescents with and without PCOM according to the PedC criteria had similar androgen levels. Serum anti-Müllerian hormone (AMH) levels were elevated in adolescents with PCOM, irrespective of the criteria used. CONCLUSIONS: Use of the new PedC diagnostic criteria for PCOM results in a lower prevalence of this ultrasonographic pattern in adolescents, but this condition is not associated with hyperandrogenism. Elevated AMH is associated with PCOM in adolescents regardless of the criteria used to determine the ultrasonographic pattern.

Hyperandrogenism in adolescent girls: relationship with the somatotrophic axis.

BACKGROUND: During puberty there is a physiologic increase in adrenal and ovarian androgens. It has been suggested that the somatotrophic axis may be related to the development of hyperandrogenism and anovulation in non-obese adult women with polycystic ovarian syndrome (PCOS). The objective of the study was to investigate whether ovarian androgen secretion in young postmenarchal girls is related to the function of their somatotropic axis. METHODS: This was a cross-sectional study of adolescent girls. We studied non-obese adolescent girls with hyperandrogenism (HA; n = 21) matched with control girls (C; n = 25) for chronological age, age at menarche and body mass index. We obtained a fasting blood sample for measurement of serum glucose, insulin, 17-hydroxyprogesterone (17OH-Prog), dehydroepiandrosterone-sulfate (DHEA-S), androstenedione, sex hormone-binding globulin (SHBG), total testosterone, IGF-I, IGF-II, IGFBP-1, IGFBP-3, ghrelin, leptin, AMH (antiMüllerian hormone), luteinizing hormone (LH) and follicle stimulating hormone (FSH) during the follicular phase of the menstrual period. We performed an oral glucose tolerance test to determine blood glucose, insulin and ghrelin levels and urine samples to measure urinary GH (growth hormone) levels. RESULTS: As expected, the hyperandrogenic girls had significantly higher Ferriman scores, basal total testosterone, free androgen index (FAI), androstenedione, AMH, and basal LH levels compared with the girls in controls. Serum IGF-I, IGF-II, IGFBP-3 and urinary GH did not differ between HA and C. There was a correlation between urinary GH and FAI in all girls (r 0.29, p < 0.05). In addition, in HA girls FAI correlated with insulin, homeostasis model assessment (HOMA) and ghrelin. CONCLUSIONS: We observed a correlation between urinary GH and FAI in the hyperandrogenic and control girls, suggesting that the function of the somatotrophic axis may influence the secretion of androgens in adolescent girls.

Pregestational type 2 diabetes and gestational diabetes exhibit different sexual steroid profiles during pregnancy.

Higher androgen levels are observed in non-pregnant women with diabetes. Whether this hormonal profile is found during pregnancy is unknown. The aim of this study was to determine the sexual steroids levels in pregnant women with pregestational type 2 (T2D) and gestational diabetes (GD) compared to healthy control (C) pregnant women during the second half of pregnancy. A prospective study of 69 pregnant women with T2D (n = 21), GD (n = 24) and control (C, n = 24) was followed up during the second half of gestation. Clinical assessments and blood samples were collected at 26.7 (25-27.8); 34 (32-34.9) and 37.5 (37-40) weeks of gestation. Androgens, sex hormone-binding globulin (SHBG), estrogens, estradiol/testosterone (E/T) ratio, insulin, glucose, HOMA-IR, were measured. Testosterone, insulin and homeostatic model assessment of insulin resistance (HOMA-IR) levels were higher in T2D compared with C at each sampling point during pregnancy, even after adjusting for BMI and age. Estrogens levels and estradiol/testosterone ratio were lower in T2D and GD compared with C. Hyperandrogenemia, and higher insulin resistance is observed in T2D, but not in GD during pregnancy. Decreased estrogen and E/T ratio found in T2D and GD suggests a diminished aromatase activity during gestation. T2D and GD are associated with specific changes in sexual steroids and insulin resistance levels during pregnancy.

Hirsutism and oligomenorrhea are appropriate screening criteria for polycystic ovary syndrome in adolescents.

