Related Experiment Video
Updated: Mar 20, 2026
An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause
Published on: August 13, 2019
Design of pathway preferential estrogens that provide beneficial metabolic and vascular effects without stimulating
Zeynep Madak-Erdogan1, Sung Hoon Kim2, Ping Gong1
1Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Abstract:
There is great medical need for estrogens with favorable pharmacological profiles that support desirable activities for menopausal women, such as metabolic and vascular protection, but that lack stimulatory activities on the breast and uterus. We report the development of structurally novel estrogens that preferentially activate a subset of estrogen receptor (ER) signaling pathways and result in favorable target tissue-selective activity. Through a process of structural alteration of estrogenic ligands that was designed to preserve their essential chemical and physical features but greatly reduced their binding affinity for ERs, we obtained "pathway preferential estrogens" (PaPEs), which interacted with ERs to activate the extranuclear-initiated signaling pathway preferentially over the nuclear-initiated pathway. PaPEs elicited a pattern of gene regulation and cellular and biological processes that did not stimulate reproductive and mammary tissues or breast cancer cells. However, in ovariectomized mice, PaPEs triggered beneficial responses both in metabolic tissues (adipose tissue and liver) that reduced body weight gain and fat accumulation and in the vasculature that accelerated repair of endothelial damage. This process of designed ligand structure alteration represents a novel approach to develop ligands that shift the balance in ER-mediated extranuclear and nuclear pathways to obtain tissue-selective, non-nuclear PaPEs, which may be beneficial for postmenopausal hormone replacement. The approach may also have broad applicability for other members of the nuclear hormone receptor superfamily.
Insights
New pathway preferential estrogens (PaPEs) offer tissue-selective benefits for menopausal women. These novel compounds provide metabolic and vascular protection without stimulating breast or uterine tissues.
Area of Science:
- Endocrinology and Pharmacology
- Molecular Biology
- Reproductive Medicine
Background:
- Estrogens are crucial for women's health, but traditional hormone replacement therapy carries risks like breast and uterine stimulation.
- There is a significant need for estrogenic compounds with beneficial metabolic and vascular effects but without adverse reproductive tissue stimulation.
Purpose of the Study:
- To develop novel, structurally altered estrogens, termed pathway preferential estrogens (PaPEs), with selective estrogen receptor (ER) signaling.
- To achieve tissue-selective activity that provides therapeutic benefits without stimulating reproductive tissues.
Main Methods:
- Structurally modified estrogenic ligands to preserve key features while reducing ER binding affinity.
- Developed PaPEs designed to preferentially activate extranuclear ER signaling over nuclear pathways.
- Evaluated PaPEs in ovariectomized mice for effects on metabolic and vascular tissues, and reproductive tissues.
Main Results:
- PaPEs demonstrated preferential activation of extranuclear ER signaling pathways.
- These novel estrogens did not stimulate reproductive tissues, mammary tissues, or breast cancer cells.
- In vivo studies showed PaPEs reduced weight gain and fat accumulation in metabolic tissues and improved vascular endothelial repair.
Conclusions:
- Designed structural alteration of ligands can create pathway preferential estrogens (PaPEs) with a favorable tissue-selective profile.
- PaPEs offer a potential new approach for hormone replacement therapy in postmenopausal women, providing metabolic and vascular benefits.
- This ligand-based strategy may be applicable to other nuclear hormone receptor superfamilies.
Related Concept Videos
01:22Target Cell Response to Hormones
Notably, the cellular response can be regulated by altering the number of receptors expressed in the cell. For example, prolonged exposure to elevated hormone levels results in a gradual decline or down-regulation in the number of receptors for that specific hormone on the cell surface. Conversely, in response to low hormone levels, cells may use up-regulation, producing an...
01:08Chemical Signaling in the Endocrine System
Lipid-soluble hormones, such as steroid hormones, demonstrate an intracellular action. These hormones traverse cell membranes due to their lipid nature. Once inside the target cell, they...
01:22Hormonal Regulation of the Menstrual Cycle
At puberty, GnRH begins a pulsatile release pattern, which triggers the anterior pituitary gland to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The frequency and amplitude of GnRH pulses vary across the menstrual cycle, with faster pulses favoring LH release and slower pulses favoring FSH...
01:24Gonadal and Placental Hormones
In males, testosterone is the primary gonadal androgen. It plays a central role in the maturation of male reproductive organs — the penis and testes. Additionally, testosterone is instrumental in the development of secondary sexual characteristics — a deep voice as well as facial and pubic hair...
01:31Transducer Mechanism: Nuclear Receptors
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
01:30Hormonal Control of the Ovarian Cycle
Before puberty, the hypothalamus releases GnRH in a low frequency, low amplitude pulsatile manner. This along with the immature hypothalamic-pituitary-gonadal axis activity, results in low estrogen levels and the absence of a fully functional ovarian cycle. At puberty, GnRH secretion increases in both frequency and...