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Female Urogenital Diseases and Pregnancy Complications

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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

Leiomyoma

Myofibroma

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Neoplasms, Connective Tissue

Connective Tissue Diseases

Uterine fibroids combined with infertile women

Uterine fibroids combined with non-infertile women

This study is a retrospective observational study without intervention.

No intervention

Shixuan Wang

Shixuan Wang, PhD

Female fertility may be affected by uterine fibroids, although this association has not been elucidated. This retrospective cohort study aims to evaluate the impact of fibroids on women fertility.

Infertility is defined as the inability of a couple to achieve pregnancy over an average period of one year of unprotected sexual intercourse. Currently, one in six couples is affected by infertility worldwide. With the development of society bringing enormous material and spiritual wealth to human beings, comprehensive factors such as environmental pollution, life and work pressure and bad habits have an important impact on fertility. Infertility is a disease that seriously affects the physical and mental health of patients and brings about serious social problems. According to the World Health Organization (WHO), infertility will become the third major disease in the 21st century following tumor and cardiovascular diseases.

Infertility can be caused by a single factor or multiple factors together. The WHO proposed a classification method based on etiological diagnosis to classify infertility into six major causes: ovulation factors, fallopian tube problems, uterine factors, cervical factors, male factors and psychosocial factors. There is a serious impact on female fertility due to heredity, auto-immunity, infection, metabolic abnormalities, surgery and other factors. The main factors leading to female infertility include patient age, education level, weight (obesity), menstrual history (irregular menstrual cycle), pregnancy history (stillbirth and abortion history), disease history (ovarian cyst, ovarian aging, endocrine autoimmune diseases, fallopian tube abnormalities, pelvic abnormalities and uterine abnormalities), sexual history, previous surgical history, smoking history, chemical exposure history, and mental stress, etc. The objective of this study is to explore the impact of uterine fibroids on female pregnancy rate.

Uterine fibroid is a common benign tumor of female reproductive tract, with 25% to 50% of women of childbearing age suffering from uterine fibroid. The fibroids can cause various clinical symptoms, including menorrhagia, prolonged menstruation, pelvic compression and pain, as well as infertility and obstetric complications, but mostly are asymptomatic. The prevalence of fibroids increases with the age of women, while the fertility rate declines with ages. This complex relationship is particularly harmful. The mechanisms related to fibroids and infertility vary with the type and location of fibroids, including anatomical structure deformation, and interference with the physiological changes of endometrium and implantation of zygotes. In addition, fibroids can destroy the anatomical structure of the pelvis and disrupt the function of the fallopian tube. The FIGO classification describes nine types of fibroids: submucosal fibroids (type 0, Ⅰ, Ⅱ), intramural fibroids (types Ⅲ, Ⅳ, Ⅴ), and subserous fibroids (types Ⅵ and Ⅶ). Among them, submucosal and some intramural fibroids can lead to endometrial inflammatory environment, affecting sperm migration and embryo implantation.

Nevertheless, there is still controversy in epidemiological studies regarding the relationship between uterine fibroids and female infertility. Parity has a significant protective effect against fibroid development, and in fact infertile women may be at higher risk for fibroids. Similarly, it is difficult to distinguish whether fibroids have a direct deleterious effect on infertility, or whether the fibroid-infertility association is mediated by concomitant factors that affect fertility. In addition, the impact of each type of fibroids on fertility varies by the difference in the number, size, and location of fibroids, and the combinations of different fibroids may have special effects. Do uterine fibroids already exist when women plan and attempt to conceive? Do uterine fibroids have negative effects on fertility during this period? It is an urgent need to solve this problem at the present. Therefore, this study is of great significance for us to understand the impact of fibroids on female fertility and guide the treatment patterns of female patients with uterine fibroids who have fertility needs.

The Effects of Uterine Fibroids on Pregnancy in Women

Fibroid types range from 0 to 8 according to the FIGO classification. The pregnancy rate varies with different types and size of fibroids. Subserosal fibroids do not exert any detrimental effects on fertility outcomes. Submucosal fibroids have negatively impact fertility. The effect of intramural fibroids on reproductive outcome has been a subject of debate in the past, but recent literature indicates that intramural myomas also negative impact fertility.

Fibroids are a source of several obstetric complications, including spontaneous abortion, preterm birth, cesarean section, placental abruption, postpartum hemorrhage, and breech presentation. Submucosal fibroids and multiple myomas have an increased risk of miscarriage. The rate is calculated as the proportion of the number of miscarriage to the total number of pregnancies in different types of fibroids.

Fibroids measuring more than 5 centimetre (cm) have been linked to delivery at earlier gestational age. The ratio is calculated as the proportion of fibroids combined with preterm birth to fibroids combined with live birth.

Greater size and number of fibroids were associated with increased incidence of cesarean delivery. The ratio is calculated as the proportion of fibroids combined with cesarean section to total births.

