Role of Ketogenic Diets and Intermittent Fasting in Neurologic Diseases, Cancers and Obesity- A Comprehensive Review of Human Studies (preprint)

Non-pharmacologic options like the ketogenic diet (KD) and intermittent fasting (IF) are practical nutritional interventions with minor reported side effects like gastrointestinal symptoms, dyslipidemia, and hypomagnesemia for various medical ailments. In conjunction with IF, KD shows promise in weight loss, diabetes management, cardiovascular disorders, polycystic ovarian syndrome, cancer, and chronic neurological disorders. Based on prior research, we have examined the mechanism of action of KD and IF and their effect on neurological diseases, cancer, and obesity. We have also suggested evidence-based recommendations for the safer practice of KD and IF. Despite potential benefits, long-term adherence to KD poses challenges. Periodic KD implementation may thus benefit newly diagnosed overweight or obese patients with type 2 diabetes mellitus, aiding blood glucose and lipid management while promoting weight loss. KD is a high-fat and low-carbohydrate diet with a ratio of fat to carbohydrates and protein being 4:1 or 3:1, and thus, for peripheral tissues and the brain, fatty acids become the mandatory source of cellular energy. Ketone bodies have been used as the primary energy source during fasting. KD has been utilized as an effective treatment for refractory epilepsy since the 1920s. Evidence of the neuroprotective role of KD in diseases like epilepsy, stroke, traumatic brain injury, Alzheimer’s disease, and other neurological diseases has been noted. Since the 1960s, KD has become a popular method for obesity treatment. In addition, KD has been suggested as a potent anticancer therapy when used alone or as an adjuvant. KD may increase tumor cell sensitivity when combined with classic chemotherapy and radiotherapy. Thus, the probability that modifying the diet can help manage obesity, cancer, and chronic neurological disease without depending on pharmacological treatment and their serious side effects for a lifetime is promising and requires further investigation. KD holds promise as a potential adjunctive therapy in various neurological disorders, offering new avenues for treatment and neuroprotection. IF has shown potential in slowing the progression of neurodegenerative diseases such as Alzheimer's and Parkinson's by promoting antioxidant defense and suppressing inflammation. KD and IF show promise in cancer therapy by targeting altered cancer cell metabolism. Additionally, KD may enhance the effects of standard treatments like chemotherapy and radiotherapy. Some of the most robust reports of keto's possible benefits have come from glioblastoma, a very aggressive brain cancer. KD has also shown strong evidence for its effectiveness in weight loss, mainly attributed to its appetite-suppressing action in ketosis. However, long-term adherence to KD can be challenging, and periodic KDs may help manage blood glucose and lipid levels in overweight or obese patients with type 2 diabetes mellitus. Likewise, IF may be more effective than regular calorie restriction for achieving weight loss goals when combined with exercise programs. More prospective human studies are warranted to evaluate both KD and IF's potential therapeutic effectiveness and safety.

An Evolutionary Model for Ancient Origins of Polycystic Ovary Syndrome (preprint)

Polycystic ovary syndrome (PCOS) is a common endocrinopathy of reproductive-aged women characterized by hyperandrogenism, oligo-anovulation and insulin resistance closely linked with preferential abdominal fat accumulation. As an ancestral primate trait, PCOS was likely further selected in humans when scarcity of food in hunter-gatherers of the late Pleistocene additionally programmed for enhanced fat storage to meet the metabolic demands of reproduction in later life. As an evolutional model for PCOS, healthy normal-weight women with hyperandrogenic PCOS have subcutaneous (SC) abdominal adipose stem cells that favor fat storage through exaggerated lipid accumulation during development to adipocytes in vitro. In turn, fat storage is counterbalanced by reduced insulin sensitivity and preferential accumulation of highly-lipolytic intra-abdominal fat in vivo. This metabolic adaptation in PCOS balances energy storage with glucose availability and fatty acid oxidation for optimal energy use during reproduction; its accompanying oligo-anovulation allowed PCOS women from antiquity sufficient time and strength for childrearing of fewer offspring with a greater likelihood of childhood survival. Heritable PCOS characteristics are now affected by today’s contemporary environment through epigenetic events that predispose to lipotoxicity with excess weight gain and pregnancy complications, calling for an emphasis on preventive healthcare to optimize the long-term, endocrine-metabolic health of PCOS women in today’s obesogenic environment.

Mitochondrial Dysfunction in PCOS: Insights into Reproductive Organ Pathophysiology (preprint)

Polycystic ovary syndrome (PCOS) is a complex, but relatively common endocrine disorder associated with chronic anovulation, hyperandrogenism, and micro-polycystic ovaries [1]. In addition to reduced fertility, people with PCOS have a higher risk of obesity, insulin resistance, and metabolic disease [1], all comorbidities that are associated with mitochondrial dysfunction. This review summarizes human and animal data that report mitochondrial dysfunction and metabolic dysregulation in PCOS to better understand how mitochondria impact reproductive organ pathophysiology. This in-depth review considers all the elements regulating mitochondrial quantity and quality, from mitochondrial biogenesis under transcriptional regulation of both the nuclear and the mitochondrial genome, to the ultrastructural and functional complexes that regulate cellular metabolism and reactive oxygen species production, to dynamics which regulate subcellular interactions that are key to mitochondrial quality control. When any of these mitochondrial functions are disrupted the energetic equilibrium within the cell changes, cell processes can fail, and cell death can occur. If this process is ongoing, it affects tissue and organ function to cause disease. The objective of this review is to consolidate and classify a broad number of PCOS studies to understand how various mitochondrial processes impact reproductive organs including the ovary (oocyte and granulosa cell), uterus, placenta, and circulation to cause reproductive pathophysiology. A secondary objective is to uncover the potential role of mitochondria in transgenerational transmission of PCOS and metabolic disorders.

