PCOS and vitamin D: a clinical appraisal.

PURPOSE: Polycystic ovary syndrome (PCOS) is the most common endocrine-reproductive disease linked not just to infertility but also to serious comorbidities. There is a reported association between low vitamin D levels and multiple health conditions including PCOS. This narrative review aims to analyze the role of vitamin D in PCOS development, use of the vitamin D in the treatment of PCOS, and the molecular basis of these observations. METHODS: A Medline and PubMed research was performed, during the years 1990-2023, using a combination of keywords on such topic. According to the author's evaluation and target, papers were identified and included for a narrative review. RESULTS: There are associations between lower levels of vitamin D and PCOS, as well as with insulin resistance, metabolic syndrome, hyperandrogenemia, metabolic and endocrine disorders as well as the onset of oxidative stress and pro-inflammatory milieu, in PCOS women. CONCLUSION: Vitamin D has a role in pathologic changes linked to PCOS. Molecular and clinical investigations which give new information about the role of vitamin D in the development of PCOS and related endocrine and metabolic disturbance are further needed.

Currently Available Treatment Modalities for Uterine Fibroids.

Uterine fibroids (leiomyomas and myomas) are the most common benign gynecological condition in patients presenting with abnormal uterine bleeding, pelvic masses causing pressure or pain, infertility and obstetric complications. Almost a third of women with fibroids need treatment due to symptoms. OBJECTIVES: In this review we present all currently available treatment modalities for uterine fibroids. METHODS: An extensive search for the available data regarding surgical, medical and other treatment options for uterine fibroids was conducted. REVIEW: Nowadays, treatment for fibroids is intended to control symptoms while preserving future fertility. The choice of treatment depends on the patient's age and fertility and the number, size and location of the fibroids. Current management strategies mainly involve surgical interventions (hysterectomy and myomectomy hysteroscopy, laparoscopy or laparotomy). Other surgical and non-surgical minimally invasive techniques include interventions performed under radiologic or ultrasound guidance (uterine artery embolization and occlusion, myolysis, magnetic resonance-guided focused ultrasound surgery, radiofrequency ablation of fibroids and endometrial ablation). Medical treatment options for fibroids are still restricted and available medications (progestogens, combined oral contraceptives andgonadotropin-releasing hormone agonists and antagonists) are generally used for short-term treatment of fibroid-induced bleeding. Recently, it was shown that SPRMs could be administered intermittently long-term with good results on bleeding and fibroid size reduction. Novel medical treatments are still under investigation but with promising results. CONCLUSIONS: Treatment of fibroids must be individualized based on the presence and severity of symptoms and the patient's desire for definitive treatment or fertility preservation.

Uterine Aging and Reproduction: Dealing with a Puzzle Biologic Topic.

Uterine aging is the process of the senescence of uterine tissue, observed in all middle-aged mammals. Since the aging-related changes in the uterus are associated with infertility and poor pregnancy outcomes, with a lack of studies discussing uterine aging, authors reviewed uterine aging and its consequences on reproduction. MEDLINE, Scopus, and PubMed searches during the years 1990-2023 were performed using a combination of keywords and terms on such topics. According to the author's evaluation, articles were identified, selected, and included in this narrative review. The aging process has an unfavorable impact on the uterus of mammals. There are different and selected molecular pathways related to uterine aging in humans and animals. Uterine aging impairs the function of the uterine myometrium, neurofibers of the human uterus, and human endometrium. These biological pathways modulate oxidative stress, anti-inflammatory response, inflammation, mitochondrial function, DNA damage repair, etc. All these dysregulations have a role in poorer reproductive performance and pregnancy outcomes in older mammals. The most recent data suggest that uterine aging is accompanied by genetic, epigenetic, metabolic, and immunological changes. Uterine aging has a negative impact on the reproductive performance in mammalian species, but it could be potentially modulated by pharmacological agents, such as quercetin and dasatinib.

