Androgens and NAFLD Longitudinal Cohort Study

Study Overview
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Brief Summary
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The researchers want to learn how androgens, a type of sex hormone, might affect nonalcoholic fatty liver (NAFLD) in young women over time. NAFLD happens when fat builds up in the liver which can cause damage to the liver such as inflammation or scarring. Young women with a condition called polycystic ovary syndrome (PCOS) have a high risk for NAFLD, and they often have high androgen levels too. So the researchers are recruiting young women with PCOS as well as those without PCOS, and will compare changes in NAFLD over time between young women with and without PCOS. This study is funded by the National Institutes of Health

Detailed Description
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The studies central hypothesis is that androgens promote liver injury and NAFLD/NASH progression in PCOS, which occurs through aberrant lipid activity (including lipotoxicity and dysregulated de novo lipogenesis), in part from androgenic effects on visceral adipose tissue (VAT). Data in young women taking exogenous testosterone show redistribution of fat from subcutaneous to visceral stores In the general population, VAT promotes NASH through several established pathways, including production of tissue injurious or lipotoxic lipids such as some phospholipid, sphingomyelin, and ceramide species. Recent data show androgen- associated increase in serum glycerophospholipids in women with PCOS, a lipid class that is associated with NASH in women. Additionally, androgen-associated de novo lipogenesis (DNL) may contribute to NASH in women. Hepatic DNL is a key source of lipid accumulation, and co-investigators at Duke University recently discovered an enzymatic balance that regulates hepatic DNL with dysregulation of this pathway (reflected by branched-chain keto and amino acids) predictive of prevalent NASH in humans. Androgen-induced de novo lipogenesis also occurs in cultured hepatocytes from women (but not men) supporting the researchers focused evaluation of the relationship between androgens, dysregulated hepatic DNL, and NASH in PCOS. As existing data support androgenic effects on hepatic and visceral fat in women, the researchers will now determine the relationship of androgens with liver injury and progression in PCOS and the potential mechanistic contributions of VAT and aberrant lipid metabolism to this process. The team includes clinical and translational researchers at two centers (UCSF and Duke) with expertise in NAFLD, PCOS, obesity, and lipid metabolism, with a track record of collaboration. The study team will leverage an existing well-characterized PCOS cohort29 to follow 150 reproductive-aged women with NASH (125 PCOS and 25 non-PCOS controls) to accomplish this.

Official Title
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Androgens and Nonalcoholic Fatty Liver Disease (NAFLD) In Reproductive-Aged Women With and Without Polycystic Ovary Syndrome (PCOS)

Conditions
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PCOS, NAFLD, NASH

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Metabolic associated steatohepatitis (MASH) (formerly NASH) PCOS Non-PCOS Exclusion Criteria: High levels of alcohol use (more than 7 drinks a week) Current pregnancy Other causes of hepatic steatosis Weight loss of more than 10% body weight in the last 6 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| MASLD and PCOS hyperandrogenism<br>Patients with MASLD and PCOS with the phenotype of hyperandrogenism | |
| MASLD and PCOS non-hyperandrogenism<br>Patients with MASLD and PCOS with the phenotype of non-hyperandrogenism | |
| MASLD and no-PCOS<br>Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and no PCOS | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Liver Stiffness Change | Mean change in liver stiffness (kPA) on magnetic resonance elastography (MRE) | from baseline to Year 3 follow- up. | 
| Visceral Adipose Tissue (VAT) association to MASH severity | VAT volume (cm3) will be determined on magnetic resonance electrography (MRE) | at baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Liver stiffness severity | Severity of liver stiffness will be determined on magnetic resonance electrography (MRE) | at baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Androgen