{"id":1894,"date":"2026-04-11T22:17:17","date_gmt":"2026-04-11T22:17:17","guid":{"rendered":"https:\/\/pge2-hypothesis.com\/?page_id=1894"},"modified":"2026-09-29T23:26:58","modified_gmt":"2026-09-29T23:26:58","slug":"hypothetical-models-of-hormonal-resistance-to-avp-insulin-leptin-fgf23-and-ifn-%ce%b3","status":"publish","type":"page","link":"https:\/\/pge2-hypothesis.com\/?page_id=1894","title":{"rendered":"A Hypothetical Model of “Hormonal Multi-Resistance"},"content":{"rendered":"\t\t
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A Hypothetical Model of
“Hormonal Multi-Resistance”<\/h3>\n

Hormones such as AVP and leptin, along with other mediators, can spontaneously induce PGE2 production, possibly as part of a homeostatic negative-feedback mechanism, since PGE2 has been reported to antagonize their effects (while they continue to stimulate its production). Excessive upregulation by additional factors may lead to a state of \u201cPGE2 dominance.\u201d<\/p>\n

Its receptor EP3 plays important homeostatic roles. In individuals with EP3 overexpression (“EP3 up”) or underexpression (“EP3 down”), homeostasis may become disrupted. In this context, PGE2 may become a persistent limiting factor, establishing a self-reinforcing cycle of \u201cHormonal Multi-Resistance\u201d that sustains chronically elevated PGE2 levels<\/p>\n

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Clarification of hypothetical hormonal resistance loops<\/strong><\/span><\/h2>\n

According to our hypothesis, PGE2 can antagonize<\/a> the receptor binding of AVP, leptin, and insulin (while they presumably drive PGE2 upregulation as a limiter on their activity). These interdependent relationships may form vicious cycles – resistance loops – that potentially reinforce one another 1<\/sup><\/a>. We refer to this presumed phenomenon as \u2018Hormonal multi-resistance\u201d, illustrated in Figure 1.<\/p>\n

A combination of factors may cause such a strong upregulation of PGE2 that its levels begin to dominate over certain endocrine hormones that spontaneously stimulate PGE2 synthesis but can also be antagonized by it. In this state of \u201cPGE2 dominance\u201d, the functions of arginine vasopressin (AVP), insulin, and\/or leptin may be suppressed. Given the functions of the PGE2 receptor EP3, homeostasis can become chronically disrupted in individuals with either \u201cEP3 up\u201d or \u201cEP3 down\u201d (enhanced or insufficient EP3 capacity), driving upregulation of PGE2. This, in turn, promotes resistance to hormones that are antagonized by PGE2 but stimulate PGE2, ultimately reinforcing resistance to additional hormones – a process we describe as \u201cHormonal multi-resistance\u201d.<\/p>\n

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