Severe Hemoperitoneum due to Ovarian Bleeding after Transvaginal Oocyte Retrieval with Surgical Management: A Retrospective Analysis and Comprehensive Review of the Literature.

Background and Objectives: Severe hemoperitoneum of ovarian bleeding origin is a rare but potentially life-threatening complication of transvaginal oocyte retrieval (TVOR) procedure. The study aimed to present a case series of surgically managed patients from our clinic with hemoperitoneum caused by ovarian bleeding after TVOR, as well as to perform a comprehensive literature review in order to summarize and analyze all published cases with this condition and their management. Materials and Methods: The data of 2939 patients, who underwent TVOR procedures for IVF/ICSI (in vitro fertilization, intracytoplasmic sperm injection) in our clinic between 2010 and 2021 were reviewed. Moreover, a systemic literature search was performed. Main outcome measures from the pooled analysis were incidence and risk factors, type of surgery, intraoperative finding and intervention leading to hemostasis. Results: In our Clinic 4 (0.136%), cases of hemoperitoneum due to ovarian bleeding were surgically managed. Moreover, 39 cases from 18 studies reported in the literature were identified. No risk factors besides lean women with PCOS were identified. In the pooled analysis, the bleeding symptoms appeared in 58.1% of patients within eight hours after TVOR and cumulatively in 81.4% cases during the 24 h after TVOR. The average time from TVOR to surgery was 27.19 ± 53.25 h. Hemostasis was mostly established using electrocoagulation, although few cases of ovariectomy were also reported. Embryo transfer at 60% of cases was postponed and embryos cryopreserved. Conclusions: Severe hemoperitoneum due to ovarian bleeding after TVOR is a rare event that should be treated by techniques of minimally invasive surgery whenever possible. Protocols should be developed to enable optimal management strategies for infertility patients. Embryos obtained should be cryopreserved.

Molecular Insights in Uterine Leiomyosarcoma: A Systematic Review.

Uterine fibroids (UFs) are the most common benign tumors of female genital diseases, unlike uterine leiomyosarcoma (LMS), a rare and aggressive uterine cancer. This narrative review aims to discuss the biology and diagnosis of LMS and, at the same time, their differential diagnosis, in order to distinguish the biological and molecular origins. The authors performed a Medline and PubMed search for the years 1990-2022 using a combination of keywords on the topics to highlight the many genes and proteins involved in the pathogenesis of LMS. The mutation of these genes, in addition to the altered expression and functions of their enzymes, are potentially biomarkers of uterine LMS. Thus, the use of this molecular and protein information could favor differential diagnosis and personalized therapy based on the molecular characteristics of LMS tissue, leading to timely diagnoses and potential better outcomes for patients.

Correlation between PAI-1, leptin and ferritin with HOMA in HIV/AIDS patients.

