Endometriosis is driven by relatively low levels of prenatal and postnatal testosterone. Testosterone affects the developing hypothalamic–pituitary–ovarian (HPO) axis, and at low levels, it can result in an altered trajectory of reproductive and physiological phenotypes that can mediate the symptoms of endometriosis. Polycystic ovary syndrome, by contrast, is known to be caused primarily by high prenatal and postnatal testosterone, and it demonstrates a set of phenotypes opposite to those found in endometriosis
Early effects of prenatal testosterone, are important because they determine how and why the female HPO axis may become subject to early dysregulation that increases risks for endometriosis and other reproductive disorders.
Testosterone is present and active prenatally among females (at lower levels than among males), being produced from fetal and maternal adrenal glands, and maternal ovaries and maternal fat tissue, with maternal sources reaching the fetus via the placenta
Among both females and males, prenatal testosterone levels have been linked with two main anatomical metrics. Anogenital distance (AGD), usually measured from the scrotal base to the anus in males, or from the distal end of the vagina to the anus in females, is much longer on average in males than females. Longer AGD is strongly associated with higher prenatal testosterone in both sexes, with considerable variation within each sex. A second metric of prenatal testosterone, the ratio of the 2nd to the 4th finger length (2D4D digit ratio) is lower among males than females, and lower digit ratio indexes higher prenatal testosterone within each sex as well, though with considerable variability. Some females thus develop under conditions of lower, or higher, prenatal testosterone than others, and lower prenatal testosterone involves a shorter AGD, longer 2D4D and notable effects on development of the HPO axis.
PCOS is thus a developmental disorder of the HPO axis, that is mediated by relatively high prenatal testosterone and other factors. AGD is higher in adult women with PCOS compared to controls and in the fetuses of women with PCOS (as measured with ultrasound), and 2D4D digits ratios are lower in women with PCOS all of which demonstrate the importance of higher prenatal testosterone in the etiology of this condition.
Endometriosis, in contrast to PCOS, exhibits a diverse set of hormonal indicators, correlates and risk factors suggesting that it is ‘opposite’ to PCOS in its causes and symptoms Most notably, women with endometriosis exhibit, relative to controls: shorter AGDs, indicative of lower prenatal testosterone (2) lower LH relative to FSH, (3) higher SHBG, (4) higher serum oxytocin, (5) lower ovarian and serum testosterone, (6) lower AMH, (7) lower WHR and BMI, (8) lower β-endorphin and (9) a suite of other differences, all of which are opposite to the differences found between PCOS versus controls. The patterns of differences between women with PCOS and endometriosis are highly concordant with one another: for example, in women without PCOS or endometriosis, higher postnatal serum testosterone has been associated with lower SHBG, longer AGD, higher LH, lower FSH, higher β-endorphin and higher WHR.