Impact of 11-oxygenated Androgens on Metabolic Dysfunction of Women With Polycystic Ovary Syndrome

NCT05246865 | Unknown

• 1 other identifier: RG_19-038
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

Polycystic ovary syndrome (PCOS) affects 10% of all women and usually presents with irregular menstrual periods and difficulties conceiving. It is also a lifelong metabolic disorder and affected women have an increased risk of type 2 diabetes, high blood pressure, and heart disease. Increased blood levels of male hormones, also termed androgens, are found in most PCOS patients. Androgen excess appears to impair the ability of the body to respond to the sugar-regulating hormone insulin (also termed 'insulin resistance'). Androgens circulating in the blood in women with PCOS are comprised of classic androgens (for example testosterone), and the less-characterised 11-oxygenated androgen subclass that arises from the adrenal glands. The investigators have recently demonstrated that 11-oxygenated androgens make up the majority of circulating androgens in women with PCOS. In preliminary studies using minimally invasive adipose tissue sampling, the investigators have found that the fat tissue of women with PCOS overproduces classic androgens. This can lead directly to disturbances in the ability of fat cells to store fat effectively (lipotoxicity), resulting in insulin resistance and the consequent risk of liver damage. However, there are no published studies on in vivo androgen concentrations in the adipose tissue of women with PCOS. Furthermore, the scientific community do not have any information on whether adipose concentrations of 11-oxygenated androgens are also increased in women with PCOS. Research Questions The investigators aim to examine the metabolism of classic and 11-oxygenated androgens in detail in both circulations and in the adipose tissue of women with PCOS. The investigators will examine how precursor variants of both 11-oxygenated and classic androgens, which are converted by the body into active hormones, are broken down (metabolised) within the adipose tissue of women with PCOS. The investigators will also investigate if the 11-oxygenated androgens have a differential impact on metabolic function as compared to classic androgens. This will give important insights into the adipose tissue metabolome in women with PCOS, and how locally generated androgens impact on adipose tissue function and metabolic risk.

Conditions

Polycystic Ovary Syndrome

Outcome Measures

Primary Outcomes (29)

• The impact of classic and 11-oxygenated androgen precursors on systemic circulation of overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline height

  During Visit 1, the research team will measure height in centimetres

  3 years

• The impact of classic and 11-oxygenated androgen precursors on systemic circulation of overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline weight

  During Visit 1, the research team will measure weight in kilogram

  3 years

• The impact of classic and 11-oxygenated androgen precursors on systemic circulation of overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline body mass index (BMI)

  During Visit 1, weight and height will be combined to report BMI in kg/m\^2

  3 years

• The impact of classic and 11-oxygenated androgen precursors on systemic circulation of overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline waist circumference

  During Visit 1, the research team will measure Waist circumference to nearest centimetre

  3 years

• The impact of classic and 11-oxygenated androgen precursors on systemic circulation of overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline blood pressure

  During Visit 1, the research team will measure both systolic and diastolic Blood pressure in mmHg after 10 minutes in sitting position

  3 years

• The impact of classic and 11-oxygenated androgen precursors on systemic circulation of overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline urea & electrolytes

  During Visit 1, the research team will collect blood to measure urea \& electrolytes in mmol/L

  3 years

• The impact of classic and 11-oxygenated androgen precursors on systemic circulation of overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline liver function test

  During Visit 1, the research team will collect blood to measure liver function tests in mmol/L

  3 years

• The impact of classic and 11-oxygenated androgen precursors on systemic circulation of overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline haemoglobin

  During Visit 1, the research team will collect blood to measure haemoglobin in grams per litre

  3 years

• The impact of classic and 11-oxygenated androgen precursors on systemic circulation of overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline white cell and platelet count

  During Visit 1, the research team will collect blood to measure White cell and platelets in number of cells per ml

  3 years

• The impact of classic and 11-oxygenated androgen precursors on systemic circulation of overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline lipid profile

  During Visit 1, the research team will collect blood to measure lipid profile in mmol/L

  3 years

• The impact of classic and 11-oxygenated androgen precursors on systemic circulation of overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline glucose

  During Visit 1, the research team will collect blood to measure glucose in mmol/L

  3 years

• The impact of classic and 11-oxygenated androgen precursors on systemic circulation of overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline glycated haemoglobin

