Inhibition of the androgen-activating enzyme AKR1C3 selectively decreases systemic and intra-adipose 11-oxygenated androgens in women

Schiffer L, Anthony AV, Wittemans LBL, Angela E. Taylor, Oestlund I, Miranda AMA, Melson E, McDonnell T, Kempegowda P, Paul Smith, Clark TJ, Wabitsch M, O’Reilly MW, Peters M, Wagenfeld A, Ingwersen J, Snoep JL, Scott WR, Hilpert J, Storbeck K, Arlt W
2026 · doi:10.64898/2026.03.27.714735
preprint OA: gold CC-BY-4.0
🔓 Open OA copy Full text JSON View at publisher
⚙ AI-generated summary by qwen3.7-flash, 2026-08-27 ⓘ

Inhibiting the enzyme AKR1C3 selectively reduces systemic and intra-adipose 11-oxygenated androgen activation in women, offering a targeted approach to managing androgen excess associated with conditions like polycystic ovary syndrome.

One-sentence paraphrase of the abstract; not a substitute for reading it. No clinical advice. How this works

⚙ AI-generated deep summary by qwen3.7-flash, 2026-09-06 · read from full text ⓘ

This study investigates the role of the enzyme AKR1C3 in converting androgen precursors into active forms, focusing on its expression in adipose tissue. The researchers utilized human female adipose tissue explants and treated premenopausal women with an AKR1C3 inhibitor to assess changes in systemic and local androgen levels. They found that adipocytes are a major site of AKR1C3 activity and that inhibiting this enzyme selectively reduces 11-oxygenated androgens without affecting classic androgens. This selective disruption offers a potential therapeutic strategy for managing conditions driven by androgen excess, such as polycystic ovary syndrome. Relevance to endometriosis: The paper is tangentially related, as it addresses hormonal mechanisms involving androgens which can influence endometriosis pathophysiology, though the primary focus is on PCOS and metabolic health rather than endometriosis or adenomyosis specifically.

Read from the paper's body, not the abstract. Not a substitute for reading the paper. No clinical advice. How this works

Abstract

Androgen excess drives metabolic and reproductive complications in polycystic ovary syndrome (PCOS), affecting 10-15% of women globally. Aldo-keto reductase 1C3 (AKR1C3) converts inactive precursors from both the classic and the recently identified 11-oxygenated androgen pathways, generating testosterone and 11-ketotestosterone, respectively, which exert comparable androgen receptor activation. Both circulate in similar concentrations in premenopausal women while 11-ketotestosterone is predominant after menopause and in PCOS. Here, we show that adipocytes are a major site of AKR1C3 and androgen receptor expression, with increased expression in women and individuals with obesity. Using human female adipose tissue explants, we find a much higher activation of 11-oxygenated over classic androgens, observing a decrease in 11-oxygenated but not classic androgen activation by AKR1C3 inhibition. Correspondingly, we demonstrate that AKR1C3 inhibitor treatment in premenopausal women selectively disrupts the activation of 11-oxygenated androgens. Pharmacological targeting of AKR1C3 provides a novel strategy to alleviate systemic and intra-adipose 11-oxygenated androgen excess. One Sentence Summary Inhibition of the androgen-activating enzyme AKR1C3 results in a major decrease in 11-oxygenated but not classic androgens in women.
Full text 1,692 characters · extracted from oa-doi-fallback · click to expand
Abstract Androgen excess drives metabolic and reproductive complications in polycystic ovary syndrome (PCOS), affecting 10-15% of women globally. Aldo-keto reductase 1C3 (AKR1C3) converts inactive precursors from both the classic and the recently identified 11-oxygenated androgen pathways, generating testosterone and 11-ketotestosterone, respectively, which exert comparable androgen receptor activation. Both circulate in similar concentrations in premenopausal women while 11-ketotestosterone is predominant after menopause and in PCOS. Here, we show that adipocytes are a major site of AKR1C3 and androgen receptor expression, with increased expression in women and individuals with obesity. Using human female adipose tissue explants, we find a much higher activation of 11-oxygenated over classic androgens, observing a decrease in 11-oxygenated but not classic androgen activation by AKR1C3 inhibition. Correspondingly, we demonstrate that AKR1C3 inhibitor treatment in premenopausal women selectively disrupts the activation of 11-oxygenated androgens. Pharmacological targeting of AKR1C3 provides a novel strategy to alleviate systemic and intra-adipose 11-oxygenated androgen excess. One Sentence Summary Inhibition of the androgen-activating enzyme AKR1C3 results in a major decrease in 11-oxygenated but not classic androgens in women. Competing Interest Statement Michaele Peters, Andrea Wagenfeld, Jan-Peter Ingwersen, and Jan Hilpert are employees of Bayer AG, Berlin, Germany. Laura B.L. Wittemans is currently employed by Novo Nordisk Research Centre Oxford but, while she conducted the research described in this manuscript, was only affiliated to the University of Oxford.

Text is read by the "Ask this paper" AI Q&A widget below. Extraction quality varies by source — PMC NXML preserves structure cleanly, OA-HTML may include some navigation residue, and OA-PDF can have broken hyphenation. The publisher copy (via DOI) is the canonical version.

My notes (saved in your browser only)

⚙ Ask this paper AI returns verbatim quotes from the full text · source: oa-doi-fallback ⓘ

Answers must be backed by verbatim quotes from this paper's full text. Hallucinated quotes are dropped automatically; if no verbatim passage answers the question, we say so. How this works

Citation neighborhood (no data yet)

We don't have any in-corpus citations linked to this paper yet. This is a recent paper (2026) — citers typically take a year or two to land, and the OpenAlex reference graph may still be filling in.

Source provenance

europepmc
last seen: 2026-09-26T06:29:11.690389+00:00
License: CC-BY-4.0 · commercial use OK · attribution required
Per Europe PMC