Dissecting the IMpact of 11-OXygenated and Classic Androgens on Skeletal Muscle Insulin Sensitivity (DIMOXIS)

Summary

Androgen excess is the cardinal biochemical feature of polycystic ovary syndrome (PCOS). Serum testosterone correlates with insulin resistance in PCOS, however, there is an urgent need to improve our understanding of the association between androgens and the risk of type 2 diabetes.

11-oxygenated steroids are the predominant androgens in PCOS and correlate closely with markers of insulin resistance. The bioactive 11-oxygenated androgen 11-ketotestosterone (11KT) binds and activates the androgen receptor with equal affinity to testosterone, yet nothing is known about its impact on metabolism or glucose homeostasis

Crucially, there are no data linking androgen excess with muscle glucose metabolism and the differential contribution of 11-oxygenated androgens to diabetes risk through these processes remains unknown.

The investigators hypothesise the following:

1. Oral androgen exposure in women with PCOS results in distinct changes in tissue-specific insulin sensitivity and muscle energy biogenesis
2. 11-oxygenated androgen exposure exerts differential changes on the above parameters in comparison to classic androgen exposure

The study has the following aims:

1. To examine the impact of oral androgen exposure on skeletal muscle insulin sensitivity and glucose disposal in women with PCOS.
2. To delineate the impact of androgen exposure on muscle mitochondrial function ex vivo in women with PCOS
3. To compare the differential impact of 11-oxygenated androgen compared to classic androgens on glucose disposal and muscle mitochondrial function

The two arms will run in parallel and all participants will undergo identical investigations before and after 7 days of either DHEA or 11KA4.

Investigations will include baseline arthrometric measurements muscle biopsy, two-step hyperinsulinaemic euglycaemic clamp, breath sampling.

This interventional metabolic phenotyping study will probe the role of classic and 11-oxygenated androgens in metabolic dysfunction in PCOS using gold-standard in vivo metabolic phenotyping techniques. Delineating the distinct contribution of 11-oxygenated androgens, through effects on skeletal muscle biology, to the risk of T2DM is an important step in the process of determining risk of type 2 diabetes in this vulnerable cohort.

Conditions

• Polycystic Ovary Syndrome
• Insulin Resistance
• Androgen; Hypersecretion
• Endocrine System Diseases

Interventions

DIETARY_SUPPLEMENT

Dehydroepiandrosterone (DHEA)

Dehydroepiandrosterone (DHEA) at a dose of 150mg once daily for 7 days.

DIETARY_SUPPLEMENT

11-ketoandrostenedione (11KA4)

11ketoandrostenedione (11KA4) at a doses of 150mg once daily for 7 days.

Sponsors & Collaborators

• University of Oxford

  collaborator OTHER

• University of Birmingham

  collaborator OTHER

• Royal College of Surgeons, Ireland

  lead OTHER

Principal Investigators

• Michael W Michael · RCSI Education & Research Centre, Beaumont Hospital, Beaumont Dublin 9 Ireland Ireland

Study Design

Allocation

RANDOMIZED

Purpose

OTHER

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

40 Years

Sex

FEMALE

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2022-08-19

Primary Completion

2024-12-31

Completion

2024-12-31

Countries

• Ireland

Study Locations