Fibroids have an increased risk of placental abruption in patients. The ratio is calculated as the proportion of fibroids combined with placental abruption to total patients.

There is an independent association of uterine leiomyomata with increased risk of severe postpartum hemorrhage. Submucosal fibroids are less implicated in bleeding events than intramural and subserosal ones. Great rates of hemorrhage are related with the biggest lesions. The ratio is calculated as the proportion of fibroids combined with postpartum hemorrhage to total patients.

Patients with fibroids have an increased risk of breech presentation. Malpresentation may be more related to multiple fibroids an to those bigger than 10 cm. The ratio is calculated as the proportion of fibroids combined with malpresentation to total patients.

Huazhong University of Science and Technology

Shandong University

Peking University People's Hospital

Wenwen Wang

Professor

Two Diamel tablets (Orally administered) three times a day (just before each meal: breakfast, lunch and dinner), for 24 weeks.

Diamel

Two Placebo tablets (Orally administered) three times a day (just before each meal: breakfast, lunch and dinner), for 24 weeks.

Placebo

Mercedes Hernandez, MD

The purpose of this study is to assess the efficacy of Diamel administration in the treatment of Polycystic Ovary Syndrome. The duration of this double-blind placebo controlled phase 3 clinical trial will be 24 weeks.

Diamel in the Treatment of Polycystic Ovary Syndrome

Efficacy of Diamel in the Treatment of Polycystic Ovary Syndrome

Catalysis SL

The decision aid is then developed further process of evidence synthesis and multidisciplinary external review.

web-based decision aid

Shiu-Yu K Lee, PhD

Wen-Fang Cheng

This study aims to develop a patient-centered, user-center, interactive web-based decision aid to support the young women with cancer in making an informed fertility-related decision and further evaluate its efficacy.

This study uses mixed-method and involves 2 stages. As following the IPDAS recommendation for developing decision aids, the first sample of 25 young woman survivors with breast, hematology or ovarian cancer, and oncologist, fertility specialists or nurses will be interviewed to assess the fertility-related decision needs from and. The decision aid is then developed further process of evidence synthesis and multidisciplinary external review. After the draft being evaluated for its validity via Think-aloud cognitive interview method, field testing via one-group quasi-experimental design on 90 young women with newly diagnosed breast, hematology or ovarian cancer will be applied to test its outcomes of decision quality, emotional health and fertility concerns.

Development and Evaluation of Web-Based Fertility-Related Decision Support for Young Female Cancer Patients

National Taiwan University Hospital

Hypothyroidism

Thyroid Diseases

Antineoplastic Agents

Letrozole

Progesterone

Aromatase Inhibitors

Enzyme Inhibitors

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Participants randomized to letrozole group will take 5mg tablets orally daily for 5 days starting on day 3 of cycle. Dose can be adjusted up to 7.5mg based on ovulation response, maintained for subsequent cycles. Treatment continues for up to 6 ovulatory cycles or until pregnancy occurs. Ovulation assessed by follicular monitoring and progesterone. Compliance monitored by pill counts and diary. Routine antenatal care if pregnant. Adverse effects monitored per guidelines. Participants followed for multiple pregnancies. Tablets taken at same time each day. Maximum treatment period is 6 months.

Participants randomized to this group will take letrozole tablets at same dose and schedule as letrozole only group. In addition, they will take levothyroxine tablets orally once daily. Levothyroxine dose will start at 25mcg and be titrated based on TSH level, with a target TSH in the normal range. Participants will take levothyroxine at approximately same time each day. Letrozole dosing and schedule as described for other group. Treatment continues for up to 6 ovulatory cycles or until pregnancy occurs. Ovulation assessed by follicular monitoring and progesterone. Compliance monitored by pill counts, TSH levels and diary. Routine antenatal care if pregnant. Adverse effects monitored per guidelines. Participants followed for multiple pregnancies. Maximum treatment period is 6 months.

Participants will receive 2.5mg letrozole tablets orally daily for 5 days starting on day 3 of menstrual cycle. The 2.5mg dose will be maintained for at least the first 3 cycles. If no ovulation after 3 cycles, dose cautiously increased up to 7.5mg maximum. Once minimum ovulation dose determined, it will be continued for up to 6 cycles total or until pregnancy occurs. Compliance monitored by pill counts and diary. Ovulation assessed by follicular monitoring and progesterone levels. Routine antenatal care if pregnant. Adverse effects monitored and managed per guidelines. Participants followed for multiple pregnancies. Maximum treatment duration is 6 ovulatory cycles or 6 months. Tablets taken at same time each day.

