Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

Androgen Responses to hCG and Ovarian Morphology in PCOS

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03489668
Recruitment Status : Recruiting
First Posted : April 5, 2018
Last Update Posted : August 9, 2018
Sponsor:
Collaborator:
University of California, San Diego
Information provided by (Responsible Party):
Beata Banaszewska, Poznan University of Medical Sciences

Brief Summary:

Rationale and Hypothesis We have previously reported that theca cells (TC) responses to hCG in women with PCOS represent a spectrum where some exhibit exaggerated increases of 17OHP while in others 17OHP responses resemble those of normal women (Maas KH et al, JCEM, 2015). The basis for this differential responsiveness is not clear. Earlier studies reported that 17OHP responses to gonadotropin stimulation were heterogeneous among PCOS women, which was attributed to the degree of hyperinsulinemia (Pasquali R et al, JCEM, 2007). However, assessment of the ovary was omitted in the analysis. In preliminary studies, we have found that in women with PCOS, insulin sensitivity was strongly correlated with insulin sensitivity index as assessed by the method of Matsuda and DeFronzo (Diabetes Care, 1999). However, the study lacked sufficient numbers. Further analysis of insulin sensitivity with respect to hCG stimulated theca cell responses is warranted.

We have also examined 17OHP responses to hCG in relationship to antral follicle count and anti-Müllerian hormone (AMH) in PCOS and normal women. In PCOS women, as expected, serum AMH correlated with antral follicle count. However, TC responses in PCOS were inversely related to AMH (Maas KH et al, JCEM, 2015). These novel observations suggested that in PCOS AMH production may reflect redistribution of the follicle population. In human ovaries maximal immunodetection of AMH is observed in small (< 4 mm) antral follicles followed by a rapid and progressive decline until an absence of the protein by 8 mm (Weenen C et al, Mol Hum Reprod, 2004). This consideration raises the issue of whether normal AMH levels represent more advanced follicle growth in some PCOS women compared with that of others with elevated AMH levels. An increased stage of follicle development would be accompanied by increased TC hyperplasia and may account for greater 17OHP responses to hCG stimulation. A comparison of TC responses to hCG with ovarian morphology has not be done in women with PCOS.

Based on these findings, we hypothesize that in PCOS, heterogeneous TC responses to hCG reflect differences in morphometric development of the follicle population. In addition, the positive correlation between insulin sensitivity and TC responses to hCG suggest an effect of hyperinsulinemia. We propose to investigate the relationship between theca cell responses to hCG, follicle morphology, and insulin sensitivity before and following treatment with an insulin lowering drug, metformin.


Condition or disease Intervention/treatment Phase
PCOS Drug: MetFORMIN 500 Mg Oral Tablet Not Applicable

Detailed Description:

50-100 PCOS and 50-100 normal women matched for age (<37 yr) and BMI (<35) will be studied. PCOS and normal women in the mid-follicular phase (day 5-7) of the menstrual cycle will receive an iv injection of hCG as previously described (see Experimental Design). Basal and stimulated blood samples will be assessed for 17OHP, androgens, gonadotropins and AMH. Detailed 3-D ultrasound imaging will be done prior to hCG stimulation (see Experimental Design). Ovarian morphology will include volume, antral follicle number, and the size of each follicle visualized.

Screening 100 women with PCOS and 100 normal women will be studied.

PCOS will be defined according to NIH criteria:

  • <8 spontaneous menses per year
  • hyperandrogenism clinically (Ferriman-Gallway score≥8 or total testosterone>0.5ng/ml).
  • Absence of CAH, hyperprolactinemia, thyroid disorder, Cushings syndrome, hypothalamic anovulation.

Subjects will have a screening visit to establish eligibility and to sign the informed consent. They will have a history and physical examination performed which will include a urine pregnancy test, a transvaginal ultrasound, thyroid studies, a fasting chemistry panel, and a hemoglobin.