BACKGROUND: Data about correlation of interleukins (IL-1 α, IL-1 ß, IFN γ, IL-2, IL-4, IL-6, IL-8, IL-10), adipocytokines (leptin, adiponectin, monocyte chemoattractant protein-1 (MCP-1), resistin, plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor alpha (TNFα), ferritin, C reactive protein (CRP) and vascular endothelial growth factor (VEGF) with homeostasis model assessment (HOMA) in HIV/AIDS patients are still limited. Therefore the aim of this study was to evaluate the possible correlations of serum levels of PAI-1, leptin and ferritin with HOMA in HIV/AIDS patients treated with combined antiretroviral therapy (cART). METHODS: This cross-sectional study included 64 HIV/AIDS patients, all Caucasians, receiving cART at the HIV/AIDS Centre, Belgrade, Serbia. PAI-1, leptin, ferritin and insulin levels were measured using the Metabolic Syndrome Array I (Randox Laboratories Ltd., London, UK), while adiponectin and resistin levels were measured using Metabolic Syndrome Array II (Randox Laboratories Ltd., London, UK), interleukins (IL-1 α, IL-1 ß, IFN γ, IL-2, IL-4, IL-6, IL-8, IL-10), MCP-1, TNF-α as well as VEGF was measured using Cytokine Array I (Randox Laboratories Ltd., London, UK). Insulin resistance was determined using the homeostasis model assessment index (HOMA). Multicollinearity of independent variables in multivariate model was analyzed using Variance Inflation Factor. RESULTS: Correlation analysis revealed significant correlations between HOMA and waist circumference, body mass index, patients' age, number of cART combinations and triglycerides (p = 0.001, p = 0.001, p = 0.050, p = 0.044, p = 0.002, respectively). HOMA negatively correlated with levels of high density lipoprotein (HDL) (Rho = -0.282; p = 0.025). PAI-1 (Rho = 0.334; p= 0.007) and leptin (Rho = 0.492; p = 0.001) together with ferritin (Rho = 0.396, p = 0.001) positively and significantly correlated with HOMA. Levels of IL-1 α, IL-1 ß, IFN γ, IL-2, IL-4, IL-6, IL-8, IL-10, adiponectin, MCP-1, resistin, TNF-α, CRP and VEGF did not significantly correlate with HOMA. Further, multiple logistic regression showed that there is a statistically significant correlation between PAI, leptin and ferritin with HOMA levels (p = 0.042; p < 0.001, p = 0.009). CONCLUSIONS: We showed significant correlation between PAI-1, leptin and ferritin, independently of each other with HOMA, in HIV/AIDS patients on cART.

Lower levels of IL-4 and IL-10 influence lipodystrophy in HIV/AIDS patients under antiretroviral therapy.

BACKGROUND: The role of interleukins in the pathogenesis of lipodystrophy in HIV/AIDS-patients is still not understood. The aim of this study was to evaluate the relationship between serum levels of interleukins between HIV/AIDS-patients with or without lipodystrophy, as well as between different subgroups of lipodystrophy (lipoatrophy, lipohypertrophy, mixed-fat-redistribution) and patients without lipodystrophy. METHODS: Cross-sectional study of 66 HIV/AIDS patients, all Caucasians. Serum levels of interleukins (IL-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10) were measured using Cytokine-Array-1 on Evidence Investigator, Biochip Array Technology. The associations between interleukins and anthropometric and metabolic variables were estimated by Spearman-correlation. Analysis of covariance with bootstrapping method (ACBM) was used to examine relationship between interleukins and lipodystrophy categories adjusted for confounding variables. RESULTS: The lipodystrophy was observed in 29 (44%) patients, while 15 (52%) had lipoatrophy, 4 (14%) lipohypertrophy and 10 (34%) patients had mixed fat redistribution. There were 37 (56%) patients without lipodystrophy. Significantly lower levels of IL-4 and IL-10 were observed in lipodystrophy vs. non-lipodystrophy (p=0.008; p=0.027, respectively). No differences were found relating IL-1α, IL-1ß, IL-2, IL-6 and IL-8 levels in lipodystrophy vs. non-lipodystrophy. In patient subgroup with lipoatrophy, significantly lower levels of IL-4 and IL-10 were found when compared to non-lipodystrophy (p=0.043; p=0.031, respectively). In lipohypertrophy subgroup significantly lower levels of IL-4 were found when compared to non-lipodystrophy (p=0.003). In order to estimate the correlation of IL-4 and IL-10 and the presence of lipodystrophy, ACBM showed that correlation of IL-4 levels in patients with lipodystrophy remains statistically significant (p=0.004) in all types of lipodystrophy: lipoatrophy, lipohypertrophy and mix-fat-redistribution (p=0.027; p=0.009; p=0.017, respectively) after adjustment for age, BMI. CONCLUSIONS: IL-4 and IL-10 levels were significantly lower in lipodystrophy vs. non-lipodystrophy. According to our knowledge, we showed for the first time significant correlation between IL-4 levels and lipodystrophy development in HIV/AIDS patients.

