Clarification of hypothetical hormonal resistance loops

According to our hypothesis, PGE2 can antagonize 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. We refer to this presumed phenomenon as ‘Hormonal multi-resistance”, illustrated in Figure 1.

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 “PGE2 dominance”, 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 “EP3 up” or “EP3 down” (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 “Hormonal multi-resistance”.

1. • AVP

When sufficiently upregulated, PGE2 has been reported to antagonize the activity of arginine vasopressin (AVP) ². AVP, in turn, stimulates PGE2 production via its receptor V1 ³. PGE2 increases osmolality through EP3 signaling ⁴ and lowers blood pressure through EP4 and EP2 signaling ⁵. Thus, PGE2 could cause AVP resistance in the following way: AVP is stimulated by hypovolemia when osmolality is high or when blood pressure is low. Hypovolemia induces AVP upregulation. However, under certain conditions, elevated PGE2 may dominate AVP activity, a state we term “PGE2 dominance”. PGE2 may prevent AVP from binding to its receptors by stimulating autoantibodies against AVP, as observed in another context ⁶. Polyuria resulting from AVP malfunction can cause low blood pressure and high osmolality. In this situation, increasing AVP levels cannot restore blood pressure or osmolality. Homeostatic imbalances will continue to stimulate AVP and PGE2 levels. Moreover, AVP itself stimulates PGE2, which, due to imbalanced EP3 expression, can either raise osmolality or lower blood pressure. Thus, both AVP and PGE2 may remain upregulated in a vicious loop. 

• • Insulin

PGE2 can increase blood glucose by inhibiting insulin secretion through EP3 signaling ⁷, but it can also lower blood glucose by attenuating glycogenolysis through EP3 ⁸. Either insufficient or enhanced EP3 capacity could lead to elevated glucose levels when stress factors upregulate PGE2. Elevated glucose levels, in turn, upregulate PGE2 ⁹. We propose that PGE2 antagonizes insulin receptor binding by stimulating phosphorylation of insulin receptors (See section 5). When insulin cannot exert its function, glucose levels remain high, which in turn sustains PGE2 upregulation. In this way, glucose levels could remain elevated in both category A (EP3-up) and category B (“EP3 down”) individuals, albeit through different pathways, while PGE2 continues to antagonize insulin activity.

• • Leptin

As discussed in the previous section, either insufficient or enhanced EP3 signaling may lead to elevated glucose levels. Leptin, which is produced in adipose tissue, is upregulated by glucose and carbohydrate intake. Leptin has been repeatedly reported to stimulate PGE2 ¹⁰. When PGE2 becomes sufficiently upregulated by various factors, it may antagonize leptin activity. Under conditions of PGE2 dominance, leptin receptor binding is impaired, resulting in leptin insensitivity. This leads to increased carbohydrate intake and adipose tissue accumulation, which, under inflammatory conditions, further stimulate PGE2 production. Chronically elevated glucose levels perpetuate leptin upregulation, but leptin remains functionally antagonized because high osmolality, adipose tissue, and leptin itself all maintain elevated PGE2 levels that block leptin activity.

According to our hypothesis, in addition to AVP, insulin, and leptin, other PGE-stimulating hormones and agents may exhibit markedly reduced responsiveness under conditions of PGE2 dominance.

Examples are:

• • Fibroblast growth factor 23 (FGF23)

One of the functions of fibroblast growth factor 23 (FGF23) is to promote phosphate excretion. Elevated phosphate levels have been reported in patients with long COVID patients ¹¹. Inflammation has been shown to cause FGF23 resistance ¹², and FGF23 itself stimulates PGE2 ¹³. Elevated PGE2 could impair FGF23 activity, for example, by stimulating autoantibodies against FGF23, as observed in other contexts ¹⁴. Increased phosphate levels stimulate higher FGF23 concentrations, and FGF23 continues to upregulate PGE2, which in turn antagonizes its function. This may result in sustained elevation of phosphate, FGF23, and PGE2 levels.

• • Cytokine interferon-gamma (IFN-γ)

Patients who develop long COVID often show marked upregulation of specific cytokines, including interferon-gamma (IFN-γ) ¹⁵. Elevated IFN-γ can have detrimental effects ¹⁶, and IFN-γ resistance has been reported in other contexts ¹⁷. IFN-γ stimulates COX-2/PGE2 production ¹⁸. According to our hypothesis, sufficiently high PGE2 levels may antagonize IFN-γ activity, keeping IFN-γ chronically elevated while PGE2 remains upregulated, possibly by stimulating autoantibodies. Autoantibodies against IFN-γ that block receptor binding have indeed been observed in other contexts ^19,20.