Impact of COVID-19 Restriction on Weight, Physical Activity, Diet and Psychological Distress on People with PCOS.

BACKGROUND: People with polycystic ovary syndrome (PCOS) have higher weight gain and psychological distress compared to those without PCOS. While COVID-19 restrictions led to population level adverse changes in lifestyle, weight gain and psychological distress, their impact on people with PCOS is unclear. The aim of this study was to investigate the impact the 2020 COVID-19 restrictions had on weight, physical activity, diet and psychological distress for Australians with PCOS. METHODS: Australian reproductive-aged women participated in an online survey with assessment of weight, physical activity, diet and psychological distress. Multivariable logistic and linear regression were used to examine associations between PCOS and residential location with health outcomes. RESULTS: On adjusted analysis, those with PCOS gained more weight (2.9%; 95% CI; 0.027-3.020; p = 0.046), were less likely to meet physical activity recommendations (OR 0.50; 95% CI; 0.32-0.79; p = 0.003) and had higher sugar-sweetened beverage intake (OR 1.74; 95% CI 1.10-2.75; p = 0.019) but no differences in psychological distress compared to women without PCOS. CONCLUSIONS: People with PCOS were more adversely affected by COVID-19 restrictions, which may worsen their clinical features and disease burden. Additional health care support may be necessary to assist people with PCOS to meet dietary and physical activity recommendations.

COVID-19 infection and women's health; which women are more vulnerable in terms of gynecological health? (preprint)

Background Given gender-specific differences and ACE2 commonly expressed in the ovaries and uterus, it may be important to know which women are at greater risk of COVID-19 infection. Therefore, this study sought to determine which women are more affected by COVID- 19 infection, especially in terms of gynecological pathologies.Methods This retrospective and descriptive study examined the effect and course of COVID-19 in terms of gynecological pathologies in a total of 380 women of reproductive age without systemic disease. General demographics, obstetric and gynecological conditions, and parameters related to COVID-19 were evaluated. All parameters were compared for three groups defined on the basis of COVID-19 severity (mild, moderate, and severe).Results A total of 380 women with a mean age of 35.39 ± 8.94 were included in the study. The mean body mass index (BMI) of the women was 24.35 ± 4.53. The proportion of women with at least one pregnancy history was 69.2%. The mean gravidity of the women was 1.47 ± 1.34 and the parity was 1.16 ± 1.02. Of the women, 112 (29.5%) mild, 207 (54.5%) moderate and 61 (16.0%) severe cases of COVID-19 were seen. The mean age and median BMI of the women were similar in all three groups (p = 0.163, p = 0.127, respectively). Severe disease rates (29.5%) were significantly higher in women with 2 or more cases of COVID-19 than mild disease (14%) (p = 0.018). Severe disease rates (57.4%) in women with at least one pregnancy history were statistically significantly lower than mild disease rates (78.6%) (p = 0.010). The median parity number was significantly higher in the mild disease group than in the moderate disease group (p = 0.021). The most common benign gynecological pathology in women was chronic urinary tract infection (13.2%). Other common pathologies were chronic vaginal infection (12.6%), and polycystic ovary syndrome (PCOS) (11.6%). A history of chronic urinary tract infection was statistically significantly higher in the severe disease group (24.6%), mild (8.9%, p = 0.015) and moderate (12.1%, p = 0.024) disease groups. PCOS, endometriosis (6.3%), abnormal uterine bleeding (AUB) (8.4%), and hormone therapy history (8.2%) were found to be higher in severe disease groups, although not statistically significant (p = 0.596, p = 0.074, p = 0.305, p = 0.059, respectively). The history of leiomyoma (7.1%) was higher in the mild and moderate disease groups than in the severe disease group, but it was not statistically significant (p = 0.794). Benign gynecological operation history (31.3%) was significantly higher in mild (36.6%, p = 0.007), and moderate (33.3%, p = 0.007) disease groups than in the severe group (9, 14.8%).Conclusion Certain obstetric and gynecological conditions are thought to affect COVID 19 susceptibility and severity in women without systemic disease.

Prevalence of Polycystic Ovary Syndrome amongst Females Aged between 15 and 45 Years at a Major Women's Hospital in Dubai, United Arab Emirates.

