Symptoms and General Pathology

All Conditions

Nutritional and Metabolic Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Neoplasms

Gland and Hormone Related Diseases

Syndrome

Obesity

Infertility

Infertility, Female

Polycystic Ovary Syndrome

Insulin Resistance

Primary Ovarian Insufficiency

Menopause, Premature

Premature Birth

Mitochondrial Diseases

Overweight

Overnutrition

Nutrition Disorders

Body Weight

Genital Diseases

Urogenital Diseases

Hyperinsulinism

Metabolic Diseases

Glucose Metabolism Disorders

Cysts

Ovarian Cysts

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Gonadal Disorders

Endocrine System Diseases

Menopause

Hypoglycemic Agents

All Drugs and Chemicals

Insulin

Insulin, Globin Zinc

Vera Várhegyi, MD

Anikó Gál, PhD

Enrolling of 150 female patients of fertile age diagnosed with PCOS, insulin resistance, infertility, or mitochondrial disease, and the same number of age- and sex-matched controls are planned.

During the research biomarkers already with mitochondrial dysfunction in the scientific literature and common mtDNA abnormalities (deletions, point mutations, copy number changes, etc.) are examined.

Mitochondrial dysfunction can be involved in the development of clinically heterogeneous diseases affecting multiple tissues and organs and can manifest at any age. Clinical signs are mainly manifested in the most energy-demanding tissues, such as the central nervous system, striated muscles, cardiac musculature, endocrine glands, liver, kidney, and sensory organs.

Polycystic ovarian syndrome (PCOS) is a multifactorial disorder with endocrine dysfunction characterized by ovulatory dysfunction, obesity, insulin resistance (IR), hirsutism, mild persistent inflammation, and ultrasonographically confirmed polycystic ovarian morphology. PCOS affects 5-15% of women of reproductive age. PCOS and IR are also common and treatable causes of infertility. As a result of delaying childbearing until later in life, this problem is affecting more and more couples. In the present study, the investigators hypothesize that PCOS, IR, and infertility associated with these conditions may also be a manifestation of mitochondrial dysfunction, the role of mitochondrial dysfunction in these conditions has been investigated to a limited extent based on the current literature.

Recent literature has shown that mitochondrial dynamics and morphology are two of the major factors in the development of insulin resistance and diabetes mellitus by regulating glucose metabolism. The investigators of this study cohort hypothesize that PCOS and IR may also be a manifestation of a primary mitochondrial pathology, the prevalence of IR and PCOS in primary mitochondrial patients has not yet been investigated based on the current literature. Recent literature suggests that mitochondrial dynamics and morphology are two of the main factors in the development of insulin resistance and diabetes mellitus by regulating glucose metabolism.

In the present experimental design, mitochondrial dynamics, bioenergetics, and autophagy pathways are hypothesized to play a key role in the pathomechanisms of PCOS and IR. A better understanding of the role of mitochondrial pathways in the pathophysiology of PCOS and IR may help to develop new biomarkers or therapeutic targets.

DNA isolated from blood sample and urine sample (urine epithelial cells)

Polycystic Ovary Syndrome, Mitochondrial Dysfunction, Obesity, Insulin Resistance Infertility (POMODORI) Cohort

Polycystic Ovary Syndrome, Insulin Resistance, Infertility, Obesity, and the Associated Mitochondrial Dysfunction With These Disorders in Hungarian Patients

The body mass index (BMI) is the metric currently in use for defining anthropometric height/weight characteristics in adults and classifying (categorizing) them into groups (expressed in kg/m2).

Daily dose of metformin used (expressed in milligrams)

Daily or weekly dose of the used glucagon-like peptide-1 (GLP-1) agonist depending on the exact type of active substance (expressed in milligrams)

The serum glucose and insulin levels are calculated by using plasma concentrations of insulin and glucose obtained during 120 min of a standard (75 g glucose) OGTT. Fasting, 1h and 2h glucose and insulin levels are measured

Clinical pregnancy rate = the number of clinical pregnancies/the total number of participants in the patient cohort × 100%

Measurement of the baseline female sex hormone: anti-Mullerian hormone (AMH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, progesterone, total testosterone, free testosterone, SHBG) and thyroid hormone levels (thyroid stimulating hormone (TSH), T3, T4 + anti-thyroid peroxidase antibody, anti-thyroglobulin antibody) - in the unit of measurement used for the hormone concerned