The Comparative Effects of Myo-Inositol and Metformin Therapy on the Clinical and Biochemical Parameters of Women of Normal Weight Suffering from Polycystic Ovary Syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a multisystem reproductive-metabolic disorder and the most common endocrine cause of infertility. The objective of our study was to determine the influence of myo-inositol (MI) on insulin resistance (IR), menstrual cycle regularity, and hyperandrogenism in women suffering from PCOS with normal BMI and diagnosed IR. METHODS: We performed a prospective randomized controlled trial (RCT) that included 60 participants with PCOS who had IR and a normal BMI. Two groups were formed. A group of thirty patients received MI, and thirty patients in the control group received metformin (MET). RESULTS: A statistically significant reduction in the area under the curve (AUC) of insulin values during the oral glucose tolerance test (OGTT) was recorded in both examined groups after the applied therapy with MI and MET. The regularity of the menstrual cycle in both groups was improved in >90% of patients. A statistically significant decrease in androgenic hormones (testosterone, SHBG, free androgen index-FAI, androstenedione) was recorded in both groups and did not differ between the groups. CONCLUSIONS: Both MI and MET can be considered very effective in the regulation of IR, menstrual cycle irregularities, and hyperandrogenism in women with PCOS.

Insulin-sensitizing agents for infertility treatment in woman with polycystic ovary syndrome: a narrative review of current clinical practice.

PURPOSE: Polycystic ovary syndrome (PCOS) is an endocrine, metabolic, and reproductive disorder which, according to the Rotterdam criteria, affects up to 24% of women of childbearing age. Although the prevalence of infertility in this subpopulation of women is high, the optimal treatment has not been fully established yet. Insulin resistance is considered to be an important mechanism involved in the development of PCOS; hence, the aim of this narrative review is to present an overview of the current pharmacological insulin-sensitizing treatment modalities for infertile women with PCOS. METHODS: A MEDLINE and PubMed search for the years 1990-2023 was performed using a combination of keywords. Clinical trials with insulin sensitizers used for infertility treatment as well as analyses of systematic reviews and meta-analyses were evaluated. When deemed necessary, additional articles referenced in the retrieved papers were included in this narrative review. RESULTS: Several insulin-sensitizing compounds and various therapeutical protocols are available for infertility treatment of women with PCOS. Metformin is the most common adjuvant medication to induce ovulation in infertile women with PCOS and is more frequently administered in combination with clomiphene citrate than on its own. Recently, inositol and glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as possible options for infertility treatment in PCOS. CONCLUSION: The future of medical treatment of PCOS women with infertility lies in a personalized pharmacological approach, which involves various compounds with different mechanisms of action that could modify ovarian function and endometrial receptivity, ultimately leading to better overall reproductive outcomes in these women.

Predictive Role of Progesterone Levels for IVF Outcome in Different Phases of Controlled Ovarian Stimulation for Patients With and Without Endometriosis: Expert View.

The study aimed to review the role of basal, trigger, and aspiration day progesterone levels (PLs) as predictors of in vitro fertilization (IVF) success for patients with and without endometriosis. A non-systematic review was conducted by searching papers published in English during the period of 1990-2023 in MEDLINE and PubMed, Embase, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register), and Web of Science. The most widely used IVF predictor success was the trigger day progesterone serum level. Many studies utilize the threshold level of 1.5-2.0 ng/ml. However, the predictive power of only progesterone level failed to show high sensitivity and specificity. Contrary, progesterone level on the trigger day combined with the number of mature retrieved oocytes had the highest predictive power. High baseline progesterone level was associated with poor IVF outcomes. Research on progesterone and IVF success in patients with endometriosis is limited but indicates that endometriosis patients seem to benefit from higher progesterone concentrations (≥ 37.1 ng/ml) in IVF cycles. Currently, there is limited data for a definitive insight into the mportance of progesterone in the estimation of IVF success. Nonetheless, this summarized evidence could serve as up-to-date guidance for the role of progesterone in the prediction of IVF outcomes, both in patients with and without endometriosis.

Reproductive and Obstetric Outcomes after Fertility-Sparing Treatments for Cervical Cancer: Current Approach and Future Directions.