  During Visit 1, the research team will collect blood to measure glycated haemoglobin (HbA1c) in mmol/mol

  3 years

• The impact of classic and 11-oxygenated androgen precursors on systemic circulation of overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline thyroid function test

  During Visit 1, the research team will collect blood to measure thyroid function test in mIU/L

  3 years

• The impact of classic and 11-oxygenated androgen precursors on systemic circulation of overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline Dehydroepiandrosterone (DHEAS)

  During Visit 1, the research team will collect blood to measure DHEAS in µmol/L

  3 years

• overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline androstenedione

  During Visit 1, the research team will collect blood to measure androstenedione in µmol/L

  3 years

• overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline testosterone

  During Visit 1, the research team will collect blood to measure testosterone in nmol/L

  3 years

• overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline sex hormone binding globulin

  During Visit 1, the research team will collect blood to measure sex hormone binding globulin in nmol/L

  3 years

• overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline 17-hydroxyprogesterone

  During Visit 1, the research team will collect blood to measure 17-hydroxyprogesterone in nmol/L

  3 years

• overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline prolactin

  During Visit 1, the research team will collect blood to measure prolactin in mIU/L

  3 years

• overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline Follicle-stimulating hormone

  During Visit 1, the research team will collect blood to measure Follicle-stimulating hormone in IU/L

  3 years

• overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline luteinizing hormone

  During Visit 1, the research team will collect blood to measure luteinizing hormone in IU/L

  3 years

• overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline oestradiol

  During Visit 1, the research team will collect approx 20 ml of blood to measure oestradiol in pmol/L.

  3 years

• The impact of classic and 11-oxygenated androgen precursors on systemic circulation of overall steroid profile and its impact on lipid and glucose metabolism-understanding steroidal activity in peripheral blood mononuclear cells.

  During Visit 1, the research team will collect approx 63 ml of blood to extract peripheral blood mononuclear cells for further experiments to measure the impact of classic and 11-oxygenated androgen precursors on downstream steroid profile

  3 years

• The impact of classic and 11-oxygenated androgen precursors on systemic circulation of overall steroid profile and its impact on lipid and glucose metabolism- to study the changes in steroid levels over time in arterialized hand vein

  Visit 2 to 4, the research team will collect blood samples (1-2ml each time) from arterialized hand vein to study the changes in steroid levels from -90 to 480 min at 30 min intervals

  3 years

• The impact of classic and 11-oxygenated androgen precursors on systemic circulation of overall steroid profile and its impact on lipid and glucose metabolism- to study the changes in steroid levels over time in abdominal vein

  Visit 2 to 4, the research team will collect blood samples (1-2ml each time) from abdominal vein to study the changes in steroid levels from -90 to 480 min at 30 min intervals

  3 years

• The impact of classic and 11-oxygenated androgen precursors on systemic circulation of overall steroid profile and its impact on lipid and glucose metabolism to study the changes in salivary steroid levels over time

  Visit 2 to 4, the research team will collect salivary samples (1-2ml each time) to study the changes in steroid levels at 0, 30, and 60 minutes and hourly thereafter until the end of Study Visits.

  3 years

• The impact of classic and 11-oxygenated androgen precursors on systemic circulation of overall steroid profile and its impact on lipid and glucose metabolism-to study the changes in urinary steroid levels over time

  Visit 2 to 4, the research team will collect urine from time point 0 to 480 minutes to study the changes in steroid levels

  3 years

• The impact of classic and 11-oxygenated androgen precursors on systemic circulation of overall steroid profile and its impact on lipid and glucose metabolism-establishing baseline hormone levels for part B of the study

  for Part B of the study, a blood sample (approx 7 ml) is collected from female volunteers undergoing elective abdominal surgery to establish baseline hormonal levels

  3 years

• The impact of classic and 11-oxygenated androgen precursors on systemic circulation of overall steroid profile and its impact on lipid and glucose metabolism- to study the downstream conversion of steroid precursor in omental and subcutaneous fat

  for Part B of the study, paired subcutaneous and omental adipose tissue samples (up to 5 g) are collected from female volunteers undergoing elective abdominal surgery. * the concentration of classic and 11-oxygenated androgen metabolites (androstenedione, testosterone, dihydrotestosterone, 11-ketoandrostenedione, 11-hydroxyandrostenedione, 11-ketotestosterone, 11-hydroxytestosterone) will be measured in the culture medium by liquid chromatography tandem mass spectrometery in nmol/L. * the relative abundance of all detectable metabolites will be determined by untargeted metabolomics using liquid chromatography tandem mass spectrometery. * the tissue will be used for gene expression analysis: Quantitative PCR will be used to determination of the relative abundance of specific mRNA transcripts. RNAseq will be used to quantify the abundace of all mRNA transcripts of the transciptome.