Semmelweis University

University professor

Skin and Connective Tissue Diseases

Heart and Blood Diseases

Infections

Diabetes Mellitus

Breast Neoplasms

Hypertension

Diabetes, Gestational

Toxemia

* Blood sample
* Questionnaires
* Arterial stiffness assessment
* Transthoracic Echocardiogram
* Coronary Computed Tomography Angiography (CTA)
* Cardiac Positron Emission Tomography (PET)

* Blood sample
* Questionnaires
* Arterial stiffness assessment

PET scan

Kerri-Anne Mullen, PhD

The full HER CROWN will be a prospective cohort study to propose a novel, women-specific cardiovascular risk score/ algorithm in the prediction of hard cardiovascular outcomes (myocardial infarction, unstable angina, coronary revascularization, stroke, total and cardiovascular mortality). This future study will be the first longitudinal cohort study, to our knowledge, that is focused entirely on researching the pathophysiology and natural history of cardiovascular disease in women with known female-specific risk factors. Further, the investigators are aiming to recruit a sample that is representative of the ethnic distribution in Canada. The proposed pilot study is a feasibility study as an essential preparatory step for HER CROWN.

Cardiovascular diseases (CVD), including ischemic heart disease (IHD), peripheral vascular disease (PVD), and stroke, remain the leading preventable cause of death among Canadian women, resulting in over 34,000 deaths per year (age-standardized death rate: 25.1%). Nearly 40% of CVD-related deaths in women are due to IHD. Increased awareness efforts and effective treatments have led to an overall decline in CVD mortality among men and women in high income countries over the past few decades; however, alarmingly, an increase in CVD mortality has been observed in women in the most recent 5 to 10 years in Canada and the United States, and an upward trend in rates of AMI among younger women.

CVD in women remains understudied, under-diagnosed, and undertreated. Clinical guidelines are largely based on studies of men. Several existing large longitudinal cohort studies (e.g., the Nurses' Health Study, The Framingham Heart Study, the PURE study) have included women; however, they have not focused recruitment specifically on high-risk cohorts of women or on risk factors that are unique to women, more common in women, or that disproportionately affect women; they have not used novel measures of subclinical disease in women (e.g., coronary computed tomography angiography and cardiac Rb-positive emission tomography); and most have not recruited representative samples of women in terms of ethnicity or socioeconomic status. CVD risk calculators (e.g., Framingham, the American College of Cardiology ASCVD) focus on traditional risk factors (e.g., tobacco smoking, hypertension, diabetes), do not include sex-specific CVD risk factors or factors that disproportionately affect women, and thus tend to underestimate risk in women. Female-specific factors that have been associated with CVD risk include: premature or late menarche, abnormal menses, premature or early menopause, gestational hypertensive disorders, gestational diabetes, preterm delivery, pregnancy loss, hormonal contraceptive use, and polycystic ovarian syndrome. Risk factors that are under-recognized or disproportionately affect women include: rheumatologic inflammatory disorders (RIDs), depression, anxiety, chronic stress, abuse and intimate partner violence, and health literacy. In addition, a more feminine gender role has been shown to be associated with higher risk of reinfarction after premature acute coronary syndrome, but no additional research on gender roles and future cardiovascular risk is available. Importantly, novel cardiovascular risk markers such as measures of arterial stiffness and aging, among others, have not been prospectively evaluated in a female population. As such, additional longitudinal research is needed to understand the natural history of CVD and the impact of these 'non-conventional' risk factors in women.

A recent article published in the Lancet by a multi-national group of women's heart health experts reviewed existing evidence, identified knowledge gaps, and provided specific recommendations related to CVD research, prevention, treatment, and access to care for women. The HER CROWN longitudinal cohort study will respond to three important gaps identified in this review, specifically: 1) describe the pathophysiology and natural history of cardiovascular disease in women; 2) determine the impact of sex-specific, psychosocial, and socioeconomic risk factors on CVD in women; and, 3) improve CVD risk prediction/ risk stratification models for women. The Vanguard phase of the study will evaluate the feasibility of the full study being planned.

The full HER CROWN will be a prospective matched-cohort study to propose a novel, women-specific cardiovascular risk score/ algorithm in the prediction of hard cardiovascular outcomes (myocardial infarction, unstable angina, coronary revascularization, stroke, total and cardiovascular mortality). This future study will be the first longitudinal cohort study, to our knowledge, that is focused entirely on researching the pathophysiology and natural history of cardiovascular disease in women with known female-specific risk factors. Further, the investigators are aiming to recruit a sample that is representative of the ethnic distribution in Canada. The proposed pilot study is a feasibility study as an essential preparatory step for HER CROWN. The study will be cross-disciplinary, including investigators who specialize in the treatment of cardiovascular disease in women, epidemiology and administrative data, cardiovascular imaging, biomarker research, physical activity, nutrition, nicotine addiction, and mental health who will each inform outcomes and sub-studies.

