**5. The mechanisms explaining the decreased ovarian response and decreased serum AMH level in infertile patients with endometriosis**

Besides the mass effect of the endometrioma, other mechanisms might be also involved in the occurrence of reduced oocytes yield since similar oocytes number was found in the contralateral ovary of women with unilateral endometriomas [42]. Moreover, more severe endometriosis seems to have an additional negative impact on oocytes number [35].

Histological studies found that the cortex of ovaries with endometrioma presents decreased follicular density, increased fibrosis, loss of cortex-specific stroma [43] and high density of atretic follicles [44]. Moreover, activated follicular recruitment was observed in ovaries with endometrioma [44], suggesting follicle 'burnout' as a possible cause of decreased follicle number. It was suggested that the structural changes are the consequence of the cytokines produced in the endometriotic tissue which might affect the surrounding ovarian tissue by diffusion [44]. It was also showed that the addition of human endometriotic fluid to mouse preantral follicles decreases the follicles survival rates proportional with the endometriotic fluid supernatant concentration [45]. These data support the hypothesis that endometriotic fluid components can influence the ovarian response to COS through long-term destructive effects of ovarian tissue and, therefore, decreased ovarian reserve, but also by directly influencing the follicles survival [45]. It is also possible that the diffusion of the endometriotic fluid components from the peritoneum or the endometrioma to be able to influence the unaffected ovary function and structure [46].

The decreased serum AMH level in patients with endometriosis might be the consequence of reduced ovarian reserve due to structural ovarian changes. However, it was shown that the endometriotic fluid components can directly induce the dysfunction of the granulosa cells [47]. Tumor necrosis factor (TNF) alpha, one of the cytokines overproduced in endometriosis, was found to be negatively associated with serum AMH level [15], suggesting its involvement in decreased circulating AMH. Indeed, an experimental study showed that TNF alpha administration decreases the expression of AMH in bovine ovarian granulosa cells [48]. In mice, TNF alpha was demonstrated to inhibit the AMH production in testis [49]. Thus, TNF alpha might be the mediator of functional decrease of AMH production in endometriosis.

Another mechanism that can contribute to low oocytes yield is a decreased response to gonadotropin stimulation in endometriosis. Thus, interleukin 1 (IL1) was found to be increased in the peritoneal fluid of patients with endometriosis [50–52]. Il1 is also a regulator of ovarian function, being able to decrease the ovary receptors of FSH and LH [53], thus inducing a reduced sensitivity to gonadotropin stimulation. Moreover, women with endometriosis seem to have a decreased expression of the soluble decoy receptor IL1-RII which can generate an augmentation of IL1 alpha and IL1 beta effects [51, 54].