We evaluated the association of hirsutism and oligomenorrhea (persistent menstrual cycles > 45 days) as screening criteria for the detection of biochemical hyperandrogenism (BH) and polycystic ovaries (PCOM) during adolescence and determined which androgens, granulosa cell hormone, ultrasonographic parameters have the best association with polycystic ovary syndrome (PCOS). Hirsute girls with oligomenorrhea (N = 26 Hirs/Oligo group) and non-hirsute girls with regular cycles (N = 63, C group) were studied. Prevalence of BH and PCOM, diagnostic performance of androgens and ultrasound parameters for PCOS diagnosis were analyzed. BH and PCOM prevalence were higher in the Hirs/Oligo girls than in the C girls (76.9% versus 25.5%; 92.3% versus 33.3%, respectively; p < 0.0001). A complete PCOS phenotype (Hirs/Oligo with BH and PCOM) was observed in 73.1% of the Hirs/Oligo group. The presence of both BH and PCOM was observed in 7.9% of the C group. The parameters with the best diagnostic performance were free androgen index ≥6.1, testosterone ≥2.4 nmol/L, follicle number ≥12 and ovarian volume ≥10 ml anti-Müllerian hormone (AMH) exhibited a low diagnostic accuracy. Hirsutism and persistent menstrual cycle over 45 days are highly associated with BH and PCOM suggesting that the presences of both criteria are necessary for the diagnosis of PCOS during adolescence.

Transient expression of progesterone receptor and cathepsin-l in human granulosa cells during the periovulatory period.

OBJECTIVE: To study in vivo the progesterone receptor (PR) expression levels in human granulosa cells (GCs) during the periovulatory period and the affect of the protein kinase A (PKA) pathway on PR expression and cathepsin-L expression-activation. DESIGN: Experimental study. SETTING: University research unit. PATIENT(S): Twenty-five women of reproductive age. INTERVENTION(S): Follicular fluid and GCs obtained from spontaneous cycles before and during the normal luteinizing hormone surge, and samples obtained 36 hours after human chorionic gonadotropin (hCG) administration in patients undergoing in vitro fertilization. MAIN OUTCOME MEASURE(S): To determine PR, cathepsin-L messenger RNA (mRNA) analysis via real-time polymerase chain reaction, and protein of PR, cathepsin-L, and PKA in human GCs. RESULT(S): The Western blot analysis revealed that bands of PR (isoform A) were the most abundant and that mRNA (PR-A and PR-B) have a temporal pattern of expression throughout the periovulatory period. The protein levels of PR and cathepsin-L were up-regulated by hCG. The abundance of PR was diminished in the presence of PKA inhibitor, and cathepsin-L with PR receptor antagonist. CONCLUSION(S): The transient expression of PR in human GCs of the preovulatory follicle suggests that PR and its ligand play a role in the activation of cathepsin-L, which is presumably involved in the degradation of the follicular extracellular matrix during human ovulation.

Contraceptive efficacy of emergency contraception with levonorgestrel given before or after ovulation.

BACKGROUND: The contraceptive efficacy of emergency contraceptive pills containing levonorgestrel (LNG-EC) has been estimated in most previous studies by judging the day of ovulation from presumptive menstrual cycle data, thus providing poorly reliable estimates. METHODS: In the present study, the efficacy of LNG-EC was determined in 393 cycles by dating ovulation on the basis of reliable hormonal and ovarian parameters validated by a database constructed in a separate study. In addition, the efficacy was determined separately for cycles in which LNG-EC was given before or after ovulation. RESULTS: For the 148 women who had sexual intercourse during the fertile days, the overall accumulated probability of pregnancy was 24.7, while altogether 8 pregnancies were observed. Thus, the overall contraceptive efficacy of LNG-EC was 68%. Among the 103 women who took LNG-EC before ovulation (days -5 to -1), 16 pregnancies were expected and no pregnancy occurred (p<.0001). Among the 45 women who took LNG-EC on the day of ovulation (day 0) or thereafter, 8 pregnancies occurred and 8.7 were expected (p=1.00). These findings are incompatible with the inhibition of implantation by LNG-EC in women. The same cases were also analyzed using the presumptive menstrual cycle data, and important discrepancies were detected between the two methods. CONCLUSION: The efficacy of LNG-EC has been overestimated in studies using presumptive menstrual cycle data. Our results confirm previous similar studies and demonstrate that LNG-EC does not prevent embryo implantation and therefore cannot be labeled as abortifacient.