A single-site, two-group, matched-cohort Vanguard study will be completed to test feasibility outcomes to inform a large, multi-site, two-group, longitudinal matched-cohort study.

Reexamining Her Cardiovascular Risk - Ottawa WomeN's Longitudinal Cohort Study

Demographics and socioeconomic information

Past, present medical history, medication, and women's health related information

This is calculated by assigning scores of 0, 1, 2, and 3 to the response categories, respectively, of "not at all," "several days," "more than half the days," and "nearly every day." GAD-7 total score for the seven items ranges from 0 to 21.

0-4: minimal anxiety 5-9: mild anxiety 10-14: moderate anxiety 15-21: severe anxiety

Several days = 1 More than half the days = 2 Nearly every day = 3

1-4 Minimal depression 5-9 Mild depression 10-14 Moderate depression 15-19 Moderately severe depression 20-27 Severe depression

PSS scores are obtained by reversing responses (e.g., 0 = 4, 1 = 3, 2 = 2, 3 = 1 \& 4 = 0) to the four positively stated items (items 4, 5, 7, \& 8) and then summing across all scale items. A short 4 item scale can be made from questions 2, 4, 5 and 10 of the PSS 10 item scale.

Both the ISA-P and ISA-NP scores range from 0 to 100 where a low score indicates the relative absence of abuse and the higher scores represent the presence of a greater degree or amount of abuse.

Responses are measured on a 5-point Likert scale (1 = never true, 2 = rarely true, 3 = sometimes true, 4 = often true, 5 = very often true). Each subscale is represented by five questions with a score range from 5 to 25; scores fall into four categories: none to low trauma exposure, low to moderate trauma exposure, moderate to severe trauma exposure and severe to extreme trauma exposure for each scale.

Respondents are asked to rate how bothered they have been by each of 20 items in the past month on a 5- point Likert scale ranging from 0-4. Items are summed to provide a total severity score (range = 0-80). 0 = Not at all 1 = A little bit 2 = Moderately 3 = Quite a bit 4 = Extremely

SF-12v2 items are scored so that a higher score indicates a better health state. For example, functioning items are scored so that a high score indicates better functioning, and the pain item is scored so that a high score indicates freedom from pain. After data entry, items are scored in three steps:

1. item recoding for the four items that require recoding;
2. computing scale scores by summing across items in the same scale (raw scale scores); and,
3. transforming raw scale scores to a 0-100 scale (transformed scale scores).

Nicotine, alcohol, cannabis use measure questionnaire. No score.

Scoring a HIGH level of physical activity on the IPAQ means your physical activity levels equate to approximately one hour of activity per day or more at least a moderate intensity activity level. Scoring a MODERATE level of physical activity on the IPAQ means you are doing some activity more than likely equivalent to half an hour of at least moderate intensity physical activity on most days. Scoring a LOW level of physical activity on the IPAQ means that you are not meeting any of the criteria for either MODERATE of HIGH levels of physical activity.

Score by giving 1 point for each correct answer (maximum 6 points). Score of 0-1 suggests high likelihood (50% or more) of limited literacy. Score of 2-3 indicates the possibility of limited literacy. Score of 4-6 almost always indicates adequate literacy.

Coronary artery calcium, plaque presence and plaque characteristics

Coronary perfusion and microvascular function

CBC, electrolytes, creatinine, fasting lipids, fasting glucose, HbA1c, hs-troponin, NT-proBNP, Lipoprotein (a), LH, FSH, estradiol, progesterone, additional sample for biobanking βhCG test for subsamples participating in PET and Coronary CTA

participant satisfaction and acceptability questionnaire. No score.

