Unopposed estrogens: current and future perspectives

M Montanino Oliva, R Gambioli, G Forte, G Porcaro, C Aragona, V Unfer
European review for medical and pharmacological sciences · 2022 · vol. 26(8) , pp. 2975–2989 · doi:10.26355/eurrev_202204_28629 · PMID:35503642
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⚙ AI-generated summary by claude@2026-06, 2026-06-09 ⓘ

Unopposed estrogens, caused by an imbalance with progestogens, drive endometrial proliferation and invasion, leading to pathologies like hyperplasia, polyps, endometriosis, and adenomyosis.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-10 · read from full text ⓘ

This review discusses how an imbalance between estrogens and progestogens—specifically “unopposed estrogens,” often due to increased aromatase-mediated estrogen production—drives proliferative and invasive endometrial phenomena. It summarizes current pharmacologic approaches (gonadotropin-releasing-hormone analogs, aromatase inhibitors, and progestogens, alone or with estrogens) and notes that undesired effects motivate research into alternative molecules. The authors highlight recent evidence for metformin and d-chiro-inositol, describing d-chiro-inositol as an insulin second messenger with insulin-sensitizing/mimetic actions and an aromatase down-regulating role, suggesting utility for conditions responsive to unopposed estrogen. Relevance to endometriosis: the paper explicitly includes endometriosis (and adenomyosis) among the diseases attributed to unopposed estrogen–induced invasive phenomena in the endometrium, though its main focus is a broad review of unopposed estrogen mechanisms and emerging therapies.

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Abstract

Estrogens and progestogens act on female reproductive tissues in opposite ways. As they counteract each other actions, the correct balance between these two classes of hormones is pivotal to avoid dangerous states. Unopposed estrogens occur when progestogen levels do not balance estrogens, primarily deriving from overproduction of estrogens via aromatase enzyme. In the endometrium, unopposed estrogens induce proliferative or invasive phenomena, which represent the first step toward different diseases. These pathologies include endometrial hyperplasia, endometrial polyps, endometriosis and adenomyosis. Endometrial hyperplasia and polyps are proliferative pathologies, while endometriosis and adenomyosis are characterized by the invasion of other tissues by endometrial cells. Current pharmacological treatments include Gonadotropin-Releasing-Hormone analogs, aromatase inhibitors and progestogens, either alone or in combination with estrogens. As these drugs usually lead to burdensome undesired effects, researchers seek to find new therapeutical molecules. Recent literature highlights the positive effects of metformin, an insulin sensitizing drug that reduces the insulin proliferative stimulus on the endometrium. d-chiro-inositol is an insulin second messenger with insulin sensitizing and mimetic properties, recently described as an aromatase down-regulator. Based on current evidence, d-chiro-inositol may be useful to treat the pathologies responsive to unopposed estrogens.
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Unopposed estrogens: current and future perspectives M. Montanino Oliva, R. Gambioli, G. Forte, G. Porcaro, C. Aragona, V. Unfer The Experts Group on Inositol in Basic and Clinical Research (EGOI), Rome, Italy. [email protected] Estrogens and progestogens act on female reproductive tissues in opposite ways. As they counteract each other actions, the correct balance between these two classes of hormones is pivotal to avoid dangerous states. Unopposed estrogens occur when progestogen levels do not balance estrogens, primarily deriving from overproduction of estrogens via aromatase enzyme. In the endometrium, unopposed estrogens induce proliferative or invasive phenomena, which represent the first step toward different diseases. These pathologies include endometrial hyperplasia, endometrial polyps, endometriosis and adenomyosis. Endometrial hyperplasia and polyps are proliferative pathologies, while endometriosis and adenomyosis are characterized by the invasion of other tissues by endometrial cells. Current pharmacological treatments include Gonadotropin-Releasing-Hormone analogs, aromatase inhibitors and progestogens, either alone or in combination with estrogens. As these drugs usually lead to burdensome undesired effects, researchers seek to find new therapeutical molecules. Recent literature highlights the positive effects of metformin, an insulin sensitizing drug that reduces the insulin proliferative stimulus on the endometrium. d-chiro-inositol is an insulin second messenger with insulin sensitizing and mimetic properties, recently described as an aromatase down-regulator. Based on current evidence, d-chiro-inositol may be useful to treat the pathologies responsive to unopposed estrogens. Free PDF DownloadThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License To cite this article M. Montanino Oliva, R. Gambioli, G. Forte, G. Porcaro, C. Aragona, V. Unfer Unopposed estrogens: current and future perspectives Eur Rev Med Pharmacol Sci Year: 2022 Vol. 26 - N. 8 Pages: 2975-2989 DOI: 10.26355/eurrev_202204_28629 Publication History Published online: 29 Apr 2022

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endometriosisadenomyosis

MeSH descriptors

Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis Adenomyosis

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