Cervical cancer is one of the leading causes of cancer-related death in women of reproductive age. The established fertility-sparing approaches for the management of early-stage cervical cancer for women who plan pregnancy are associated with a decline in fecundity and an increased risk of pregnancy complications. This article aims to offer an overview of fertility-sparing approaches and the management of potential subfertility and pregnancy complications after these treatments. An extensive search for the available data about infertility and cervical cancer, fertility-sparing techniques in patients with cervical cancer, fertility treatment, obstetrical complications, and pregnancy outcomes in cervical cancer patients was completed. Fertility-preserving procedures such as loop electrosurgical excision procedure (LEEP), cold-knife conization, and trachelectomy in women diagnosed with cervical cancer can be considered as safe and effective treatments that preserve reproductive potential. Current fertility-preserving procedures, based on the balance of the oncological characteristics of patients as well as their desire for reproduction, allow one to obtain acceptable reproductive and obstetric outcomes in women treated for cervical cancer. Nevertheless, careful monitoring of pregnancies obtained after fertility-preserving procedures is recommended, since this cohort of patients should be considered at higher risk compared with a healthy population.

Prevalence, Risk Factors, and Pathophysiology of Nonalcoholic Fatty Liver Disease (NAFLD) in Women with Polycystic Ovary Syndrome (PCOS).

Background: Polycystic Ovary Syndrome (PCOS) is one of the most common endocrine disorders in women's reproductive period of life. The presence of nonalcoholic fatty liver disease NAFLD, one of the leading causes of chronic liver disease in the Western world, is increased in women with PCOS. This review aims to present current knowledge in epidemiology, pathophysiology, diagnostics, and treatment of NAFLD in PCOS with an emphasis on the molecular basis of development of NAFLD in PCOS women. Methods: Authors investigated the available data on PCOS and NAFLD by a MEDLINE and Pub Med search during the years 1990-2021 using a combination of keywords such as "PCOS", "NAFLD", "steatohepatitis", "insulin resistance", "hyperandrogenaemia", "inflammation", "adipose tissue", and "obesity". Peer-reviewed articles regarding NAFLD and PCOS were included in this manuscript. Additional articles were identified from the references of relevant papers. Results: PCOS and NAFLD are multifactorial diseases, The development of NAFLD in PCOS women is linked to insulin resistance, hyperandrogenemia, obesity, adipose tissue dysfunction, and inflammation. There is the possible role of the gut microbiome, mitochondrial dysfunction, and endocannabinoid system in the maintenance of NAFLD in PCOS women. Conclusions: There is a need for further investigation about the mechanism of the development of NAFLD in PCOS women. New data about the molecular basis of development of NAFLD in PCOS integrated with epidemiological and clinical information could influence the evolution of new diagnostic and therapeutic approaches of NAFLD in PCOS.

Fibroid Removal after Myomectomy: An Overview on the Problems of Power Morcellation.

The authors reviewed uterine fibroid (UF) morcellation and its potential consequences, notably a hypothetical spread and dissemination of occult uterine leiomyosarcoma (LMS) tissue, evaluating the effect of laparoscopic versus open myomectomies with and without morcellation on patients' outcomes, as well as related medical-legal issues. MEDLINE and PubMed search was performed for the years 1990-2021, using a combination of keywords on this topic. Relevant articles were identified and included in this narrative review. There is an individual risk, for all patients, for LMS diagnosis after myomectomy. However, the risk for occult LMS diagnosis during a laparoscopic myomectomy is generally reduced when the guidelines of scientific societies are followed, with an overall benefit from the laparoscopic approach with morcellation in appropriate cases. Gynecological societies do not ban morcellation and laparoscopic hysterectomy/myomectomy per se, but recommend their use on the basis of the patients' clinical characteristics. It is suggested for gynecologists to provide detailed information to patients when obtaining an informed consent for open or laparoscopic hysterectomy/myomectomy. A detailed preoperative assessment of patients and the risk benefit ratio of laparoscopic morcellation of uterine mass could overcome the "a priori" banning of the morcellation technique.