Experimental Design Phase 1 (Pretreatment)

  1. In all subjects images of the both ovaries will be obtained using 3D technology and the number, size, and spatial arrangement of ovarian follicles will be noted for both ovaries in each subject.
  2. Normal subjects will be studied during the mid-follicular phase of the cycle (Days 5-9) while PCOS women will be anovulatory and will not have a cycle day parameter.
  3. On study day one, recombinant-hCG (r-hCG) will be administered intravenously at a dose of 25 micrograms.
  4. Blood samples will be obtained at 1 hour before (T = -1), immediately prior (T = 0), and 24 hours after (T = +24) iv hCG injection.
  5. Sera will be assayed at all time points for steroid and peptide hormones including 17OHP, androstenedione, testosterone, estradiol, progesterone, LH, FSH, and AMH.
  6. All subjects will undergo an oral glucose tolerance test. Each will be placed on a 300-gram carbohydrate diet for three days before the study. On the day of testing each subject will ingest 75 gm of a glucose solution and blood samples for glucose and insulin will be obtained at 0, 15, 30, 60, 120 and 180 minutes after the glucose load.

Phase 2 (Posttreatment)

  1. Each PCOS subject will be administered metformin, 1500 mg/day for 3 months. All subjects will be encouraged to maintain same dietary and exercise activity throughout the course of study.
  2. After 3 months of treatment, all tests as described in Phase 1 will be repeated.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Health Services Research
Official Title: The Relationship Between Theca Cell Responses to hCG and Ovarian Morphology in Women With PCOS Compared to Normal Women
Actual Study Start Date : January 20, 2018
Estimated Primary Completion Date : January 31, 2020
Estimated Study Completion Date : March 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: PCOS
Metformin administration 1500mg/day
Drug: MetFORMIN 500 Mg Oral Tablet
metformin administration 1500mg per day

No Intervention: Control



Primary Outcome Measures :
  1. 17-OHP responses to hCG in PCOS and normal women [ Time Frame: 2 years ]
    Demonstrating a relationship between theca cell responses to hCG, and insulin sensitivity before and following treatment with an insulin lowering drug, metformin.


Secondary Outcome Measures :
  1. Ovarian morphology in PCOS and normal women [ Time Frame: 2 years ]
    Demonstrating a relationship between theca cell responses to hCG and follicle morphology, before and following treatment with an insulin lowering drug, metformin.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 37 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • <8 spontaneous menses per year • hyperandrogenism clinically (Ferriman-Gallway score≥8 or total testosterone>0.5ng/ml).

Exclusion Criteria:

  • CAH, hyperprolactinemia, thyroid disorder, Cushings syndrome, hypothalamic anovulation

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03489668


Contacts
Layout table for location contacts
Contact: Beata E Banaszewska, MD PhD +48501303173 bbeata48@gmail.com
Contact: Antoni Duleba, Prof antoni.duleba@yale.edu

Locations
Layout table for location information
Poland
Division of Infertility and Reproductive Endocrinology, Department of Gynecology and Obsterics Recruiting
Poznan, Poland
Contact: Beata Banaszewska, MD PhD       bbeata48@gmail.com   
Contact: Mateusz Trzciński, MD       mtrzcinski13@gmail.com   
Sub-Investigator: Antoni J Duleba, Prof         
Sub-Investigator: Leszek A Pawelczyk, Prof         
Sub-Investigator: Robert Z Spaczyński, Prof         
Sub-Investigator: Piotr Piekarski, MD         
Sub-Investigator: Jeff Chang, Prof         
Sponsors and Collaborators
Poznan University of Medical Sciences
University of California, San Diego

Layout table for additonal information
Responsible Party: Beata Banaszewska, MD PhD Asssociate Professor, Poznan University of Medical Sciences
ClinicalTrials.gov Identifier: NCT03489668     History of Changes
Other Study ID Numbers: PoznanUMS6
First Posted: April 5, 2018    Key Record Dates
Last Update Posted: August 9, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Beata Banaszewska, Poznan University of Medical Sciences:
PCOS
Androgen
3D ultrasound

Additional relevant MeSH terms:
Layout table for MeSH terms
Metformin
Androgens
Hypoglycemic Agents
Physiological Effects of Drugs
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists