Prenatal Origins of Endometriosis Pathology and Pain: Reviewing the Evidence of a Role for Low Testosterone

Abstract

Endometriosis is a polygenic, estrogen-dependent, inflammatory disorder of uncertain aetiology associated with pain, infertility and reduced quality of life. While the positive association between endometriosis and estrogen is established, a suite of recent studies has demonstrated an inverse association between the presence of endometriosis lesions and levels of testosterone both prenatally and postnatally. The following narrative review provides new insights into the roles of testosterone in the aetiology, diagnosis, and management of endometriosis and associated symptoms, especially pain. A relatively short anogenital distance (AGD) is indicative of lower levels of testosterone during fetal development. A shorter AGD has recently been correlated with both a higher risk of developing endometriosis in adult life, and with known correlates of endometriosis including earlier onset of reproductive cycling, lower ovarian follicle number, lower postnatal testosterone, and premature ovarian insufficiency. During adult life, lower levels of testosterone are positively associated with key comorbidities of endometriosis, including days per month of pelvic pain and increased pain sensitivity. Biochemically, lower levels of testosterone are associated with higher levels of pro-inflammatory IL-1β and lower levels of β-endorphin. In rodents, prenatal administration of testosterone to females reduces their pain sensitivity in adulthood. The emerging convergent links of endometriosis with low prenatal and postnatal testosterone provide evidence of a centrally mediated effect beginning in early prenatal development, and persisting through adult life, with notable effects on pain sensitivity. They generate a novel conceptual framework for understanding, studying and treating this disorder, whereby endometriosis is mediated by a combination of high estrogen in endometrial tissue with low systemic and ovarian testosterone.

Effects of the menstrual cycle on the performance of female football players. A systematic review

“…Prenatal testosterone levels could also confound the impact of the different phases of the menstrual cycle on performance. Both the digit-ratio (2D:4D) and the anogenital distance indicate the level of testosterone exposure prenatal and early postnatal in male and female children ( Zheng and Cohn, 2011 ; Crespi and Evans, 2023 ). Lower D2:D4 Digit and lower anogenital distance indicate higher testosterone exposure in early life, and higher early life exposure to testosterone is related with less pain sensitivity and premenstrual symptoms ( Crespi and Evans, 2023 ) and greater success rate in Olympic sports ( Eklund et al, 2020 ).…”

Systemic Effect of Human Follicular Fluid from Endometriotic and Healthy Subjects on Female Mice

“…However, not all endometriosis-affected women have compensatory hyperinsulinemia or are insulin-resistant. 20 The clinical signs of hyperandrogenemia, on the other hand, generally appear during adolescence in women with endometriosis and are largely characterized by an excess of androgens and a high LH level. 21 Similar to the results obtained in this study.…”

Polygenic risk score phenome-wide association study reveals an association between endometriosis and testosterone

“…Nevertheless, a role for alterations to the hypothalamic-pituitary–gonadal (HPG) axis, and a role for testosterone, specifically lower prenatal testosterone in endometriosis, has been previously discussed [ 26 – 28 ]. Differences in anogenital distance, a proxy for prenatal testosterone, between endometriosis cases and controls implicates lower prenatal testosterone in endometriosis cases [ 29 ].…”

“…Testosterone is a controller of HOXA10 expression [ 34 ], which is a key player in the development of the female reproductive tract, and has been implicated in endometriosis [ 35 ]. Low testosterone could also contribute to pain in endometriosis, through mechanisms such as the inverse association with inflammation, and/or through links with β-endorphin levels within the central nervous system [ 28 ]. Importantly, a role for prenatal testosterone and early disturbance of the HPG axis in endometriosis would imply a developmental origin for endometriosis [ 28 ].…”