Transcriptional and Epigenetic Program of PCOS Women

PCOS Clinical Trial

— EPIC  

Official title:

Transcriptional and Epigenetic Program of PCOS Women

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04034706
• Other study ID #: 1354588
• Status: Active, not recruiting
• Start date: January 31, 2020
• Est. completion date: December 2025

Study information

• Verified date: January 2024
• Source: AdventHealth Translational Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The main goal is to reveal differences in global gene expression in two different adipose tissue (AT) depots of females with and without polycystic ovary syndrome (PCOS) and how these are influenced by upstream epigenetic markers

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 108
• Est. completion date: December 2025
• Est. primary completion date: December 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

Inclusion Criteria:

1. Women;

2. Age 18-45 years inclusive;

3. BMI 23-40 kg/m2 inclusive;

4. HbA1C = 6.0% or fasting plasma glucose < 126 mg/dL;

5. Weight stable (± 3 kg) during the 3 months prior to enrollment;

6. Women must be > 9 months post-partum;

7. For PCOS: A documented history of PCOS from their physician according to the Androgen Excess (AE)-PCOS criteria: (defined by the presence of hyperandrogenism (clinical and/or biochemical), ovarian dysfunction (oligo-anovulation and/or polycystic ovaries), and the exclusion of related disorders (eg. hypoadrenalism, ovarian tumors)

8. Regular menstrual cycle for females without PCOS

9. Able to provide written, informed consent.

Exclusion Criteria:

1. Postmenopausal women

2. Women with hysterectomy

3. Pregnancy, lactation or < 9 months postpartum from the scheduled date of screening.

4. Fasting plasma glucose > 126 mg/dL, or HbA1c > 6% or diagnosis with Type 2 Diabetes (T2D) or Type 1 Diabetes (T1D)

5. History or presence of cardiovascular disease (unstable angina, myocardial infarction or coronary revascularization within 6 months, clinically significant abnormalities on EKG), presence of cardiac pacemaker, implanted cardiac defibrillator.

6. Liver disease (AST or ALT >2.5 times the upper limit of normal)

7. Kidney disease (creatinine >1.6 mg/dl or estimated GFR <60 ml/min)

8. Dyslipidemia, including triglycerides >500 mg/dl, LDL >200 mg/dl

9. Anemia (hemoglobin <11 g/dl)

10. Thyroid dysfunction (suppressed thyroid-stimulating hormone, elevated TSH <10 µIU/ml if symptomatic or elevated TSH >10 µIU/ml if asymptomatic)

11. Uncontrolled hypertension (BP >160 mmHg systolic or >100 mmHg diastolic)

12. Elevated hsCRP or known active infection

13. History of cancer within the last 5 years (skin cancers, with the exception of melanoma, may be acceptable)

14. History of drug or alcohol abuse (> 3 drinks per day) within the last 5 years. Current drug use may be determined by plasma or urine drug screens.

15. psychiatric disease prohibiting adherence to study protocol.

16. History of organ transplant.

17. Known history of HIV, active Hepatitis A, B or C or tuberculosis.

18. History of bariatric surgery.

19. Current smokers (smoking within the past 3 months).

20. Current use of beta-adrenergic blocking agents.

21. Use of oral or injectable anti-hyperglycemic agents: metformin, sulfonylureas, DPP IV inhibitors, SGLT-2 inhibitors, thiazolidinediones, acarbose, GLP-1 analogs and insulin unless willing to undertake a washout period of 15 days for metformin and GLP-1 analogs and undergo subsequent laboratory screening tests.

22. Gonadotropin Releasing Hormone (GnRH) and/or Antiandrogen use within the last 2 months.

23. Use of any medications known to influence fat and/or energy metabolism (eg growth hormone therapy, glucocorticoids [steroids], etc.)

24. Initiation or change in hormone replacement therapy within the past 3 months (including, but not limited to thyroid hormone, estrogen replacement therapy or In Vitro Fertilization therapy).

25. Current treatment with blood thinners or antiplatelet medications that cannot be safely stopped for biopsy and testing procedures.

26. Not able or willing to have DXA scans or are above the acceptable weight limit (450 lbs) of the DXA scanner.

27. Presence of any condition that, in the opinion of the Investigators, compromises participant safety or data integrity or the participant's ability to complete study visits.