Ottawa Heart Institute Research Corporation

Immune System Diseases

Hypersensitivity

Breast Diseases

Skin Diseases

Patients will be genotyped for single nucleotide polymorphism previously found to be associated with age at natural menopause

Blood sample for genetic test

at each visit : 2x7ml. At the end of the study hormonal measurements (AMH, P4, LH, FSH, E25)

Blood sample for hormonal measurement

Ovarian ultrasound scan at follow up visits (Y1,Y1.5, Y2.5 Y3.5 Y4.5 Y5.5)

Ovarian ultrasound scan

Charlotte SONIGO, MD

Michael Grynberg, MD, PhD

Over the past decade, advances in diagnosis and treatments have dramatically increased the rates of cure for young patients with cancer. As a consequence, a new population of cancer survivors has emerged whose fertility is compromised after cancer therapy. Indeed, gonadotoxicity is a well-known long-term side effect of cancer treatment in young patients having survived malignant diseases. More than 80% of women of childbearing age, treated for breast cancer with standard protocol of neoadjuvant (4 cycles of 5-fluorouracile - epirubicin- cyclophosphamide (FEC) and 4 cycles of docetaxel) or adjuvant chemotherapy (3 FEC and 3 docetaxel), show an alteration of their ovarian reserve 2 years after completion of the treatment, as a result of chemotherapy-related follicular loss. Therefore, according to the extent of the follicular damages, the gonadal function may vary from moderate to severe diminished ovarian reserve (DOR) and possibly to the ultimate stage of premature ovarian insufficiency (POI).

Investigators propose a multicentric and prospective study of a cohort of young women with breast cancer to evaluate whether genetic polymorphisms, previously identified as being correlated with age at menopause in the healthy population, are associated with the intensity of the follicular decline following chemotherapy in young breast cancer survivors.

With 48 763 new cases in 2012, breast cancer represents the first female cancer in France. Although the incidence of this malignancy peaks after the age of 60 years, nearly 2500 of reproductive-age women are diagnosed with breast cancer every year. Recent advances in cancer therapy markedly improved the rates of cure for young adult suffering from cancers. Over the past decade, the mortality rates in breast cancer patients has decreased by more than 1.6% per year. The five year survival rate for women under 45 with breast cancer is now approaching 80%. As a consequence, a new population of young cancer survivors has emerged whose fertility is compromised after cancer therapy. Thus, the question of fertility preservation (FP) in young cancer patients has become a major issue in the care-personalized path. Indeed, information regarding the risks of infertility and FP counselling may contribute to improving the quality of life and the coping of patients with the burden of cancer treatment. Therefore, oncofertility counselling by a specialist is now recommended for all young cancer patients having to undergo treatment that may reduce the fertility potential.

Gonadotoxicity is a well-known long-term side effect of cancer treatment in young patient having survived malignant diseases. Neoadjuvant or adjuvant chemotherapy usually combining alkylating agent and taxane, is often recommended for young women presenting with breast cancer. However, alkylating agents, such as cyclophosphamide have been shown to cause extensive dose-dependent loss of primordial follicles in cancer patients. Beside a enhancement of apoptosis, cyclophosphamide might induce a follicular loss through an activation of the primordial follicle recruitment: the "burnout" phenomenon.

Moreover, the extent of ovarian damages depends not only on the nature and dose of chemotherapy but also on age and ovarian reserve before treatment. Women age at chemotherapy administration is one of the most predictive risk factor of follicular depletion after the end of treatment. Therefore, according to the extent of the follicular damages, the gonadal function may vary from moderate to severe diminished ovarian reserve (DOR) and possibly to the ultimate stage of premature ovarian insufficiency (POI).

Currently, patients' age and the values of markers of the follicular ovarian status (serum anti-Müllerian hormone (AMH) levels and ultrasonographic antral follicle count (AFC), measured before the initiation of gonadotoxic treatment, are considered the most accurate predictive factors of post chemotherapy ovarian function. However, they may have some limitations since important inter-individual variations in the ovarian reserve two years after completion of treatment are reported in patients displaying similar age, AMH as well as AFC. This observation suggests that, besides environmental and pathologic variables, genetic variations, inducing different ovarian sensitivity to chemotherapy, might be at play.

Indeed, in healthy women, age at natural menopause varies from 40 to 55 years and is characterized by a strong familial concordance. Many studies of large genome-wide association (GWAS) found a link between the age and variants of some genes involved in DNA repair, DNA maintenance and folliculogenesis as initial follicular recruitment. Since these genes may have an influence on the ovarian reserve (together with the effects of gonadotoxic treatment regimens), investigators hypothesize that genetic polymorphisms known to be associated with age at menopause (BRSK1 (rs1 172822), ARHGEF7 (rs7333181), MCM8 (rs236114), PCSK1 (rs271924), IGF2R (rs9457827), TNF (rs909253), AMH (rs10407022) and AMHR2 (rs2002555) could be linked to the intensity of the follicular depletion after chemotherapy.