Objective criteria have been scarce in published data on the occurrence of polycystic ovary syndrome (PCOS) in the United Arab Emirates (UAE). It is crucial that we enhance our comprehension of PCOS prevalence in the UAE to inform key stakeholders about the disease's burden and enable comparisons with other nations. This research aimed to examine the PCOS prevalence at a large academic tertiary centre in Dubai, UAE, called Latifa Women and Children's Hospital. We performed a cross-sectional study by reviewing the electronic medical records of patients accessing care between 2017 and 2022 (5 years). By utilizing the international classification of diseases codes (ICD-10), we discovered a period prevalence of PCOS of 1.6% among 64,722 women aged between 15 and 45 years. It is worth noting that the estimated annual point prevalence rose from 1.19% in 2020 (at the beginning of the COVID19 pandemic) to 2.72% in 2022 (after the start of the COVID-19 pandemic). Therefore, the odds ratio of the risk of a PCOS diagnosis in 2022 compared to 2020 was 2.28. The majority of the women diagnosed with PCOS in this study had an ICD-10 code of E28.2. Women with PCOS were younger than the controls, less likely to be pregnant, and had a higher body mass index and systolic and diastolic blood pressure. This is the most extensive research to date examining PCOS prevalence in the UAE, and it emphasizes the significance of this condition. It is crucial to prioritize PCOS to prevent morbidity and mortality from reproductive and long-term health consequences, including infertility, type 2 diabetes and endometrial cancer, which is presently the most frequent gynecological cancer in the UAE.

Capability, Opportunity, and Motivation-Identifying Constructs for Increasing Physical Activity Behaviours in Women with Polycystic Ovary Syndrome (PCOS).

Polycystic ovary syndrome (PCOS) is the commonest endocrinopathy in reproductive-aged women. Because increased adiposity is pivotal in the severity of PCOS-related symptoms, treatment usually incorporates increasing energy expenditure through physical activity (PA). This study aimed to understand the reasons why women with PCOS engage in PA/exercise, which could support the development of targeted behavioural interventions in this at-risk population. Validated questionnaires were administered for self-reported PA levels, quality of life, mental health, illness perception, sleep quality, and capability, opportunity, and motivation (COM) for PA. Using categorical PA data, outcomes were compared between groups; ordinal logistic regression (OLR) was used to identify whether COM could explain PA categorisation. A total of 333 participants were eligible; favourable differences were reported for body mass index, depression, mental wellbeing, self-rated health, illness perception, and insomnia severity for those reporting the highest PA levels. COM scores increased according to PA categorisation, whilst OLR identified conscious and automatic motivation as explaining the largest PA variance. The most active participants reported favourable data for most outcomes. However, determining whether health is protected by higher PA or ill health is a barrier to PA was not possible. These findings suggest that future behavioural interventions should be targeted at increasing patient motivation.

Risk of severe acute respiratory syndrome coronavirus 2 infection among women with polycystic ovary syndrome.

OBJECTIVE: To determine whether women with polycystic ovary syndrome (PCOS) had a higher incidence of testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) than those without PCOS and evaluate whether PCOS diagnosis independently increased the risk of moderate or severe disease in those with positive SARS-CoV-2 test results. DESIGN: Retrospective cohort study using the National COVID Cohort Collaborative (N3C). SETTING: National COVID Cohort Collaborative. PATIENT(S): Adult nonpregnant women (age, 18-65 years) enrolled in the N3C with confirmed SARS-CoV-2 testing for any indication. Sensitivity analyses were conducted in women aged 18-49 years and who were obese (body mass index, ≥30 kg/m2). INTERVENTION(S): The exposure was PCOS as identified by the N3C clinical diagnosis codes and concept sets, which are a compilation of terms, laboratory values, and International Classification of Diseases codes for the diagnosis of PCOS. To further capture patients with the symptoms of PCOS, we also included those who had concept sets for both hirsutism and irregular menses. MAIN OUTCOME MEASURE(S): Odds of testing positive for SARS-CoV-2 and odds of moderate or severe coronavirus disease 2019 (COVID-19) in the PCOS cohort compared with those in the non-PCOS cohort. RESULT(S): Of the 2,089,913 women included in our study, 39,459 had PCOS. In the overall cohort, the adjusted odds ratio (aOR) of SARS-CoV-2 positivity was 0.98 (95% confidence interval [CI], 0.97-0.98) in women with PCOS compared to women without PCOS. The aORs of disease severity were as follows: mild disease, 1.02 (95% CI, 1.01-1.03); moderate disease, 0.99 (95% CI, 0.98-1.00); and severe disease, 0.99 (95% CI, 0.99-1.00). There was no difference in COVID-19-related mortality (aOR, 1.00; 95% CI, 0.99-1.00). These findings were similar in the reproductive-age and obese reproductive-age cohorts. CONCLUSION(S): Women with PCOS had a similar likelihood of testing positive for SARS-CoV-2. Among those who tested positive, they were no more likely to have moderate or severe COVID-19 than the non-PCOS cohort. Polycystic ovary syndrome is a chronic condition associated with several comorbidities, including cardiovascular disease and mental health issues. Although these comorbidities are also associated with COVID-19 morbidity, our findings suggest that the comorbidities themselves, rather than PCOS, drive the risk of disease severity.