Letrozole 2.5mg

Participants will take letrozole at same doses as letrozole only group. Also receive levothyroxine starting at 25mcg orally once daily, titrated by 25mcg every 4 weeks to reach normal TSH, maximum 100mcg daily. Once appropriate dose determined to normalize TSH, it is maintained throughout treatment period. Compliance monitored by pill counts, TSH levels, and diary. Treatment continues for up to 6 ovulatory cycles or until pregnancy, whichever is first, maximum 6 months. Ovulation assessed by monitoring and progesterone. Routine antenatal care if pregnant. Adverse effects monitored and managed per guidelines. Participants followed for multiple pregnancies. Letrozole and levothyroxine taken daily at same time. All other procedures same as letrozole only group.

Levothyroxine 25 Mcg (0.025 Mg) Oral Tablet

Muhamed Alhagrasy, M.D.

Muhamed A Alhagrasy, M.D.

The goal of this randomized controlled trial is to compare letrozole alone versus letrozole plus levothyroxine for ovulation induction in infertile women with both PCOS and subclinical hypothyroidism. The main questions it aims to answer are:

Is letrozole plus levothyroxine superior to letrozole alone in achieving ovulation in these patients? Does combining levothyroxine with letrozole lead to higher pregnancy and live birth rates compared to letrozole alone?

Participants will be randomized into two groups:

Group 1 will receive letrozole only, starting at 2.5 mg daily from day 3 to 7 of the menstrual cycle. The dose will be increased up to 7.5 mg if no ovulation occurs, for a maximum treatment period of 6 months or until pregnancy is achieved.

Group 2 will receive letrozole at the same doses as group 1 plus 25 mcg levothyroxine daily.

This study will only enroll female participants. Patients must be of reproductive age with intact uteri and ovaries to meet the inclusion criteria.

The study aims to induce ovulation for conception in infertile women with PCOS and subclinical hypothyroidism. As such, only individuals biologically born as females and currently identifying as women will be eligible.

All enrolled participants must have functioning ovaries and intact reproductive organs capable of sustaining a pregnancy. Patients who have undergone surgical sterilization procedures like tubal ligation or hysterectomy will be excluded.

Confirmation of female gender will be through medical history, physical examination, and review of medical records if needed. Pregnancy tests will be done at screening and before each treatment cycle.

The reproductive status, ovaries and uterus will be assessed by medical history, physical examination and imaging like ultrasound when indicated.

Best Treatment for Women With Both (Polycystic Ovary Syndrome) PCOS and Subclinical Hypothyroidism

Letrozole Alone vs. Letrozole Plus Levothyroxine for Ovulation Induction in Infertile Women With Both (Polycystic Ovary Syndrome) PCOS and Sub-clinical Hypothyroidism.

To protect participant confidentiality, individual-level data from this study will not be made publicly available. However, de-identified aggregated data and results can be shared with other researchers upon request after publication. Any data provided will be limited, non-identifiable, and subject to a data use agreement to ensure participant privacy. Only select excerpts needed to validate findings will be shared under approved research objectives. The investigators reserve the right to reject requests that may compromise anonymity. We aim to promote transparency through controlled data access rather than public availability of the full dataset due to re-identification risks for participants.

Biochemical evidence of pregnancy by positive urine or serum β-hCG test.

The number of deliveries that resulted in a live born baby, documented by hospital delivery records.

Evidence of ovulation by ultrasound monitoring of dominant follicle development and serum progesterone level \> 3 ng/mL in mid-luteal phase.

Loss of clinical pregnancy before 20 weeks gestation, confirmed by ultrasound or histopathology.

Normal ovulatory menstrual cycles defined as cycle length 21-35 days.

Participant reports of adverse effects of letrozole or levothyroxine, graded per standard criteria.

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
The Effects of Uterine Fibroids on Pregnancy in Women	NCT06020924	Female Infertil... Uterine Fibroid	No intervention	20 Years - 50 Years	Tongji Hospital
Diamel in the Treatment of Polycystic Ovary Syndrome	NCT01051024	Polycystic Ovar...	Diamel Placebo	18 Years - 40 Years	Catalysis SL
Development and Evaluation of Web-Based Fertility-Related Decision Support for Young Female Cancer Patients	NCT03786458	Infertility, Fe... Female Infertil...	web-based decis...	20 Years - 44 Years	National Taiwan University Hospital
Development and Evaluation of Web-Based Fertility-Related Decision Support for Young Female Cancer Patients	NCT03786458	Infertility, Fe... Female Infertil...	web-based decis...	20 Years - 44 Years	National Taiwan University Hospital
Best Treatment for Women With Both (Polycystic Ovary Syndrome) PCOS and Subclinical Hypothyroidism	NCT06041204	PCOS (Polycysti... Subclinical Hyp... Female Infertil...	Letrozole 2.5mg Levothyroxine 2...	20 Years - 40 Years	Al-Azhar University
Best Treatment for Women With Both (Polycystic Ovary Syndrome) PCOS and Subclinical Hypothyroidism	NCT06041204	PCOS (Polycysti... Subclinical Hyp... Female Infertil...	Letrozole 2.5mg Levothyroxine 2...	20 Years - 40 Years	Al-Azhar University
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

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