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Female Urogenital Diseases and Pregnancy Complications

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Progesterone

Progestins

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PCOS: Seventeen PCOS subjects underwent two endometrial biopsies after the first P4-treated cycle, the first between days 5-9 of the cycle and the other between days 20-22 (i.e., under P4 treatment) of the cycle.

Controls: Thirteen ovulatory control women under two endometrial biopsies, performed after the first month of luteal P4 treatment, the first between days 5-9 and the second between days 20-22 of the cycle To quantify the parameters of interest, images were captured using a high-resolution camera (AxioCam-MCR, Carl Zeiss) adapted to a light microscope (Axiolab, Carl Zeiss) and adjusted with 40× objective lenses. The images were transmitted to a computer with AxioVision Rel 4.2 software (Carl Zeiss). For assessment of glandular and surface epithelial thickness, cell count, and counting newly formed blood vessels, ten images of each endometrial sample were made for each patient. For VEGF-C determination, the numerical density of blood vessels per mm2 was established

The same drug will be used in control group

Progesterone 400 Mg Vaginal Suppository on PCOS

Objective: To study the influence of metabolic factors on the action of progesterone on the endometrium of women with PCOS.

Design: A prospective open-label clinical trial. Setting: Participants were recruited from an outpatient reproductive endocrinology clinic at an academic tertiary medical care center from 2014 to 2019.

Subjects: To assess the sole effect of progesterone (P4) on the endometrium we studied amenorrheic (cycles\> 90 days) women with PCOS (n=23), comparing them to healthy eumenorrheic control women ( n=13).

Intervention(s): All subjects underwent an endometrial biopsy (EB) in the follicular phase of the first study cycle. They were then treated with micronized P4 (400 mg/day x 10 days intravaginally) from days 14-28 of the cycle, and a second EB was performed between days 20-24 of the cycle (second phase).

Main Outcome Measure(s): EB samples were analyzed under light microscopy for histomorphometric analysis.

PATIENTS AND METHODS

Subjects Inclusion criteria for PCOS women will be: a) ages 18 to 35 years, and b) PCOS was defined by the Rotterdam criteria, which includes two of the following three features: a) oligo-amenorrhea; b) clinical or biochemical signs of hyperandrogenism; and c) polycystic ovaries (6). These criteria yield four PCOS phenotypes (A thru D) (1-3). Controls were recruited from the family planning outpatient office. All participants will be healthy women ages 18 to 35 years with regular menstrual cycles, no evidence of hirsutism, no comorbidities, and not using hormone medications in the previous 3 months.

Exclusion criteria are as follows: a) use of any hormone treatment in the previous 3 months; b) other causes of anovulation as evidenced by abnormal levels of prolactin, cortisol, dehydroepiandrosterone sulphate (DHEAS), 17-hydroxyprogesterone (17-OHP), androstenedione, thyroid-stimulating hormone (TSH), and free T4, in blood samples obtained between days 2 and 5 of the cycle in cycling subjects or on any other day in amenorrheic subjects; c) gynecologic disorders or other associated diseases, such as endometriosis, hypertension, or diabetes mellitus; d) follicle-stimulating hormone (FSH) \>15 UI/L (cycle days 2-5); or e) a positive β-subunit of human chorionic gonadotropin (β-HCG).

Study Protocol

This trial was previously approved by the Research Ethics Committee (#21253613.6.0000.0068) of the Faculdade de Medicina, Hospital das Clínicas, Universidade de São Paulo (FMUSP), São Paulo, Brazil. The patients will be evaluated at Gynecology Outpatient office. The patients will be divided into two groups: a) PCOS and b) controls. All subjects will be cared for at the Endocrinology Gynecology Section and the Human Reproductive Center of the Gynecology Division, Hospital das Clínicas, FMUSP. After signing the informed consent will be written in accordance with Resolution 196/96 of the National Health Board (Resolução 196/96 do Conselho Nacional de Saúde), all subjects will be included in the study and evaluated as follows:

Preselection: This visit includes the following: interview for medical history; overall physical and gynecologic examinations; weight measurement (scale Filizola, model PL-150, with a capacity for 150 kg); height measurement with a metal stadiometer attached to the scale; abdominal circumference (AC) measurement with a measuring tape at the narrowest region between the last costal arch and the iliac crest; hip circumference (HC) measured around the circumference of hips at the top of the iliac crest and buttocks, body mass index (BMI) and blood pressure (BP) measurement; hirsutism according to the modified Ferriman-Gallwey (mFG) scoring system with nine areas, with patients with a score higher than 8 score deemed hirsute.