The primary objective is to evaluate whether genetic polymorphisms, previously identified as being correlated with age at menopause onset in the healthy population, are associated with the intensity of the follicular decline following chemotherapy in young breast cancer survivors.

The secondary objectives are to evaluate the association between genetic polymorphisms and other parameters related to female fertility, as menstrual cycle profile, pregnancy rate, serum anti-mullerian hormone (AMH) levels and ultrasonographic antral count (AFC) after chemotherapy such as the menstrual cycle profile and pregnancy rates.

Eligible subjects followed in the different participating centers will be included in this study. Informed consent will be obtained from all participating individuals before blood sample collection and molecular studies. AMH measurement and AFC will be performed before the cancer treatment randomly during the menstrual cycle phase. In the same time, blood samples will be taken for the genotyping. All patients will receive adjuvant or neoadjuvant chemotherapy containing cyclophosphamide, epirubicin, 5-FU and docetaxel. Patients will be evaluated 12 and 24 months after the end of the treatment. A clinical (menstrual cyclicity) and hormonal (AMH, FSH) evaluation associated with ultrasound evaluation of AFC of enrolled patients will be performed. Thus, association between genetic polymorphism and the depth of ovarian decline (classified as: normal ovarian reserve, moderate DOR, severe DOR or POI) after healing will be evaluated.

Evaluation of Individual Sensitivity to the Gonadotoxicity of Chemotherapy in Young Patients With Breast Cancer

is an aggregated measure of FSH, AMH serum level, Antral Follicle Count and menstrual profile :

* Normal ovarian reserve: persistence of menstrual cycle, FSH\<40 IU/L and AMH\>1.1 ng/mL or AFC\>7 follicles
* Moderate diminished ovarian reserve : persistence of menstrual cycle, FSH\<40 IU/L and 0.5≤AMH≤1.1 ng/mL or 5≤AFC≤7 follicles
* Severe diminished ovarian reserve : persistence of menstrual cycle and AMH\<0.5 ng/mL or AFC\<5 follicles
* Premature ovarian insufficiency is defined by amenorrhea above four months and FSH level ≥40 IU/L in women before 40 years.

AMH serum levels and ultrasonographic evaluation of AFC will be evaluated FIVEyears after the end of chemotherapy.

To evaluate the association between genetic polymorphisms and other parameters related to female fertility after chemotherapy such as the menstrual cycle profile. These data will be obtained from clinical interrogatory performed by medical doctors.

These data will be obtained from clinical interrogatory performed by medical doctors.

To assess the evolution of ovarian reserve tests at the end of chemotherapy AMH level will be performed before the initiation of chemotherapy and 6, 12, 24, 36, 48, 60 months following the end of chemotherapy.

To assess the evolution of ovarian reserve tests at the end of chemotherapy Measurements of ultrasonographic AFC will be performed before the initiation of chemotherapy and 6, 12, 24, 36, 48, 60 months following the end of chemotherapy.

A follicular decline will be defined as a moderate/severe DOR or a POI

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Polycystic Ovary Syndrome, Mitochondrial Dysfunction, Obesity, Insulin Resistance Infertility (POMODORI) Cohort	NCT06167135	Infertility, Fe... Polycystic Ovar... Insulin Resista... Primary Ovarian... Mitochondrial A... Obesity		20 Years - 45 Years	Semmelweis University
Reexamining Her Cardiovascular Risk - Ottawa WomeN's Longitudinal Cohort Study	NCT05632601	Cardiovascular ...	PET scan	25 Years - 55 Years	Ottawa Heart Institute Research Corporation
Reexamining Her Cardiovascular Risk - Ottawa WomeN's Longitudinal Cohort Study	NCT05632601	Cardiovascular ...	PET scan	25 Years - 55 Years	Ottawa Heart Institute Research Corporation
Evaluation of Individual Sensitivity to the Gonadotoxicity of Chemotherapy in Young Patients With Breast Cancer	NCT03731845	Breast Cancer	Blood sample fo... Blood sample fo... Ovarian ultraso...	18 Years - 36 Years	Assistance Publique - Hôpitaux de Paris
Polycystic Ovary Syndrome, Mitochondrial Dysfunction, Obesity, Insulin Resistance Infertility (POMODORI) Cohort	NCT06167135	Infertility, Fe... Polycystic Ovar... Insulin Resista... Primary Ovarian... Mitochondrial A... Obesity		20 Years - 45 Years	Semmelweis University

Spots Global Cancer Trial Database for primary ovarian insufficiency