Endometriosis and ovulatory menstruation: beyond the Sampson principle
Serdar E. Bulun
Serdar E. Bulun
Published July 1, 2025
Citation Information: J Clin Invest. 2025;135(13):e188787. https://doi.org/10.1172/JCI188787.
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Endometriosis and ovulatory menstruation: beyond the Sampson principle

Abstract

Endometriosis is an estrogen-dependent chronic inflammatory syndrome characterized by viable endometrial tissue outside the uterine cavity and associated with pain and infertility. Endometriosis, as tissue or a pathological process, is dynamic in that its establishment and progression require repeated episodes of retrograde travel of shed endometrial tissue, which implants in the lower abdominal cavity following ovulatory cycles and survives. Estrogen-rich follicular fluid released onto peritoneal surfaces during ovulation may also support endometriotic implants. DNA evidence indicates that endometriosis originates from eutopic endometrial tissue, which may reach the abdominal cavity in a retrograde manner primarily via the uterine tubes. Unlike uterine bleeding associated with non-ovulatory circumstances, retrograde menstruation following an ovulation maximizes shedding of epithelial cells localized to deep invaginations of the basalis portion of the endometrium, which likely carry somatic cancer-driver mutations such as KRAS. The attached endometrial stromal cells are mostly mutation free but display epigenetic defects including overexpression of aromatase and estrogen receptor-β and downregulation of progesterone receptor, causing estrogen excess and progesterone resistance. These tissue clones may form implants in involuting ovarian corpus luteum cysts and peritoneal surfaces and induce tissue remodeling and fibrosis, manifested as deep-infiltrating endometriosis. The first-line treatment for chronic pelvic pain associated with endometriosis is suppression of ovulation, with the goal of relieving pain. Infertility is often managed using in vitro fertilization, which improves the embryo quality and alters endometrial development.

Authors

Serdar E. Bulun

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Figure 2

Ovulatory cycle.

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Ovulatory cycle. Repetitious ovulatory cycles initiated by hypothalamic ...
Repetitious ovulatory cycles initiated by hypothalamic gonadotropin-releasing hormone (GnRH) neurons are essential for the establishment and progression of endometriosis (see Figure 3). GnRH, which is secreted in a pulsatile manner, acts on its seven-transmembrane G protein–coupled receptor on the gonadotroph and induces sequential secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary. FSH and LH, via their specific G protein–coupled receptors on ovarian granulosa and theca cells, stimulate sequential secretion of estradiol and progesterone. Estradiol during the proliferative phase builds the functionalis layer of the endometrium, whereas progesterone during the secretory phase stimulates endometrial differentiation. In the absence of pregnancy, endometrial tissue is shed through the vagina and also in a retrograde manner through the uterine tubes into the lower abdominal cavity.