The menstrual cycle are considered as normal when the interval between periods was 21 to 35 days, and the blood flow lasted no more than 7 days. The cycle was characterized as anovulatory when the span between blood flows was \>35 days (1). Amenorrhea is defined as the absence of a menstrual flow for a period corresponding to the three previous cycles or for \>90 days (1,20).

Bloods will be collected and a transvaginal pelvic ultrasound will be performed on all study subjects.

Study A: Six PCOS patients with amenorrhea (cycles \>90 days) and negative β-HCG will be prescribed daily micronized P4 (400 mg) administrated via the vaginal route for 10 days. Two endometrial biopsies will be performed, one between the 5th and 9th day and the other between the 21st and 24th day (under the second treatment cycle with P4) of the menstrual cycle (day 1 being the first day of vaginal bleeding). A third biopsy will be repeated on the 4th cycle of P4 treatment, between cycle days 21 and 24 (Fig. 2). This part of the study will be designed to assess whether P4 could transform proliferative into secretory endometrium, regardless of the number of treatment cycles.

Study B:

PCOS: Seventeen PCOS subjects underwent two endometrial biopsies after the first P4-treated cycle, the first between days 5-9 of the cycle and the other between days 20-22 (i.e., under P4 treatment) of the cycle.

Controls: Thirteen ovulatory control women under two endometrial biopsies, will be performed after the first month of luteal P4 treatment, the first between days 5-9 and the second between days 20-22 of the cycle.

Assays The oral glucose tolerance test (OGTT) consisted of 75 grams of glucose administered orally after three days of a carbohydrate-rich diet; blood samples for glucose and insulin measurements were drawn before administration of the glucose solution and 30, 60, 90, and 120 minutes after taking the glucose solution.

Plasma glucose concentration was determined by the glucose oxidase method. All lipid measurements were taken directly in the plasma samples. Total cholesterol and triglycerides were assessed using enzyme methods (Roche Laboratories). The HDL-C was quantified by the same method and LDL-C was estimated with the Friedwald formula. The glycated hemoglobin were measured using high-performance liquid chromatography (with the use of the Tosoh A1c 2.2 Plus Glycohemoglobin Analyzer method in 2003-2004 and the Tosoh G7 method in 2007-2008, Tosoh Corp).

For hormone analyses, the blood samples were processed in a centrifuge. Progesterone was measured by the immunofluorometric assay (Wallac, Finland) using Auto DELFIA kits; androstenedione, PRL, LH, and FSH, by the immunofluorometric assay; dehydroepiandrosterone sulfate (DHEAS), by radioimmunoassay (Cisbio International, France and DSL, Texas, USA); and insulin and 17-OHP, by radioimmunoassay using DSL kits. The testosterone and SHBG levels were measured using the electrochemiluminescent immunoassay (Modular, Roche). The free testosterone index was calculated based on the followed formula: total testosterone/SHBG\*100. Free testosterone was calculated by Vermeulen's formula. All analyses were performed twice and the intra-assay and interassay coefficients of variation did not exceed 10% and 15%, respectively.

Endometrial biopsies Endometrial samples will be obtained using the Pipelle de Cornier catheter (Laboratoire CCD, Paris, France). Part of the material was embedded in paraffin for histomorphometric and immunohistochemical analyses, and the remainder was preserved in RNA for later molecular analyses.