Depression and Anxiety in Infertility Patients (preprint)

Depression and anxiety are common emotional responses among infertility patients, with research showing that they can negatively impact the mental well-being and quality of life of individuals struggling with infertility. This study aimed to conduct a bibliometric analysis of the existing literature on depression and anxiety in infertility patients, in order to shed light on the current state of research and identify potential areas for future study. The majority of research on depression and anxiety in infertility patients has been conducted in recent years, with a growing interest in the topic. Numerous investigations have assessed the effect of infertility treatments on patients’ psychological health, with some examinations delving into the application of cognitive behavioral therapy and mindfulness-based stress reduction as potential methods for mitigating symptoms of depression and anxiety. Polycystic ovary syndrome, fertility preservation of cancer patients, COVID-19 pandemic, and assisted reproductive technology are also hot spots in this field. The findings of this bibliometric analysis highlight the importance of addressing depression and anxiety in infertility patients, and imply that further investigation is required to fully comprehend the intricate connections between infertility, depression, and anxiety.

A rapid evidence map of womens health (preprint)

The rapid evidence map focuses on identifying the nature and extent of published literature on the following topic areas: healthcare professionals communication with women about womens health issues and broader health problems during clinical encounters; access to specialist healthcare; endometriosis; menopause; womens health and mental health issues, and mental health issues associated with specific conditions related to menopause or menstrual health (adenomyosis; endometriosis; fibroids; heavy menstrual bleeding, polycystic ovary syndrome and premenstrual dysphoric disorder). The purpose of this rapid evidence map was to identify research gaps and priorities that will be beneficial to womens health in Wales. The rapid evidence map uses abbreviated systematic mapping or scoping review methods to provide a description of the nature, characteristics and volume of the available evidence. There is a lack of primary and secondary research that explores communication between women and healthcare professionals within primary and secondary care settings. Secondary research evidence exists but there are gaps in the evidence base regarding access to services providing minor gynaecological procedures and pain management, or care for menstrual health and wellbeing, endometriosis, polycystic ovarian syndrome, menopause, heart conditions, autoimmune diseases, hypermobility spectrum disorders, myalgic encephalomyelitis, long COVID, fibromyalgia, skin conditions, or palliative and end of life care, which are priority areas identified by the Womens Health Wales Coalition (2022). There are no active funding calls exploring these topics. Regarding endometriosis, there is a lack of review evidence regarding education and resources for health care professionals and doctors to reduce diagnostic times and improve care. There is an evidence gap for primary research regarding information, support interventions and tools for women with endometriosis to help them manage their symptoms and improve their quality of life. A substantial amount of secondary evidence exists on menopause along with a plethora of research priorities around treatment and symptom management. It was beyond the scope of this work to determine if any research had been conducted in these priority areas since the production of the guidelines and recommendations. There is a lack of research recommendations and review evidence that address mental health issues and specific issues that affect a womens menstrual health such as adenomyosis, fibroids, heavy menstrual bleeding and premenstrual dysphoric disorder. Funding statement The Wales Centre for Evidence Based Care was funded for this work by the Wales COVID-19 Evidence Centre, itself funded by Health and Care Research Wales on behalf of Welsh Government. Wales COVID-19 Evidence Centre (WCEC) Rapid Evidence Map: Women’s health Report number – REM 00045 (October 2022) Rapid Evidence Map Details Review conducted by Wales Centre For Evidence Based Care Review Team ▪ Deborah Edwards ▪ Judit Csontos ▪ Elizabeth Gillen Review submitted to the WCEC October 2022 Stakeholder consultation meeting 24 th October 2022 Rapid Evidence Map report issued by the WCEC November 2022 WCEC Team ▪ Adrian Edwards, Ruth Lewis, Alison Cooper, Micaela Gal involved in drafting the topline summary, reviewing, editing, publication process. This review should be cited as REM00045. Wales COVID-19 Evidence Centre, Rapid Evidence map: Womens health. October 2022 Disclaimer The views expressed in this publication are those of the authors, not necessarily Health and Care Research Wales. The WCEC and authors of this work declare that they have no conflict of interest. Rapid Evidence Map: Women’s health Report number – REM00045 (October 2022) TOPLINE SUMMARY What are Rapid Evidence Maps? Our Rapid Evidence Maps (REMs) use abbreviated systematic mapping or scoping review methods to provide a description of the nature, characteristics and volume of the available evidence for a particular policy domain or research question. They are mainly based on the assessment of abstracts and incorporate an a priori protocol, systematic search, screening, and minimal data extraction. They may sometimes include critical appraisal, but no evidence synthesis is conducted. Priority is given, where feasible, to studies representing robust evidence synthesis. They are designed and used primarily to identify a substantial focus for a rapid review, and key research gaps in the evidence-base . ( N . B. Evidence maps are not suitable to support evidence-informed policy development, as they do not include a synthesis of the results .) Who is this summary for? Health and Care Research Wales Background / Aim of Rapid Evidence Map (REM) The Welsh Government Research and Development Division intends to run a commissioned funding call on understanding and tackling gender inequalities in health and social care in Wales. The purpose of this REM was to identify research gaps and priorities that will be beneficial to women’s health in Wales to inform the proposed funding call. It was decided, based on a preliminary review of the literature, feedback