Ovarian function in adolescents with McCune-Albright syndrome.

OBJECTIVE: To evaluate ovarian function, especially ovulation rate, in adolescents with McCune-Albright syndrome (MAS) and a history of peripheral precocious puberty. DESIGN: Prospective cross-sectional study. SETTING: Academic center. PATIENT(S): A total of eight adolescents with MAS were compared with 15 healthy adolescents matched by age, Tanner stage and body mass index. INTERVENTION(S): We determined basal gonadotropins, sex steroids, sex hormone binding globulin, anti-Müllerian hormone, glucose and insulin. A leuprolide acetate test was performed to measure luteinizing hormone (LH) and follicle stimulating hormone (FSH) (at 0 and 3 h), and 17B-estradiol, testosterone and 17-OH-progesterone (at 0 and 24 h). Salivary progesterone levels were used to assess ovulation during the 13th, 18th, 23rd and 28th days of each menstrual cycle for three to five consecutive cycles, and one pelvic ultrasound was performed during the follicular phase. MAIN OUTCOME MEASURE(S): Ovulation rate in adolescents with MAS. RESULT(S): The proportion of ovulatory cycles was 52.6% in controls compared with 35.7% in patients with MAS. CONCLUSION(S): The adolescent girls with MAS appear to have a lower ovulatory rate compared with controls.

Elevated anti-Müllerian hormone (AMH) and inhibin B levels in prepubertal girls with type 1 diabetes mellitus.

OBJECTIVE: Elevated anti-Müllerian hormone (AMH) and adrenal androgen levels have been observed during childhood in girls at risk of developing polycystic ovarian syndrome (PCOS). The aim of this study was to evaluate ovarian function and adrenal steroid levels in prepubertal girls with type 1 diabetes mellitus (T1D). DESIGN: Cross-sectional study. PATIENTS/MEASUREMENTS: We evaluated hormonal and ultrasonographic characteristics in girls with T1D (N = 73) and compared them to characteristics found in a control group of healthy girls (N = 86). Data are reported as geometric means (95% CI). RESULTS: Prepubertal girls with T1D had higher levels of AMH (29·1 pmol/l (23·2-36·3) vs 20·9 pmol/l (16·6-26·1), P = 0·038), inhibin B (arithmetic mean: 16·7 pg/ml (11·6-21·7) vs 11·7 pg/ml (10·0-13·5), P = 0·044) and dehydroepiandrosterone sulphate (DHEAS) (0·3 nmol/l (0·2-0·6) vs 0·2 nmol/l (0·1-0·3)) than controls (P = 0·045). During puberty, decreasing AMH levels were observed in girls with T1D only (P < 0·0001). Girls with T1D in Tanner stages 4-5 had lower AMH levels than their paired healthy controls (10·1 pmol/l (7·4-13·9) vs 15·7 pmol/l (11·6-21·3), respectively, P = 0·047). CONCLUSIONS: Our observations indicate that prepubertal girls with T1D may exhibit similar endocrine findings to those of other girls at risk of developing PCOS. The elevated levels of AMH and inhibin B suggest that higher numbers of follicles are present in the ovary during childhood in these patients and that insulin treatment may act as a local growth factor. In addition, AMH levels differed in prepubertal and pubertal girls, suggesting that the effect of T1D on ovarian folliculogenesis changes once gonadotrophin levels rise during puberty.

Polycystic ovarian morphology in postmenarchal adolescents.