Gestational Diabetes Mellitus and Antenatal Corticosteroid Therapy-A Narrative Review of Fetal and Neonatal Outcomes.

BACKGROUND: There, we review the pathogenesis of gestational diabetes mellitus (GDM), its influence on fetal physiology, and neonatal outcomes, as well as the usage of antenatal corticosteroid therapy (ACST) in pregnancies complicated by GDM. METHODS: MEDLINE and PubMed search was performed for the years 1990-2022, using a combination of keywords on such topics. According to the aim of the investigation, appropriate articles were identified and included in this narrative review. RESULTS: GDM is a multifactorial disease related to unwanted pregnancy course and outcomes. Although GDM has an influence on the fetal cardiovascular and nervous system, especially in preterm neonates, the usage of ACST in pregnancy must be considered taking into account maternal and fetal characteristics. CONCLUSIONS: GDM has no influence on neonatal outcomes after ACST introduction. The ACST usage must be personalized and considered according to its gestational age-specific effects on the developing fetus.

Uterine Fibroids and Diet.

Uterine myomas or fibroids are the most common benign female tumors of the reproductive organs, associated with significant morbidity and quality of life impairment. Several epidemiological risk factors for their occurrence have been identified so far, including nutrition and dietary habits. In this investigation, authors reviewed, as a narrative review, the data about diet and uterine myoma development in order to homogenize the current data. A PubMed search was conducted for the years 1990-2020, using a combination of keywords of interest for the selected topic. The authors searched the databases, selecting the randomized clinical studies, the observational studies, and the basic (experimental), clinical, and epidemiological researches. Once they collected the articles, they analyzed them according to the number of citations of each article, starting from the most cited to the least cited articles. Subsequently, authors collected the data of each article and inserted them in the various research paragraphs, summarizing the data collected. In this way, they crossed the available data regarding the association between nutrition habits and dietary components and myoma onset and growth. Many nutrients and dietary habits are associated with myoma development risk. These factors include low intakes of fruit, vegetables, and vitamin D, as well as pollutants in food. Despite the available data on the influence of some foods on the development of fibroids, further research is mandatory to understand all the nutrition risk factors which contribute to myoma growth and how exactly these risk factors influence myoma pathogenesis.

Correlation between metabolic syndrome and relative telomere length shortening in HIV/AIDS patients on combined antiretroviral therapy.

BACKGROUND: Components of the metabolic syndrome (MetS) play an important role in the accelerated aging process. Relative telomere length (RTL) is a marker of biological aging. The aim of our study was to determine RTL and its possible association with MetS and the components of MetS in HIV-infected patients treated with cART. METHODS: We included 24 HIV-infected men, all Caucasians, with successful cART (<50 HIV-RNA copies/mL) and on stable cART for at least 24 months. The presence of MetS and its components was determined by the criteria prescribed by the International Diabetes Federation. RTL was determined by Real-Time PCR and ΔΔCt method. We performed a multiple linear regression modeling on log-transformed RTL (dependant variable) to evaluate which components of the metabolic syndrome as well as cART duration and cART type, had an impact on RTL. RESULTS: Eleven (45.8%) patients had and 13 (54.2%) had not MetS. All patients, had an undetectable viral RNA and a relatively good immune status. The mean RTL was 0.62 ± 0.15 and 0.95 ± 0.36 in patients with and without MetS, respectively (p = 0.01). Multiple linear regression model showed no significant association between duration of cART, cART type and RTL (p = 0.2165, p = 0.8628, respectively). The same analysis showed that an increase in number of MetS components was associated with shorter telomere length (ß = -0.4982, p = 0.042). CONCLUSIONS: We showed for the first time association between RTL shortening in HIV-infected men with metabolic syndrome. Furthermore, our study also indicated that an increment of metabolic syndrome components is strongly associated with shorter telomere length.