from an NHS public consultation exercise in Wales, and further discussion with the stakeholder group, that the REM would focus on identifying the nature and extent of the literature on the following prioritised topic areas: healthcare professionals’ communication with women about women’s health issues and broader health problems during clinical encounters; access to specialist healthcare ; endometriosis ; menopause ; women’s health and mental health issues, and mental health issues associated with specific conditions related to menopause or menstrual health (adenomyosis; endometriosis; fibroids; heavy menstrual bleeding, polycystic ovary syndrome and premenstrual dysphoric disorder). Research gaps in other areas and health conditions, in which women might also experience inequality, were not explored in this REM. Key Findings Extent of the evidence base ▪ Communication within health care encounters The evidence base included one systematic review (of endometriosis) and nine primary studies. The primary studies focused on breast cancer (n=2), maternal medicine (n=3), perinatal mental health (n=1), gynaecological conditions (n=1), and non-specific conditions (n=2). Three studies focused on specific populations: urban Africans, Iraqi Muslim refugees, and undocumented migrants. Planned and ongoing NIHR funded projects include clinicians’ perspectives of listening to women’s health, menstrual and gynaecological conditions, menopause, and women’s cancers ▪ Access to specialist healthcare The evidence base consisted of 19 reviews and 9 protocols. Conditions covered were maternal medicine (n=8), sexual and reproductive health (n=5), cancer and cancer screening (n=4), perinatal mental health (n=4), mental health (n=2), HIV (n=2), and non-specific conditions (n=3). Specific populations investigated were refugees or displaced people (n=6), those in differing social, economic, and environmental circumstances (n=4), physical disabilities (n=3), homeless (n=2), migrants (n=2), experiencing intimate partner violence (n=1), and minority ethnicity black (n=1). The reviews focused on barriers and facilitators (n=10), barriers (n=5), experiences (n=3), mapping the evidence (n=3), factors (n=2), management (n=1), facilitators (n=1), predictors (n=1), associations (n=1), and prevalence (n=1). ▪ Endometriosis The evidence base included 121 systematic reviews covering different topics including medical management (n=22), surgical management (n=15), biology/molecular (n=12), risk factors (n=11), and comorbid conditions (n=9). Research priorities were identified by the James Lind Alliance (JLA), NICE guideline, a Wales-specific primary study (Boivin et al 2018), and researchers within the field (n=2). Recent UK funding calls were identified covering laboratory research, aetiology of endometriosis and uterine disorders, and medical and surgical management. ▪ Menopause The evidence base included 108 systematic reviews covering different topics including hormonal therapies (n=17), homeopathic therapies (n=13), non-hormonal therapies (n=10), genitourinary symptoms of menopause (n=7), alternative therapies (n=6), and lifestyle interventions (n=6). Research priorities were identified as part of a NICE guideline, by the British Menopause Society, and researchers within the field (n=3). Recent UK funding calls were identified covering reproductive and menopausal health, testosterone for the treatment of symptoms, women’s reproductive health in the workplace, and women’s health hub landscape. ▪ Women’s health and mental health issues The evidence base included 37 reviews covering: perinatal mental health (n=23), general mental health (n=9), polycystic ovary syndrome (n=3), and intimate partner violence (n=2). Some reviews focused on specific populations including women in prison, women in inpatient mental health services, mental health of migrants and refugee women, and mental health of women from different minority groups. Recent UK funding calls were identified covering: young women’s mental health, women and partners who have experienced pregnancy not ending in live births, and perimenopause and the risk of psychiatric disorders. ▪ Mental health issues associated with specific conditions related to menopause or menstrual health The evidence base included 10 systematic reviews covering: polycystic ovary syndrome (n=4), endometriosis (n=4) menopause (n=1), and menstruation (n=1). The reviews focused on prevalence (n=4), associations (n=4), and management (n=2). Recency of the evidence base ▪ The review included evidence available (from 2012, 2018, and 2021) up until September 2022. (Separate searches were conducted for different topics, with variable time limits due to the varying volume of research published in certain areas.) Summary of the evidence gaps ▪ There is a lack of primary and secondary research that explores communication between women and healthcare professionals (HCPs) within primary and secondary care settings. ▪ Secondary research evidence exists but there are gaps in the evidence base regarding access to services providing minor gynaecological procedures and pain management, or care for menstrual health and wellbeing, endometriosis, polycystic ovarian syndrome, menopause , heart conditions, autoimmune diseases, hypermobility spectrum disorders, myalgic encephalomyelitis, long COVID, fibromyalgia, skin conditions, or palliative and end of life care, which are priority areas identified by the Women’s Health Wales Coalition (2022). There are no active funding calls exploring these topics. ▪ Regarding endometriosis, there is a lack of review evidence regarding education and resources for HCPs and doctors to reduce diagnostic times and improve care . There is an evidence gap for primary research regarding information, support interventions and tools for women with endometriosis to help them manage their symptoms and improve their quality of life . ▪ A substantial amount of secondary evidence exists on menopause along with a plethora of research priorities around treatment and symptom management . It was beyond the scope of this REM to determine if any research had been conducted in these priority areas since the production of the guidelines and recommendations. Researchers in the field would like to see primary research conducted in the area of quality of life . ▪ There is a lack of research recommendations and review evidence that address mental health issues and specific issues that affect a women’s menstrual health such as adenomyosis, fibroids, heavy menstrual bleeding and premenstrual dysphoric disorder .

