Therapies that target progesterone action hold potential as contraceptives and in managing gynecological disorders. Recent literature reviews describe the role of steroid hormones in regulating the mammalian oviduct and document that estrogen is required to stimulate epithelial differentiation into a fully functional ciliated and secretory state. However, these reviews do not specifically address progesterone action in nonhuman primates (NHPs). Primates differ from most other mammals in that estrogen levels are >50 pg/mL during the entire menstrual cycle, except for a brief decline immediately preceding menstruation. Progesterone secreted in the luteal phase suppresses oviductal ciliation and secretion; at the end of the menstrual cycle, the drop in progesterone triggers renewed estrogen-driven tubal cell proliferation ciliation secretory activity. Thus, progesterone, not estrogen, drives fallopian tube cycles. Specific receptors mediate these actions of progesterone, and synthetic progesterone receptor modulators (PRMs) disrupt the normal cyclic regulation of the tube, significantly altering steroid receptor expression, cilia abundance, cilia beat frequency, and the tubal secretory milieu. Addressing the role of progesterone in the NHP oviduct is a critical step in advancing PRMs as pharmaceutical therapies.

This study investigated how chronic pelvic pain (CPP) develops using rhesus macaques with naturally occurring endometriosis and a multiple lesion induction mouse model (MIM), as repeated retrograde menstruation is considered an underlying mechanism of endometriosis pathogenesis. MIM increased lesion numbers and elevated hypersensitivity. Elevated persistent glial cell activation was observed across multiple brain regions or spinal cords in MIM and rhesus macaques. Elevated TRPV1, SP, and CGRP expressions in the dorsal root ganglia (DRG) were persistent in MIM. MIM induced the severe disappearance of TIM4 ^hi MHCII ^lo residential macrophages and an influx of increased pro-inflammatory TIM4 ^lo MHCII ^hi macrophages in the peritoneal cavity. Cytokine levels were persistently elevated in MIM. Furthermore, dienogest (a synthetic progestin) and fingolimod (a selective immunosuppressor) reduced hyperalgesia and neuroinflammation. Our results indicate that recurrent retrograde menstruation can be a peripheral stimulus that induces nociceptive pain and creates a composite chronic inflammatory stimulus, leading to neuroinflammation and sensitization of the central nervous system. The circuits of neuroplasticity and stimulation of peripheral organs via a feedback loop of neuroinflammation may mediate widespread endometriosis-associated CPP. These findings in mice were further supported by results from the spontaneously developed advanced endometriosis in rhesus macaques via recurrent retrograde menstruation. Repeatedly occurring retrograde menstruation intensifies central sensitization driven by neuroinflammation in rhesus macaques and a mouse model of endometriosis.

Altered peristaltic and ciliary dysfunction is a feature of females with endometriosis. To further explore this premise, we examined the ampulla of rhesus macaques (Macaca mulatta) with and without spontaneous endometriosis for the expression of adenylate kinase 7 (AK7), a mitochondrial-dwelling nucleotide converting enzyme with critical roles in cellular kinesis, forkhead protein box J1 (FOXJ1), a marker of cilia abundance, and Anoctamin 1 (ANO1) as a marker of both smooth muscle contraction and ciliogenesis. We further performed an in vitro experiment that treated ampullary segments with peritoneal fluid from animals with and without endometriosis. We report significantly downregulated expression of ANO1 in the ampulla of monkeys with endometriosis (in vivo), and in the ampullary segments exposed to peritoneal fluid of animals with endometriosis. We did not observe statistically significant differences in the expression of AK7 or FOXJ1 both in vivo and in vitro. This highlights potentially essential roles of Anoctamin 1 in the oviduct, the dampening of which may lead to a specific subtype of endometriosis-caused subfertility.