OBJECTIVE: To evaluate the association of polycystic ovary morphology (PCOM) with ovarian function in adolescents and to determine its time course during two years of follow-up. DESIGN: Prospective study. SETTING: Academic center. PATIENT(S): Twenty healthy adolescents were followed from 2-4 years after menarche. INTERVENTION(S): We performed annual ultrasonographic and hormonal studies. Ovulation was assessed during 6 consecutive months by measuring salivary progesterone levels. MAIN OUTCOME MEASURE(S): Persistence of PCOM during the years following menarche; ovulation in girls with PCOM. RESULT(S): PCOM was observed in 40%, 35%, and 33.3% of the ultrasonographic studies performed at 2, 3, and 4 years after menarche, respectively. The concordance between ultrasonographic diagnosis at 2 and 4 years postmenarche (50%) was nonsignificant (kappa = 0.08). PCOM was not associated with abnormalities in ovulatory rate, menstrual cycle duration, lipid levels, or homeostatic model assessment of insulin resistance. However, lower FSH (4.8 ± 1.3 vs. 6.1 ± 1.9 mUI/ml) were observed in girls with PCOM compared with those without PCOM. Similar T and stimulated 17-hydroxyprogesterone on the leuprolide test were observed in girls with and without PCOM. CONCLUSION(S): PCOM is an inconstant finding in healthy adolescents and does not appear to be associated with decreased ovulatory rate or metabolic abnormalities in healthy adolescents. This finding suggests that PCOM may correspond to a physiologic condition during early adolescence.

Contraceptive efficacy of emergency contraception with levonorgestrel given before or after ovulation.

BACKGROUND: We aimed to evaluate whether emergency contraception with levonorgestrel (LNG-EC) administered after ovulation is equally effective to LNG-EC administered before ovulation. STUDY DESIGN: We studied a cohort of women attending a family planning clinic for EC. From interview, we recorded menstrual history, time of intercourse and of intake of LNG-EC. On the day of intake of LNG-EC and during 5 days' follow-up, blood samples were taken for examination of luteinizing hormone, estradiol and progesterone concentrations, and vaginal ultrasound examinations were done for size of the leading follicle and/or corpus luteum. Thereafter women were not contacted until next menses or pregnancy occurred. RESULTS: Of 388 women attending for LNG-EC, 122 women had intercourse on fertile cycle days according to ultrasound and endocrine findings. At the time of LNG-EC intake, 87 women were in Days -5 to -1 and 35 women were in Day 0 (day of ovulation) or beyond. With the use of the probability of clinical pregnancy reported by Wilcox et al. [N Engl J Med 333 (1995) 1517-1521], expected numbers of pregnancies among the 87 and 35 women were 13 and 7, respectively, while 0 and 6 pregnancies, respectively, occurred. CONCLUSION: We conclude that LNG-EC prevents pregnancy only when taken before fertilization of the ovum has occurred.

Assessment of diagnostic competence of plasmatic androgens on polycystic ovary syndrome based on receiver operator characteristic curves.

OBJECTIVE: This study was designed to assess the diagnostic potency of different androgens in hyperandrogenaemia criterion on polycystic ovary syndrome (PCOS) based on receiver operator characteristic (ROC) curves analysis. METHODS: We evaluated 55 PCOS patients and 27 healthy fertile women (control). Androgen evaluation included bio-available testosterone (BAT) by ammonium sulphate precipitation, Free Testosterone Index (FTI), androstenedione (A), total testosterone and dehydroepiandrosterone sulphate (DHEA-S). RESULTS: The androgen tests with the best diagnostic capacities were FTI and BAT. Although T and A had similar diagnostic potencies, A detected 5% of PCOS patients that could not be recognised by FTI, BAT (%), or T. The association of FTI, BAT (%) and A identified 96.36% of the hyperandrogenaemic patients. DHEA-S showed a wide dispersion of values and therefore poor discriminatory competence. DISCUSSION: This study suggests that routine androgen evaluation in PCOS should include FTI, BAT and A to avoid misdiagnosis. ROC curve analysis of these tests on patients with the complete spectrum of PCOS phenotypes is needed to confirm these results.