Dysmenorrhea, intermenstrual bleeding, and irregularities post COVID-19 vaccination and associated factors: a retrospective observational study (preprint)

Background coronavirus SARS-CoV-2 disease 2019 (COVID-19) vaccines have provided a fertile ground for research, especially with the unprecedented misinformation spread. One of the most reported side effects of the vaccine among women has been menstrual disturbances. In this paper, we aim to investigate the extent of the COVID-19 vaccine effects on the menstrual cycle as well as identify the associated factors that predispose an individual to dysmenorrhea, intermenstrual bleeding, change in flow volume, or irregularity post vaccine.Methods Any woman of menstruating age who received at least one dose of the COVID-19 vaccine and currently resides in Saudi Arabia was invited to complete an online questionnaire. The questionnaire compared menstruation characteristics—regularity, volume, intermenstrual bleeding, and dysmenorrhea—before receiving the COVID-19 vaccine with after, taking into consideration possible predisposing factors such as polycystic ovarian syndrome (PCOS), contraceptives, or period blocking pills.Results Women without PCOS experienced less changes in dysmenorrhea post COVID-19 vaccine compared to those with PCOS (23.88% vs 27.78% p-value = 0.045). Women using contraceptives were about two times more likely to experience volume changes compared to those not using contraceptives (OR = 2.09, 95%CI 1.23–3.57, p-value = 0.006). COVID-19 vaccine skeptics were about three times more likely to perceive changes in regularity post vaccine compared to non-skeptics (OR = 2.96, 95%CI, 1.79–4.90, p-value < 0.001). They were, also, 3 times more likely to perceive changes in volume post vaccine (OR = 3.04, 95%CI = 1.95–4.74, p-value < 0.001).Conclusion COVID-19 vaccine skepticism has a significant association with perceived post vaccine menstrual disturbances. Therefore, public education is crucial to combat the spread of misinformation and controversy surrounding the vaccines.

Usage of mobile health interventions among overweight/obese PCOS patients undergoing assisted reproductive technology treatment during the COVID-19 pandemic.

Objective: In the context of the coronavirus disease 2019 (COVID-19) pandemic, telemedicine is a promising tool for providing clinical care for patients. Since the first-line treatment for infertile women with polycystic ovarian syndrome (PCOS) is lifestyle modification, a mobile-based service that provides lifestyle modification education would be helpful in the treatment of PCOS patients. In this observational study, the effect of a mobile Health (mHealth) application for lifestyle modification on PCOS patients undergoing assisted reproductive technology (ART) treatment was evaluated.Methods: A total of 79 overweight/obese patients (40 in the paper group and 39 in the WeChat application group) with PCOS from the First Affiliated Hospital of University of Science and Technology of China were enrolled in the study. The changes in the outcomes of BMI and ART treatment were analyzed between the two groups.Results: After three months of intervention, the BMIs in the control and mHealth groups were 24.5 ± 3.3 and 23.7 ± 3.1, respectively. The percentage of patients who lost weight was higher in the WeChat group than in the control group (87.2% vs. 67.5%). Furthermore, PCOS patients in the WeChat group were found to have a higher live birth rate than those in the control group (p = 0.005).Conclusion: Lifestyle modifications for PCOS patients undergoing ART treatment using the WeChat application improved weight loss and oocyte quality. Infertile patients with PCOS were more likely to make lifestyle modifications based on the usage of mobile applications during the COVID-19 pandemic.

Metformin is Associated with Reduced COVID-19 Severity in Patients with Prediabetes (preprint)

Background With the continuing COVID-19 pandemic, identifying medications that improve COVID-19 outcomes is crucial. Studies suggest that use of metformin, an oral antihyperglycemic, is associated with reduced COVID-19 severity in individuals with diabetes compared to other antihyperglycemic medications. Some patients without diabetes, including those with polycystic ovary syndrome (PCOS) and prediabetes, are prescribed metformin for off-label use, which provides an opportunity to further investigate the effect of metformin on COVID-19. Participants In this observational, retrospective analysis, we leveraged the harmonized electronic health record data from 53 hospitals to construct cohorts of COVID-19 positive, metformin users without diabetes and propensity-weighted control users of levothyroxine (a medication for hypothyroidism that is not known to affect COVID-19 outcome) who had either PCOS (n = 282) or prediabetes (n = 3136). The primary outcome of interest was COVID-19 severity, which was classified as: mild, mild ED (emergency department), moderate, severe, or mortality/hospice. Results In the prediabetes cohort, metformin use was associated with a lower rate of COVID-19 with severity of mild ED or worse (OR: 0.630, 95% CI 0.450 - 0.882, p < 0.05) and a lower rate of COVID-19 with severity of moderate or worse (OR: 0.490, 95% CI 0.336 - 0.715, p < 0.001). In patients with PCOS, we found no significant association between metformin use and COVID-19 severity, although the number of patients was relatively small. Conclusions Metformin was associated with less severe COVID-19 in patients with prediabetes, as seen in previous studies of patients with diabetes. This is an important finding, since prediabetes affects between 19 and 38% of the US population, and COVID-19 is an ongoing public health emergency. Further observational and prospective studies will clarify the relationship between metformin and COVID-19 severity in patients with prediabetes, and whether metformin usage may reduce COVID-19 severity.

