Resolution of the 1st Ukrainian expert forum on abnormal uterine bleeding

The menstrual cycle is an important indicator not only of the female reproductive system health but also an integral part of women's health. The issues of therapeutic approaches for menstrual disorders, considering the general trend towards an increase in the proportion of this pathology among the total gynecological disorders in Ukraine, are susceptible and require close attention. The problem of abnormal uterine bleeding (AUB) has a significant impact on women and health care worldwide. Algorithms for the diagnosis and therapy of AUB need to be regularly revised as international recommendations are updated, clinical trials are published, and a new look at pathogenetic mechanisms is made.The prerequisites for holding of this Expert Forum were the updating of the FIGO classification of uterine bleeding in 2018, the NICE guidelines “Heavy menstrual bleeding: assessment and management” in 2018 and 2021, as well as the new conditions of the pandemic era, which has taken its toll on the care of patients with AUB.The Resolution summarized all data unaccounted for in the current clinical protocol for AUB issued in 2016 and updated data from international guidelines and key studies in patients with AUB; highlighted in detail current thinking on the pathogenetic therapy of functional AUB, with an emphasis on chronic AUB associated with ovulatory dysfunction (AUB-O) and endometrial disorders (AUB-E), as the most common; provided modern approaches to the management of chronic AUB associated with non-structural causes (ovulatory dysfunction and endometrial factors), and prevention of acute AUB for implementation in clinical practice and improving the provision of evidence-based medical care and individualized patient care.The Resolution aims to optimize clinical approaches to patient management and ensure therapy personalization, which together will improve the reproductive health and general well-being of Ukrainian women.

Autoimmunity to the Follicle-Stimulating Hormone Receptor (FSHR) and Luteinizing Hormone Receptor (LHR) in Polycystic Ovarian Syndrome

Hyperandrogenemia and ovulatory dysfunction are hallmarks of polycystic ovary syndrome (PCOS), pointing to a deranged hypothalamus-pituitary-ovarian (HPO) axis. An autoimmune etiology of PCOS is suspected in a subset of patients due to the relatively high concordance of PCOS with common autoimmune diseases. For this reason, we tested the hypothesis that natural autoantibodies (aAb) to the follicle-stimulating hormone receptor (FSHR) or luteinizing hormone receptor (LHR) are prevalent in PCOS. To this end, new luminometric assays for quantifying aAb to the FSHR (FSHR-aAb) or LHR (LHR-aAb) were developed using full-length recombinant human receptors as fusion proteins with luciferase as reporter. Prevalence of FSHR-aAb and LHR-aAb was determined in serum samples from healthy controls and PCOS patients. Steroid hormone profiles were compared between patients with and without FSHR-aAb or LHR-aAb. Signal linearity and detection ranges were characterized and both methods passed basic performance quality checks. The analysis revealed a relatively low prevalence, with 4 out of 430 samples positive for FSHR-aAb in the control versus 11 out of 550 samples in the PCOS group, i.e., 0.9% versus 2.0%, respectively. Similarly, there were only 5 samples positive for LHR-aAb in the control versus 2 samples in the PCOS group, i.e., 1.2% versus 0.4%, respectively. Samples positive for FSHR-aAb displayed steroid hormones in the typical range of PCOS patients, whereas the two samples positive for LHR-aAb showed relatively elevated free testosterone in relation to total testosterone concentrations with unclear significance. We conclude that the FSHR and LHR constitute potential autoantigens in human subjects. However, the prevalence of specific autoantibodies to these receptors is relatively low, both in control subjects and in women with PCOS. It is therefore unlikely that autoimmunity to the LHR or FSHR constitutes a frequent cause of hyperandrogenemia or ovulatory dysfunction in PCOS.

Clinical Manifestations of Hyperandrogenism and Ovulatory Dysfunction Are Not Associated with His1058 C/T SNP (rs1799817) Polymorphism of Insulin Receptor Gene Tyrosine Kinase Domain in Kashmiri Women with PCOS

