Distinct immunomodulatory effects of synthetic progestins compared with natural progesterone in human immune cells

Apurva J Patel; Ankur N Karandikar; Aracely Miron-Ocampo; Nitin J Karandikar; Ashutosh K Mangalam

doi:10.1093/immhor/vlag046

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Distinct immunomodulatory effects of synthetic progestins compared with natural progesterone in human immune cells

Journal article

Open access

Peer reviewed

Distinct immunomodulatory effects of synthetic progestins compared with natural progesterone in human immune cells

Apurva J Patel, Ankur N Karandikar, Aracely Miron-Ocampo, Nitin J Karandikar and Ashutosh K Mangalam

ImmunoHorizons, Vol.10(8), vlag046

08/04/2026

DOI: 10.1093/immhor/vlag046

PMID: 42607301

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Abstract

Progesterone exerts important immunomodulatory functions, yet the immune effects of structurally diverse synthetic progestins remain incompletely defined. Given their variable receptor-binding profiles and links to altered inflammatory outcomes, we examined how commonly used progestins regulate immune signaling in primary human cells. Peripheral blood mononuclear cells from healthy female donors were exposed to physiologically relevant concentrations of natural progesterone (P4) and representative synthetic progestins spanning multiple generations. Cytokine responses were quantified at both the protein and transcript levels. Baseline steroid receptor expression and age of donor was correlated with cytokine output. High-dimensional flow cytometry coupled with unsupervised clustering was used to define the cellular sources of inflammatory cytokine production. In parallel, naïve CD4+ T-cell differentiation was performed to determine effects on T helper (Th) cell polarization. Only P4 induced immunoregulatory cytokine IL-10, whereas all progestins, except first-generation norethindrone, induced markedly higher IL-6 production compared with media control. Gene expression analysis confirmed induction of multiple proinflammatory genes at physiologically relevant concentrations. High-dimensional flow cytometry identified CD14+ monocytes as the dominant cellular source of IL-6 following progestin exposure. In contrast, P4 selectively suppressed Th1 differentiation and promoted Th2 lineage commitment, whereas synthetic progestins failed to reproduce these immunoregulatory effects. Together, these findings demonstrate that synthetic progestins differentially regulate innate and adaptive immune responses compared with P4 and promote proinflammatory responses that may influence immune homeostasis.

Adult

Cell Differentiation - drug effects

Cells, Cultured

Cytokines - metabolism

Female

Humans

Interleukin-10 - metabolism

Interleukin-6 - metabolism

Leukocytes, Mononuclear - drug effects

Leukocytes, Mononuclear - immunology

Progesterone - pharmacology

Progesterone Congeners - pharmacology

Progestins - pharmacology

Th1 Cells - drug effects

Th1 Cells - immunology

Th2 Cells - drug effects

Th2 Cells - immunology

Details

Title: Subtitle: Distinct immunomodulatory effects of synthetic progestins compared with natural progesterone in human immune cells
Creators: Apurva J Patel - University of Iowa
Ankur N Karandikar - University of Iowa
Aracely Miron-Ocampo - University of Iowa
Nitin J Karandikar - University of Iowa
Ashutosh K Mangalam - University of Iowa
Resource Type: Journal article
Publication Details: ImmunoHorizons, Vol.10(8), vlag046
DOI: 10.1093/immhor/vlag046
PMID: 42607301
NLM abbreviation: Immunohorizons
ISSN: 2573-7732
eISSN: 2573-7732
Publisher: Oxford University Press
Grant note: Margaret Heppelmann and Micheal Wacek
Language: English
Date published: 08/04/2026
Academic Unit: Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Dental Research
Record Identifier: 9985219326702771

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