The effects of obesity on the menstrual cycle.

The prevalence of childhood and adolescent obesity has significantly increased in the United States and worldwide since the 1970s, a trend that has been accelerated by the COVID-19 pandemic. The complications of obesity range from negative effects on the cardiovascular, endocrine, hepatobiliary, and musculoskeletal systems to higher rates of mental health conditions such as depression and eating disorders among affected individuals. Among adolescent girls, childhood obesity has been associated with the earlier onset of puberty and menarche, which can result in negative psychosocial consequences, as well as adverse effects on physical health in adulthood. The hormones leptin, kisspeptin and insulin, and their actions on the hypothalamic-pituitary-ovarian axis, have been implicated in the relationship between childhood obesity and the earlier onset of puberty. Obesity in adolescence is also associated with greater menstrual cycle irregularity and the polycystic ovary syndrome (PCOS), which can result in infrequent or absent menstrual periods, and heavy menstrual bleeding. Hyperandrogenism, higher testosterone and fasting insulin levels, and lower levels of sex hormone-binding globulin, similar to the laboratory findings seen in patients with PCOS, are also seen in individuals with obesity, and help to explain the overlap in phenotype between patients with obesity and those with PCOS. Finally, obesity has been associated with higher rates of premenstrual disorders, including premenstrual syndrome and premenstrual dysphoric disorder, and dysmenorrhea, although the data on dysmenorrhea appears to be mixed. Discussing healthy lifestyle changes and identifying and managing menstrual abnormalities in adolescents with obesity are key to reducing the obstetric and gynecologic complications of obesity in adulthood, including infertility, pregnancy complications, and endometrial cancer.

Ovarian granulosa cells from women with PCOS express low levels of SARS-CoV-2 receptors and co-factors.

PURPOSE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is global pandemic with more than 5 million deaths so far. Female reproductive tract organs express coronavirus-associated receptors and factors (SCARFs), suggesting they may be susceptible to SARS-CoV-2 infection; however, the susceptibility of ovary/follicle/oocyte to the same is still elusive. Co-morbidities like obesity, type-2 diabetes mellitus, cardiovascular disease, etc. increase the risk of SARS-CoV-2 infection. These features are common in women with polycystic ovary syndrome (PCOS), warranting further scope to study SCARFs expression in ovary of these women. MATERIALS AND METHODS: SCARFs expression in ovary and ovarian tissues of women with PCOS and healthy women was explored by analyzing publically available microarray datasets. Transcript expressions of SCARFs were investigated in mural and cumulus granulosa cells (MGCs and CGCs) from control and PCOS women undergoing in vitro fertilization (IVF). RESULTS: Microarray data revealed that ovary expresses all genes necessary for SARS-CoV-2 infection. PCOS women mostly showed down-regulated/unchanged levels of SCARFs. MGCs and CGCs from PCOS women showed lower expression of receptors ACE2, BSG and DPP4 and protease CTSB than in controls. MGCs showed lower expression of protease CTSL in PCOS than in controls. Expression of TMPRSS2 was not detected in both cell types. CONCLUSION: Human ovarian follicle may be susceptible to SARS-CoV-2 infection. Lower expression of SCARFs in PCOS indicates that the risk of SARS-CoV-2 infection to the ovary may be lesser in these women than controls. This knowledge may help in safe practices at IVF settings in the current pandemic.

Investigation of common risk factors between polycystic ovary syndrome and Alzheimer's disease: a narrative review.

BACKGROUND: The most common endocrine and metabolic disorders in premenopausal women is polycystic ovary syndrome (PCOS), characterized by hyperandrogenism, chronic anovulation, and/or ultrasound evidence of small ovarian cysts. Obesity and insulin resistance are also the main factors influencing the clinical manifestations of this syndrome. Alzheimer's disease (AD) is the most typical progressive neurodegenerative disorder of the brain, and recent studies suggest a relationship between endocrinal dysregulation and neuronal loss during AD pathology. AIM: This study aimed to evaluate the common risk factors for Alzheimer's and PCOS based on previous studies. Knowing the common risk factors and eliminating them may prevent neurodegenerative Alzheimer's disease in the future. METHOD: In this narrative review, international databases, including Google Scholar, Scopus, PubMed, and the Web of Science, were searched to retrieve the relevant studies. The relevant studies' summaries were categorized to discuss the possible pathways that may explain the association between Alzheimer's and PCOS signs/symptoms and complications. RESULTS: According to our research, the factors involved in Alzheimer's and PCOS disorders may share some common risk factors. In patients with PCOS, increased LH to FSH ratio, decreased vitamin D, insulin resistance, and obesity are some of the most important factors that may increase the risk of Alzheimer's disease.