Background. Polycystic ovary syndrome (PCOS) is the most common endocrine metabolic disorder affecting premenopausal women. Besides primary features like anovulation, hyperandrogenism, and polycystic ovaries, women with PCOS present with multiple metabolic, cardiovascular, and psychological disorders. The etiology is multifactorial and the different genetic variants are suggested to play an important role in pathogenesis. Insulin resistance is a ubiquitous finding in PCOS and SNPs in genes involved in the insulin signaling pathway are possible candidates that can explain the development of clinical manifestations of PCOS. Aim. We aimed to investigate the association of INSR His1058 C/T (rs1799817) single nucleotide polymorphism with PCOS in Kashmiri women. The genotypic-phenotypic correlation of the tested SNP with hyperandrogenism, ovulatory dysfunction, and metabolic markers was evaluated. Results. The allele frequency (OR = 1.00, 95% CI = 0.67–1.48, χ2 = 0.01, P = 0.99 ) and genotype distribution (χ2 = 3.73, P = 0.15 ) in INSR C/T polymorphism were comparable with controls. No significant association was found with PCOS in dominant ( P = 0.194 ), recessive ( P = 0.442 ), and homo vs. het. ( P = 0.5 ) genotype models. Genotype-phenotype correlation analysis revealed that variant TT genotype had significantly higher HOMA ( P = 0.029 ) and reduced insulin sensitivity QUICKI ( P = 0.037 ) values. There was no significant variation in the prevalence of hirsutism, acne, alopecia, menstrual disturbances, acanthosis nigricans, and obesity (all P > 0.05 ) in different INSR C/T genotypes. Conclusion. The INSR C/T SNP (rs1799817) does not increase the risk of PCOS in Kashmiri women. This SNP is unlikely to play a significant role in the development and manifestation of clinical symptoms of polycystic ovary syndrome.

Anti-Müllerian Hormone in Pathogenesis, Diagnostic and Treatment of PCOS

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-aged women. It is characterized by chronic anovulation, hyperandrogenism, and the presence of polycystic ovary in ultrasound examination. PCOS is specified by an increased number of follicles at all growing stages, mainly seen in the preantral and small antral follicles and an increased serum level of Anti-Müllerian Hormone (AMH). Because of the strong correlation between circulating AMH levels and antral follicle count on ultrasound, Anti-Müllerian Hormone has been proposed as an alternative marker of ovulatory dysfunction in PCOS. However, the results from the current literature are not homogeneous, and the specific threshold of AMH in PCOS and PCOM is, therefore, very challenging. This review aims to update the current knowledge about AMH, the pathophysiology of AMH in the pathogenesis of PCOS, and the role of Anti-Müllerian Hormone in the treatment of this syndrome.

Abnormal Uterine Bleeding in Adolescence: When Menarche Reveals other Surprises

Introduction Abnormal uterine bleeding is more frequent in adolescence. Although, most commonly, it has a non-structural etiology, it may be due to any cause described. Clinical case A 12-year-old adolescent, with no relevant personal history, menarche 1 month before, was observed in the emergency department for severe menstrual bleeding with progressive worsening, and hemodynamic repercussion in need of transfusion support. Physiological ovulatory dysfunction associated with possible previously unknown coagulopathy was considered to be the most likely diagnosis and medical treatment was initiated. Without response, the patient was submitted to sedated observation and uterine aspiration, which ultimately led to the diagnosis of a Burkitt Lymphoma. Discussion Although structural causes, and particularly malignancy, whether gynecological or not, are a rare cause of abnormal uterine bleeding in this age group, they must be considered, thus enhancing the fastest and most appropriate treatment.

Prevalence and Causes of Infertility in Overweight and Obese Women in a Tertiary Care Hospital Setup in Mangalore - A Retrospective Secondary Data Analysis

BACKGROUND Obesity has become an epidemic worldwide. Several mechanisms are involved in the relationship of fertility and obesity, including metabolic and reproductive functions. In light of the fact that most of the causes of infertility are treatable, there is a need to document the diagnostic findings in overweight and obese infertile women. The causes of infertility prevalent in a particular region can be provided by hospital-based studies. So, the present study is designed to find out the common causes of infertility in overweight & obese women and to gain knowledge regarding the prevalence of primary and secondary infertility among these infertile women. METHODS The data of 115 infertile women (18 to 45 years) were collected from hospitals under Kasturba Medical College (KMC), Mangalore retrospectively. Data of history of previous conception, body mass index (BMI), type of infertility, duration of infertility, age and the causes of infertility were collected. The prevalence of each cause was evaluated. RESULTS Among 115 infertile women, 92 (80 %) were pre–obese and 23 (20 %) were obese (P - .001). Primary infertility was most common in pre obese women and secondary infertility in obese women which was statistically significant (P < .05). Ovulatory dysfunction was the most common cause in obese infertile women (P - .004), whereas in pre obese women, it was uterine and adnexal causes. CONCLUSIONS Comparatively, maintaining a healthy lifestyle can avoid fertility problems in pre obese women, because the effect of BMI on hypothalamic–pituitary-gonadal (HPG) axis is higher in obese women in whom ovulatory disorders were the leading cause. The significance of weight reduction before pregnancy should be informed to overweight and obese patients and should be aided to lose weight. Treatment of anaemia itself may resolve the infertility issues and should be taken as a first line treatment in all cases. KEYWORDS Female Infertility, Adipose Tissue, Obesity, Infertility Causes, Ovulatory Dysfunction

P–601 Anovulatory patients with PCOS have lower euploidy rates compared to those with hypothalamic amenorrhea and to normo-ovulatory patients

