Effects of Etonogestrel Treatment in the Reproductive Organs and Uterine Arteries of Nonoophorectomized Guinea Pigs

Abstract

The endometria of women treated with long-term progestin-only contraceptives (LTPOCs) display abnormally enlarged, fragile blood vessels, decreased endometrial blood flow, oxidative stress, and unpredictable focal abnormal endometrial bleeding. Because human studies on the effects of LTPOC treatment are constrained for ethical and practical reasons, we assessed the suitability of nonoophorectomized guinea pigs (GPs) to best mimic the hormonal milieu of women. The present study demonstrates that treatment of GPs parallels the morphological changes following LTPOC treatment of the human endometrium and ovaries. Specifically, treatment resulted in larger hyperemic, uteri compared with controls. Histopathologic and immunohistochemical analysis demonstrated fewer endometrial glands, decreased luminal mucus, increased numbers of blood vessels, and focal hemorrhage. While increased staining for the cell mitosis marker, Ki67, was present in the zona functionalis, no such increase occurred in the basalis. Lastly, effects on vasomotor features of uterine arteries suggest changes that favor increased resistance and reduced blood flow promoting decreased ability to withstand elevations in transmural pressure.

Long-acting progestin-only contraceptives impair endometrial vasculature by inhibiting uterine vascular smooth muscle cell survival

“…Our previous studies (8,9) demonstrated that, as in human endometria, LAPC administration to GPs results in such endometrial vascular changes as focal hemorrhage, increased oxidative stress, high apoptotic indices, and elevated lipid peroxidation. Similarly, as in endometria of women receiving Depo, the present study confirmed reduced numbers of αSMA (+) cells and decreased VSMC Fig.…”

“…The endometria of women receiving LAPCs contain elevated levels of VEGF and angiopoietin-2 (Ang-2) (4). Like women, the guinea pig (GP) exhibits spontaneous estrous cycling and hemochorial placentation (5)(6)(7) and is a relevant animal model to study LAPCinduced AUB (1,(8)(9)(10). In humans and GPs, this hyperangiogenic milieu creates endometria displaying superficial, irregularly distributed enlarged, thin-walled capillaries and venules (2,9,10).…”

“…Women administered LAPCs display significantly reduced endometrial blood flow (14), consistent with constriction of uterine arteries and arterioles. Although ETO administration constricts GP uterine radial arteries (8), it paradoxically induces hyperdilation in microvasculature in the functional endometrium (2, 9, 10). We postulate that LAPCs suppress VSMC and pericyte differentiation, proliferation, and migration to create fragile, thinwalled hyperdilated vessels prone to bleed.…”

Endometrial breakdown with sustained progesterone release involves NF-κB-mediated functional progesterone withdrawal in a mouse implant model

“…The aberrant activities of proteins that regulate angiogenesis appear to contribute to breakthrough bleeding (Lockwood, ; Kayisli et al, ; Hapangama and Bulmer, ), although the exact molecular mechanism is not yet fully elucidated. The use of progesterone subcutaneous implants in mice and guinea pigs represent a convenient model for the investigation of the mechanisms underlying irregular endometrial tissue breakdown or abnormal bleeding in women using LTPOCs (Morison et al, ; Alvarez Gonzalez et al, ; Krikun et al, ).…”

Effect of injectable medroxyprogesterone acetate and etonogestrel implants on GABA-A and serotonin receptors in white and gray matter of the brain: experimental study in rats

“…The marked increment of immune-positivity from day 10 to day 50 showed that the change was timedependent, which we considered to be related to the up-regulation of serotonin receptors. ENG is a derivative of synthetic progesterone and is frequently used in daily gynecologic practice [26][27][28]. Many previous studies have associated usage of an ENG implant with mood abnormalities, but the universal scales that measure depression would not have been used in these investigations, which is probably why it was not possible to distinguish between symptoms of mood changes and symptoms of depression.…”