28. Not able to participate in MRI assessments due to:

1. Metal implants (pacemaker, non-removable body piercings, aneurysm clips) based on Investigator's judgment at screening

2. Physical limitations or equipment tolerances (e.g., MRI bore size) based on Investigator's judgment at screening

3. Inability to tolerate MRI imaging without sedation or claustrophobia

Related Conditions & MeSH terms

• PCOS

Intervention

Other:
• DEXA
DEXA Scans will be performed to measure body fat and estimate muscle mass using a General Electric Lunar iDXA whole-body scanner.
• Magnetic Resonance (MR) Assessment of the Abdomen
Include measures to assess liver lipid content and stiffness and perform volumetric fat quantitation.
• MR assessment of Whole Body Fat
Volumetric measurement of fat, muscle and bone

Procedure:
• Adipose tissue biopsy
0.5 cm incision of the upper-outer right vastus lateralis, and either a 3-4mm Mercedes Liposuction needle, or a 4-6 mm Bergstrom needle will be inserted to aspirate approximately 7 grams of adipose tissue.

Other:
• Oral glucose tolerance test
Glucose tolerance will be assessed with a 75 g oral glucose tolerance test (OGTT). Subjects will be studied after an overnight fast.

Locations

Country	Name	City	State
United States	AdventHealth Translational Research Institute	Orlando	Florida

Sponsors (1)

Lead Sponsor	Collaborator
AdventHealth Translational Research Institute

Country where clinical trial is conducted

United States, 

References & Publications (22)

Abbott DH, Barnett DK, Bruns CM, Dumesic DA. Androgen excess fetal programming of female reproduction: a developmental aetiology for polycystic ovary syndrome? Hum Reprod Update. 2005 Jul-Aug;11(4):357-74. doi: 10.1093/humupd/dmi013. — View Citation

Abbott DH, Dumesic DA, Eisner JR, Colman RJ, Kemnitz JW. Insights into the development of polycystic ovary syndrome (PCOS) from studies of prenatally androgenized female rhesus monkeys. Trends Endocrinol Metab. 1998 Feb;9(2):62-7. doi: 10.1016/s1043-2760(98)00019-8. — View Citation

Azziz R, Carmina E, Chen Z, Dunaif A, Laven JS, Legro RS, Lizneva D, Natterson-Horowtiz B, Teede HJ, Yildiz BO. Polycystic ovary syndrome. Nat Rev Dis Primers. 2016 Aug 11;2:16057. doi: 10.1038/nrdp.2016.57. — View Citation

Barber TM, Golding SJ, Alvey C, Wass JA, Karpe F, Franks S, McCarthy MI. Global adiposity rather than abnormal regional fat distribution characterizes women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2008 Mar;93(3):999-1004. doi: 10.1210/jc.2007-2117. Epub 2007 Dec 18. — View Citation

Bjorntorp P. Adipose tissue distribution and function. Int J Obes. 1991 Sep;15 Suppl 2:67-81. — View Citation

Bos G, Snijder MB, Nijpels G, Dekker JM, Stehouwer CD, Bouter LM, Heine RJ, Jansen H. Opposite contributions of trunk and leg fat mass with plasma lipase activities: the Hoorn study. Obes Res. 2005 Oct;13(10):1817-23. doi: 10.1038/oby.2005.221. — View Citation

Ciaraldi TP, Aroda V, Mudaliar S, Chang RJ, Henry RR. Polycystic ovary syndrome is associated with tissue-specific differences in insulin resistance. J Clin Endocrinol Metab. 2009 Jan;94(1):157-63. doi: 10.1210/jc.2008-1492. Epub 2008 Oct 14. — View Citation

de Koning L, Merchant AT, Pogue J, Anand SS. Waist circumference and waist-to-hip ratio as predictors of cardiovascular events: meta-regression analysis of prospective studies. Eur Heart J. 2007 Apr;28(7):850-6. doi: 10.1093/eurheartj/ehm026. Epub 2007 Apr 2. — View Citation

Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev. 2012 Dec;33(6):981-1030. doi: 10.1210/er.2011-1034. Epub 2012 Oct 12. — View Citation

Divoux A, Karastergiou K, Xie H, Guo W, Perera RJ, Fried SK, Smith SR. Identification of a novel lncRNA in gluteal adipose tissue and evidence for its positive effect on preadipocyte differentiation. Obesity (Silver Spring). 2014 Aug;22(8):1781-5. doi: 10.1002/oby.20793. Epub 2014 May 23. — View Citation