  3 years

Study Arms (2)

Women with PCOS

EXPERIMENTAL

Women with polycystic ovary syndrome

Drug: oral androgen challenge with dehydroepiandrosterone (DHEA)

Age and BMI-matched healthy volunteers

EXPERIMENTAL

Otherwise healthy women without PCOS but matching in age and body mass index to the above group

Drug: oral androgen challenge with dehydroepiandrosterone (DHEA)

Interventions

oral androgen challenge with dehydroepiandrosterone (DHEA) DRUG

The oral androgen challenge is a safe and well-validated means of studying the androgen generation profiles of different study groups.

Also known as: oral androgen challenge with 11-ketoandrostenedione

Age and BMI-matched healthy volunteers; Women with PCOS

Eligibility Criteria

• Age: 18 Years - 40 Years
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• BMI between 30-40 kg/m2
• Age range 18-40 years
• Ability to provide informed consent
• For women participating in the PCOS group, the diagnosis of PCOS will be established during their recruitment to DAISy-PCOS study on the basis of the Rotterdam Consensus Criteria for the Diagnosis of PCOS, as recommended by the current international PCOS guidelines (at least 2 out of 3 criteria):
• Androgen excess (clinical and/or biochemical evidence)
• Chronic oligo-/anovulation (clinical and/or biochemical evidence)

You may not qualify if:

• Pregnancy or breastfeeding at the time of planned recruitment
• History of significant renal (eGFR\<30) or hepatic impairment (aspartate aminotransferase or alanine transaminase \>two-fold above ULN; pre-existing bilirubinaemia \>1.2 ULN)
• Any other significant disease or disorder that, in the opinion of the Investigator, may either put the participant at risk because of participation in the study, or may influence the result of the study, or the participant's ability to participate in the study.
• Participants who have participated in another research study involving an investigational medicinal product in the 12 weeks preceding the planned recruitment
• Glucocorticoid use via any route within the last six months
• Current intake of drugs known to impact upon steroid synthesis or metabolism or on metabolic function or intake of such drugs during the six months preceding the planned recruitment
• Use of oral or transdermal hormonal contraception in the three months preceding the planned recruitment
• Use of contraceptive implants in the twelve months preceding the planned recruitment
• Allergy or intolerance to any of the ingredients in the high fat meal, or any of the ingredients in the dehydroepiandrosterone and 11-ketoandrostenedione preparations.
• Diabetes or impaired glucose metabolism
• Women undergoing elective, abdominal, non-cancer surgery
• Age range 18-70 years
• Ability to provide informed consent
• Pregnancy or breastfeeding at the time of planned recruitment
• Glucocorticoid use via any route within the last six months

Sponsors & Collaborators

• University of Birmingham: lead

Study Sites (1)

Institute of Metabolism and Systems Research

Birmingham, West Midlands, B15 2TT, United Kingdom

RECRUITING

MeSH Terms

Conditions

Polycystic Ovary Syndrome

Interventions

Dehydroepiandrosterone; adrenosterone

Condition Hierarchy (Ancestors)

Ovarian Cysts; Cysts; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Gonadal Disorders; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Androstenols; Androstenes; Androstanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; 17-Ketosteroids; Ketosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Testosterone Congeners; Gonadal Steroid Hormones; Gonadal Hormones

Study Officials

• Wiebke Arlt, Dsc

  Director, Institute of Metabolism and Systems Research (IMSR)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Punith Kempegowda, MD MRCP

CONTACT

+441214147525; p.kempegowda@bham.ac.uk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A prospective human in-vivo physiology study

Study Record Dates

• First Submitted: July 26, 2019
• First Posted: February 18, 2022
• Study Start: October 10, 2021
• Primary Completion: December 31, 2022
• Study Completion: May 30, 2025
• Last Updated: November 2, 2022

Record last verified: 2022-11

Locations

GB (1)