Histochemistry Endometrial samples will be fixed for 24 hrs. in 10% formaldehyde, dehydrated in increasing concentrations of ethyl alcohol, cleared in xylene, and then embedded in paraffin. The paraffin-embedded samples will be then cut into ten 3-μm sections per subject. Eight of these sections were stained for Vascular Endothelial Growth Factor C (VEGF-C) and for immunohistochemistry (see below), and the two remaining sections will be stained with hematoxylin and eosin (H\&E) to confirm the menstrual cycle phase using the criteria suggested by Noyes et al. (1953) and morphometry (see below).

Sections willl be dewaxed conventionally; 0.3% H2O2 will be used to inactivate endogenous peroxidase at room temperature for 10 min, followed by washing with distilled water three times. The sections were immersed in 0.01 M citrate buffer (pH 6.0) and then placed in a microwave oven for heating up to the boiling point. After 10 min, this process will be repeated twice; then, the sections were cooled at room temperature and washed twice with phosphate-buffered saline (PBS) (pH 7.4). A 5% bovine serum albumin (BSA) blocking solution was added at room temperature for 20, min and the excess liquid was discarded. Rabbit anti-human VEGF-C polyclonal antibodies (Cell Signaling, Danvers, MA, USA) (VEGF-C: diluted at 1:100) were added to the incubation at 37°C for 24 h, and the sections were then washed for 5 min. thrice. A biotinylated goat anti-rabbit IgG (Cell Signaling, Danvers, MA, USA) working solution will be added at 1:1000 dilution for incubation at 37°C for 20 min. After washing, SABC will be added to the incubation at 37°C for 20 min, followed by washing and color development via diaminobenzidine (DAB) (DAB color development kit, Dako, Dinamarca) at room temperature for 5 to 30 min., followed by washing with distilled water, haematoxylin re-staining dehydration via graded ethanol, transparency via xylene, sealing via neutral gum, and inspection under light microscope. The primary antibody was replaced with PBS as a negative control. The positive sections that stained satisfactorily in the pre-experiment were used as positive controls.

Morphological and histomorphometric analyses To quantify the parameters of interest, images were captured using a high-resolution camera (AxioCam-MCR, Carl Zeiss) adapted to a light microscope (Axiolab, Carl Zeiss) and adjusted with 40× objective lenses. The images were transmitted to a computer with AxioVision Rel 4.2 software (Carl Zeiss). For assessment of glandular and surface epithelial thickness, cell count, and counting newly formed blood vessels, ten images of each endometrial sample were made for each patient. For VEGF-C determination, the numerical density of blood vessels per mm2 will be established.

Statistical analyses The minimum sample size needed for each group will be determined from a pilot study with 10 women per group after pilot study. Thus, in calculating the sample size, the correlation between the group measurements will be considered. For the results of the number of endometrial glands, a type I error of 5% and a type II error of 20% (sample with 0.8% power) were adopted for the detection of \>20% difference between groups. Commensurate with homogeneity, the quantitative data will be expressed as mean ± standard deviation. In conformity with data distribution, the Student t test or the Mann-Whitney U test will be used. The significance level was set at 95% (α ≤ 5%). Moreover, ANOVA or the Kruskal-Wallis test will be used for histologic and immunohistochemical comparisons, when the additional group (PCOS during the proliferative phase) was included. Then, in line with data distribution, either the Tukey test or the Dunn test will be applied. When possible, the subjects of Study A and B were combined for analysis.

Progesterone Action on Endometrium of PCOS

Abnormalities of the Endometrium Persist Despite Adequate Progesterone Supplementation in the Polycystic Ovary Syndrome

Number of patients with adequate changes of endometrium similar to luteal phase.

University of Sao Paulo General Hospital

Full Professor and head of Discipline

Endometrial Neoplasms

Hyperplasia

Endometrial Hyperplasia

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Diseases

Hypoglycemic Agents

Antineoplastic Agents

Reproductive Control Agents

Metformin

Letrozole

Ethinyl Estradiol

Cyproterone Acetate

Cyproterone

Estradiol 17 beta-cypionate

Estradiol 3-benzoate

Estradiol

Polyestradiol phosphate

Cyproterone acetate, ethinyl estradiol drug combination

Aromatase Inhibitors

Enzyme Inhibitors

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Contraceptive Agents

Contraceptives, Oral

Contraceptives, Oral, Hormonal

Contraceptive Agents, Female

Contraceptive Agents, Hormonal

Androgens

Androgen Antagonists

20 non-obese EEC patients will be randomized to GnRHa + Letrozole group.Then every 12 weeks, an hysteroscope will be used to evaluate the endometrial condition, and the pathological findings will be recorded.