Study question How do euploidy rates differ in anovulatory women with polycystic ovarian syndrome (PCOS) and hypothalamic hypogonadism (HH) compared to normo-ovulatory women undergoing IVF/ICSI? Summary answer Patients with PCOS have a significantly lower euploidy rate compared to patients with HH and patients with tubal factor infertility. What is known already Previous studies have demonstrated similar blastocyst conversion rates in women with PCOS and tubal factor infertility. Reported aneuploidy rates in preimplantation genetic testing cycles are similar in women with PCOS and tubal infertility. There are no data on blastocyst conversion or aneuploidy rates in women with HH. While PCOS and HH are different physiologic processes, patients with these disorders are reported together to SART and to the CDC National ART Surveillance System under the diagnosis of “ovulatory dysfunction”. Study design, size, duration: Retrospective cohort study of all autologous IVF and ICSI cycles for patients with oligo-anovulation (PCOS, n = 552 and HH, n = 48) and normo-ovulation (tubal factor infertility, n = 423) from 1/1/2012 to 6/30/2019. A total of 1023 cycles from 720 patients were analyzed. Participants/materials, setting, methods Cycle outcomes, including number of oocytes, mature oocytes, blastocysts and euploid blastocysts were assessed for each diagnosis. Adjusted relative risks (aRR) and 95% confidence intervals (CI) were calculated adjusting for age, BMI, AMH, and stimulation protocol. Poisson regression was used for counts and with an offset for ratios. Patients contributing multiple cycles were accounted for using general estimating equations. Main results and the role of chance PCOS patients were given a lower starting dose of gonadotropins and received less total gonadotropins compared to patients with tubal factor infertility or HH, but had similar stimulation durations as tubal-factor patients. Patients with HH received higher total doses of gonadotropins and had longer stimulation durations. PCOS patients had significantly more oocytes retrieved and a higher number of blastocysts than patients with tubal factor infertility (18.9 vs. 13.6 aRR 1.16 95% CI: 1.05–1.28 and 6.6 vs. 3.7 aRR 1.32 95% CI 1.10–1.57, respectively). Patients with HH had a similar number of oocytes retrieved and number of blastocysts compared to tubal factor patients. The blastocyst conversion rate was higher for PCOS than tubal (59.4% vs. 49.7%), but not significantly different (aRR 1.04 95% CI: 0.94–1.15). Blastocyst conversion and euploidy rates were similar for HH and tubal factor patients (51.9% vs. 49.7% and 39.1% vs. 44.9%, respectively, aRR 1.01 95% CI: 0.81–1.26 and aRR 1.05 95% CI: 0.85–1.31, respectively). In the adjusted model, patients with PCOS had a significantly lower euploidy rate than patients with tubal infertility (aRR 0.75 95% CI: 0.58–0.96). Patients with HH also had a significantly higher euploidy rate compared to women with PCOS (aRR 1.41 95% CI: 1.05–1.89). Limitations, reasons for caution This study is limited by its retrospective nature and the small sample size of women with hypothalamic hypogonadism. Additionally, these data represent outcomes from a single academic center, so generalizability of our findings may be limited. Wider implications of the findings: Cycle outcomes differ for ovulatory dysfunction patients with PCOS as compared to those with HH. HH patients require higher total doses of gonadotropins and longer stimulations to achieve similar cycle outcomes as normo-ovulatory patients. While PCOS patients have more embryos, the percent of euploid blastocysts is lower. Trial registration number Not applicable

Homeopathic Treatment in Patients with Polycystic Ovarian Syndrome: A Case Series

Background and Objectives Polycystic ovary syndrome (PCOS) is a common heterogeneous endocrine disorder in women of reproductive age. It is characterized by various clinical presentations such as ovulatory dysfunction, polycystic ovaries, and hyperandrogenism. Considering the side effects associated with conventional treatment and the patients who fail to respond to these measures, there is a demand for a complementary therapy that would alleviate symptoms of PCOS without side effects. Homeopathy is a complementary system of medicine that has been successfully used in different disease conditions, including PCOS. A case series of PCOS is hereby presented, to demonstrate some positive results of individualized homeopathic treatment. Methods Seven cases of young women with PCOS were treated with individualized homeopathic medicines. Each case was followed up with clinical and ultrasonographic evidence and was reported according to the criteria set out in the HOM-CASE guidelines. The assessment of causal attribution of homeopathic treatment effect was carried out using the Modified Naranjo Criteria. Results Marked improvement was observed in all seven cases of PCOS. The irregular menstrual cycles and other associated symptoms became normal, along with a resolution of cysts in ovaries as evidenced by ultrasonography. All cases improved within 4 to 12 months of treatment. The Modified Naranjo Criteria total score was +9/13 for each case, which indicates a positive causal attribution of homeopathy in relieving the symptoms of PCOS. Conclusion This case series suggests a significant role of individualized homeopathic medicines in PCOS by regularizing the menstrual cycle along with the resolution of cysts and associated symptoms.