Polycystic ovary syndrome is a disorder of the female reproductive system that can be caused by hormonal disorders. The disease is detected by an ultrasound of the ovaries with small ovarian cysts. Obesity and insulin resistance are among the factors that can affect the clinical symptoms of this disease. Obesity due to high-fat consumption can affect cognitive functions with age. Alzheimer's is the most common disease associated with disorders in brain cells; a link between hormonal disorders and Alzheimer's has recently been reported. We conducted a review of reports and articles published in connection with polycystic ovary syndrome and neurodegenerative disorders in reputable scientific databases. Studies have shown that the factors involved in polycystic ovary syndrome and Alzheimer's disease may indicate that both diseases have common risk factors. It may be linked to the symptoms and/or complications of Alzheimer's disease and polycystic ovary syndrome. Future preclinical studies are needed to closely examine the mechanisms associated with polycystic ovary syndrome and the association with Alzheimer's. The novelty of our study is from the fact that the PCOS may be to some extent considered as a cause (exposure) among others of AD's (outcome) and the association might be confounded by some or all the risk factors assessed in this review. The nature of the method­the narrative review­is relatively subjective (in the determination of which studies to include, the way the studies are analyzed, and the conclusions drawn) and hence may not help mitigate bias.

Preliminary Results for Personalized Therapy in Pregnant Women with Polycystic Ovary Syndrome During the COVID-19 Pandemic.

Increased androgen level, hyperinsulinemia, diabetes, impaired fibrinolysis, obesity, hypertension, chronic inflammation, abnormal immune response to infections and hyperhomocysteinemia are the most common abnormalities related to polycystic ovary syndrome (PCOS) women and are the factors predisposing to the severe course of COVID-19. The SARS-Cov-2 infection during pregnancy is associated with an increased risk of complications (spontaneous abortion), similar to those in PCOS. The treatment of PCOS pregnant women with a history of fertility failures raises many doubts, especially during the COVID pandemic. However, due to the increasing incidence of infections among reproductive people and the potentially more serious course in pregnant women, numerous questions about the safety and effectiveness of the treatment are still very current. In our study we presented a series of cases of recurrent miscarriages or recurrent implantation failure PCOS pregnant women with confirmed COVID-19. The diagnosis of infertility confirmed the presence of plasminogen activator inhibitor type 1 and/or 5,10-methylenetetrahydrofolate reductase polymorphisms in each of them. Moreover, some of the women presented immune dysfunction associated with infertility. We have described the personalized treatments of each pregnant patient included: metformin, enoxaparin and tacrolimus. The treatment applied had the expected effect, supporting the implantation processes. Furthermore, despite the ambiguous data according to immunological therapy of infertile women during the COVID pandemic, we observed a mild or asymptomatic COVID-19 course and we noticed no pregnancy complications.

Metformin: Sex/Gender Differences in Its Uses and Effects-Narrative Review.

Metformin (MTF) occupies a major and fundamental position in the therapeutic management of type 2 diabetes mellitus (T2DM). Gender differences in some effects and actions of MTF have been reported. Women are usually prescribed lower MTF doses compared to men and report more gastrointestinal side effects. The incidence of cardiovascular events in women on MTF has been found to be lower to that of men on MTF. Despite some promising results with MTF regarding pregnancy rates in women with PCOS, the management of gestational diabetes, cancer prevention or adjunctive cancer treatment and COVID-19, most robust meta-analyses have yet to confirm such beneficial effects.

Impact of social isolation during COVID-19 pandemic on health behaviors and weight management in women with polycystic ovary syndrome.

PURPOSE: COVID-19 pandemic has far-reaching psychosocial implications for chronic health conditions. We aimed to investigate whether COVID-19 associated social isolation affects lifestyle and weight control in women with polycystic ovary syndrome (PCOS). METHODS: We conducted an online survey involving 232 women with PCOS and 157 healthy controls on weight changes, physical activity, sleep and eating patterns using Three-Factor Eating Questionnaire (TFEQ-18), Pittsburgh Sleep Quality Index (PSQI), and International Physical Activity Questionnaire Short Form (IPAQ-SF). PCOS-related quality of life questionnaire (PCOSQ) was also completed by the patients. RESULTS: While 48.5% of all participants gained weight, 13.9% maintained a stable weight, and 37.6% lost weight during the 14-week social isolation. The distribution of weight change was similar between groups (p = 0.44). All participants reported a decrease in physical activity (p < 0.001). While eating behavior showed no significant change in both groups, reduced sleep quality was found only in the PCOS group (p < 0.001). In women with weight gain, increase in BMI values was higher in patients (1.3 ± 1 kg/m2) than controls (1.0 ± 0.6 kg/m2; p = 0.01). Among those who gained weight, delta BMI values showed positive correlations with delta sleep induction time (r = 0.25, p = 0.001), delta PSQI (r = 0.24, p = 0.004) and delta TFEQ-18 scores (r = 0.25, p = 0.001). CONCLUSION: Weight changes during social isolation are similar in women with PCOS and healthy women. However, within those who gain weight, increase in BMI is more pronounced in women with PCOS. Weight gain appears to be related to alterations in sleep quality and eating habits rather than reduced physical activity. LEVEL III: Evidence obtained from cohort or case-control analytic studies.