20 non-obese EEC patients will be randomized to Diane-35 + metformin group.Then every 12 weeks, an hysteroscope will be used to evaluate the endometrial condition, and the pathological findings will be recorded.

20 non-obese EAH patients will be randomized to GnRHa + Letrozole group.Then every 12 weeks, an hysteroscope will be used to evaluate the endometrial condition, and the pathological findings will be recorded.

20 non-obese EAH patients will be randomized to Diane-35 + metformin group.Then every 12 weeks, an hysteroscope will be used to evaluate the endometrial condition, and the pathological findings will be recorded.

Gonadotropin-releasing hormone analogue, intramuscular injection of 3.75mg will be given every 4 weeks , and the maximum using courses will be 6.

GnRHa

Letrozole 2.5mg

Periodic use. Patients will receive one pill po qd for 21 days, and next period should be started after 7 days.

Diane-35

Xiaojun Chen, PhD

Bingyi Yang

Bingyi Yang, MD

Xiaojun Chen

Pengfei Wu

To investigate the efficacy of GnRHa plus letrozole vs Diane-35 plus metformin in non-obese progestin-insensitive early-stage endometrial cancer (EEC) and atypical hyperplasia(EAH) patients asking for conservative treatment.

There were more and more women with early endometrioid endometrial cancer (EEC) and atypical endometrial hyperplasia (EAH) who want to preserve fertility. Approximately 70% to 80% of females who meet the criteria for conservation treatment are able to achieve CR after progestin therapy, with a median time of 6-7 months, but about 20% to 30% of patients get no response or need to take longer time to achieve remission (over one year). With long duration of treatment, there will be more side effects such as weight gain, impaired liver function, endometrial injury, ovarian reserve inhibition etc. which will decrease the efficacy of conservative treatment. Previous researches had shown that GnRHa plus letrozole or ethinylestradiol cyproterone plus metformin could be a better second-line treatment for progestin-insensitive patients. Till now, no similar studies were found, so we design this study to explore the efficacy of GnRHa plus letrozole and ethinylestradiol cyproterone plus metformin in progestin-insensitive EEC and EAH patients to provide new evidences for improving conservative treatment efficacy. Considered there will be more thrombotic risks in obese patients using ethinylestradiol cyproterone, we enrolled patients with BMI \< 30kg/m2 only in this study.

This will be a single-centred prospective pilot study. Patients diagnosed as progestin-insensitive EAH or EEC by dilatation and curettage (D\&C) or hysteroscopy will be enrolled. Non-obese patients will be stratified by pathological diagnosis (EEC or EAH) and then they will be randomly assigned (1:1) to two arms. One will be GnRHa + letrozole group and another will be ethinylestradiol cyproterone + metformin group.

The primary endpoint is cumulative complete response (CR) rate at 28 weeks of treatment. The secondary endpoints include adverse events, duration of complete response, recurrent rate, pregnancy rate and quality of life of patients.

GnRHa + Letrozole in Non-obese Progestin-insensitive Endometrial Cancer and Atypical Hyperplasia Patients

Gonadotropin-releasing Hormone Agonist (GnRHa) Plus Letrozole in Non-obese Progestin-insensitive Early-stage Endometrial Cancer and Atypical Hyperplasia Patients With Conservative Treatment

The cumulative 28-week CR rates will be calculated in two groups. Patients will be evaluated with an hysteroscopy every 12 weeks. For some may delay the evaluation as personal reasons, we define the primary outcome measure as complete response rates within 28 weeks of treatment.

Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 will be recorded, as well as incidence of adverse events.