Elbers JM, Asscheman H, Seidell JC, Gooren LJ. Effects of sex steroid hormones on regional fat depots as assessed by magnetic resonance imaging in transsexuals. Am J Physiol. 1999 Feb;276(2):E317-25. doi: 10.1152/ajpendo.1999.276.2.E317. — View Citation

Elbers JM, Asscheman H, Seidell JC, Megens JA, Gooren LJ. Long-term testosterone administration increases visceral fat in female to male transsexuals. J Clin Endocrinol Metab. 1997 Jul;82(7):2044-7. doi: 10.1210/jcem.82.7.4078. — View Citation

Frayn KN. Adipose tissue as a buffer for daily lipid flux. Diabetologia. 2002 Sep;45(9):1201-10. doi: 10.1007/s00125-002-0873-y. Epub 2002 Jul 24. — View Citation

Guo Z, Johnson CM, Jensen MD. Regional lipolytic responses to isoproterenol in women. Am J Physiol. 1997 Jul;273(1 Pt 1):E108-12. doi: 10.1152/ajpendo.1997.273.1.E108. — View Citation

Horowitz JF, Klein S. Whole body and abdominal lipolytic sensitivity to epinephrine is suppressed in upper body obese women. Am J Physiol Endocrinol Metab. 2000 Jun;278(6):E1144-52. doi: 10.1152/ajpendo.2000.278.6.E1144. — View Citation

Jason J. Polycystic ovary syndrome in the United States: clinical visit rates, characteristics, and associated health care costs. Arch Intern Med. 2011 Jul 11;171(13):1209-11. doi: 10.1001/archinternmed.2011.288. No abstract available. — View Citation

Karastergiou K, Fried SK, Xie H, Lee MJ, Divoux A, Rosencrantz MA, Chang RJ, Smith SR. Distinct developmental signatures of human abdominal and gluteal subcutaneous adipose tissue depots. J Clin Endocrinol Metab. 2013 Jan;98(1):362-71. doi: 10.1210/jc.2012-2953. Epub 2012 Nov 12. — View Citation

Kirchengast S, Huber J. Body composition characteristics and body fat distribution in lean women with polycystic ovary syndrome. Hum Reprod. 2001 Jun;16(6):1255-60. doi: 10.1093/humrep/16.6.1255. — View Citation

Kokosar M, Benrick A, Perfilyev A, Fornes R, Nilsson E, Maliqueo M, Behre CJ, Sazonova A, Ohlsson C, Ling C, Stener-Victorin E. Epigenetic and Transcriptional Alterations in Human Adipose Tissue of Polycystic Ovary Syndrome. Sci Rep. 2016 Mar 15;6:22883. doi: 10.1038/srep22883. Erratum In: Sci Rep. 2016 May 09;6:25321. — View Citation

Lavebratt C, Almgren M, Ekstrom TJ. Epigenetic regulation in obesity. Int J Obes (Lond). 2012 Jun;36(6):757-65. doi: 10.1038/ijo.2011.178. Epub 2011 Sep 13. — View Citation

Manneras-Holm L, Leonhardt H, Kullberg J, Jennische E, Oden A, Holm G, Hellstrom M, Lonn L, Olivecrona G, Stener-Victorin E, Lonn M. Adipose tissue has aberrant morphology and function in PCOS: enlarged adipocytes and low serum adiponectin, but not circulating sex steroids, are strongly associated with insulin resistance. J Clin Endocrinol Metab. 2011 Feb;96(2):E304-11. doi: 10.1210/jc.2010-1290. Epub 2010 Nov 17. — View Citation

Manolopoulos KN, Karpe F, Frayn KN. Gluteofemoral body fat as a determinant of metabolic health. Int J Obes (Lond). 2010 Jun;34(6):949-59. doi: 10.1038/ijo.2009.286. Epub 2010 Jan 12. — View Citation

* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Epigenomic and transcriptomic differences in abdominal vs gluteal subcutaneous adipose tissue between females with and without polycystic ovary syndrome	Epigenetic profiles (DNA methylation) and gene expression (RNA-seq) will be performed on whole tissue abdominal fat and gluteofemoral fat biopsies in addition to cultured pre-adipocytes and adipocytes.	6 months after the last participant will be enrolled

External Links

•   Website for AdventHealth Translational Research Institute