The median CR time will be calculated in two groups

Professor

Nutritional and Metabolic Diseases

Obesity

This group including 29 EEC cases. Interventional Study Model was Simon two-stage optimal design. Eleven patients were needed for the first stage, and if eight or more patients achieved CR at 28 weeks, the trial can enter into the second stage.

Then every 12 to 16 weeks, an hysteroscope will be used to evaluate the endometrial condition, and the pathological findings will be recorded.

Gonadotropin-releasing hormone analogue, intramuscular injection of 3.75mg will be given every 4 weeks, and the maximum treatment courses will be 6. If the patient get CR within 6 courses, another 2 courses will be used as consolidation therapy.

GnRH antagonist

To investigate the efficacy of GnRHa plus letrozole in obese progestin-insensitive EEC patients.

There were more and more women with early endometrioid endometrial cancer (EEC) and atypical endometrial hyperplasia (EAH) who want to preserve fertility.

Approximately 70% to 80% of females who meet the criteria for conservation treatment are able to achieve CR after progestin therapy, with a median time of 6-7 months, but about 20% to 30% of patients get no response or need to take longer time to achieve remission (over one year). With long duration of treatment, there will be more side effects such as weight gain, impaired liver function, endometrial injury, ovarian reserve inhibition etc. which will decrease the efficacy of conservative treatment. Previous researches had shown that GnRHa plus letrozole could be a better second-line treatment for obese progestin-insensitive patients. Till now, no similar studies were found, so we design this study to explore the efficacy of GnRHa plus letrozole in obese progestin-insensitive EEC and EAH patients to provide new evidences for improving conservative treatment efficacy. We defined obese patients as these with BMI ≥ 30kg/m2.

This will be a single-centred prospective pilot study. Patients diagnosed as obese progestin-insensitive EEC by dilatation and curettage (D\&C) or hysteroscopy will be enrolled. The primary endpoint is cumulative complete response (CR) rate at 28 weeks of treatment. The secondary endpoints include adverse events, duration of complete response, recurrent rate, pregnancy rate and quality of life of patients.

GnRHa + Letrozole in Obese Progestin-insensitive Endometrial Cancer Patients

Gonadotropin-releasing Hormone Agonist (GnRHa) Plus Letrozole in Obese Progestin-insensitive Early-stage Endometrial Cancer Patients With Conservative Treatment

The cumulative 28-week CR rates will be calculated in two groups. Patients will be evaluated with an hysteroscopy every 12 to 16 weeks. For some may delay the evaluation as personal reasons, we define the primary outcome measure as complete response rates within 28 weeks of treatment.

Data on treatment and hysteroscopy management will be collected, and deviations from study protocol will be recorded in writing. For example, the time of drug interruptions due to related toxicities or AEs, and delay of hysteroscopy for personal reasons.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Progesterone Action on Endometrium of PCOS	NCT05062135	Polycystic Ovar... Progesterone Re...	Progesterone 40...	18 Years - 35 Years	University of Sao Paulo General Hospital
GnRHa + Letrozole in Non-obese Progestin-insensitive Endometrial Cancer and Atypical Hyperplasia Patients	NCT05316935	Endometrial Neo... Atypical Endome... Progesterone Re...	GnRHa Letrozole 2.5mg Diane-35 MET	18 Years - 45 Years	Fudan University
GnRHa + Letrozole in Non-obese Progestin-insensitive Endometrial Cancer and Atypical Hyperplasia Patients	NCT05316935	Endometrial Neo... Atypical Endome... Progesterone Re...	GnRHa Letrozole 2.5mg Diane-35 MET	18 Years - 45 Years	Fudan University
Progesterone Action on Endometrium of PCOS	NCT05062135	Polycystic Ovar... Progesterone Re...	Progesterone 40...	18 Years - 35 Years	University of Sao Paulo General Hospital
GnRHa + Letrozole in Obese Progestin-insensitive Endometrial Cancer Patients	NCT06379113	Endometrial Neo... Atypical Endome... Progesterone Re... Obesity	GnRH antagonist Letrozole 2.5mg	18 Years - 45 Years	Fudan University

Spots Global Cancer Trial Database for progesterone resistance