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The traditionally recognized role of vitamin D consists in the regulation of bone metabolism and calcium-phosphorus homeostasis but recently a lot of in vitro and in vivo studies recognized several “noncalcemic” effects of vitamin D metabolites. Accumulating evidence suggests that the metabolic pathways of this vitamin may play a key role in the developing of gynaecological/obstetric diseases. VDR-mediated signalling pathways and vitamin D levels seem to (deeply) affect the risk of several gynaecological diseases, such as polycystic ovary syndrome (PCOS), endometriosis, and ovarian and even breast cancer. On the other hand, since also the maternal-fetal unit is under the influence of vitamin D, a breakdown in its homeostasis may underlie infertility, preeclampsia, and gestational diabetes mellitus (GDM). According to our literature review, the relationship between vitamin D and gynaecological/obstetric diseases must be replicated in future studies which could clarify the molecular machineries behind their development. We suggest that further investigation should take into account the different serum levels of this vitamin, the several actions which arise from the binding between it and its receptor (taking into account its possible polymorphism), and finally the interplay between vitamin D metabolism and other hormonal and metabolic pathways.

In the genetic regulation of Müllerian structures development, a key role is played by Hoxa and Wnt clusters, because they lead the transcription of different genes according to the different phases of the organogenesis, addressing correctly cell-to-cell interactions, allowing, finally, the physiologic morphogenesis. Accumulating evidence is suggesting that dysregulation of Wnt and/or Hox genes may affect cell migration during organogenesis and differentiation of Müllerian structures of the female reproductive tract, with possible dislocation and dissemination of primordial endometrial stem cells in ectopic regions, which have high plasticity to differentiation. We hypothesize that during postpubertal age, under the influence of different stimuli, these misplaced and quiescent ectopic endometrial cells could acquire new phenotype, biological functions, and immunogenicity. So, these kinds of cells may differentiate, specializing in epithelium, glands, and stroma to form a functional ectopic endometrial tissue. This may provoke a breakdown in the peritoneal cavity homeostasis, with the consequent processes of immune alteration, documented by peripheral mononuclear cells recruitment and secretion of inflammatory cytokines in early phases and of angiogenic and fibrogenic cytokines in the late stages of the disease.

Chronic Pelvic Pain (CPP) could be defined as the presence of non-cyclic pain of 6 months duration or longer that localizes to the pelvis and is severe enough to cause functional disability and require medical or surgical treatment. Among women who undergo laparoscopy for CPP, endometriosis results in approximately 1/3 of the cases; conversely, among women who do not have CPP, endometriosis is present in only 5% of cases. Moreover, accumulating evidences support the opinion for which CPP has poor correlation with endometriosis stage, moderate correlation with isolated presence of ovarian endometrioma, strong correlation with Deep Infiltrating Endometriosis (especially if it affects bowel or urinary tract) and/or adhesion. Endometriosis-related CPP could arise through different pathways: one of the clearest reason is that endometriotic lesion could provoke a compression or infiltration of nerves; another possible causes of arising CPP could be represented by the increase of Nerve Growth Factor (NGF) in the endometriotic lesion area; last but not least, CPP could arise and be exacerbated also by inflammation of the peritoneal microenvironment. The hormonal therapies do not eliminate the endometriotic implants and, for this reason, stopping the treatment pelvic pain and other typical symptoms of endometriosis may recur and exacerbate the pre-treatment condition. The surgical treatment of endometriosis-related CPP is still not perfectly encoded, due to the unclear etiology and the different response to therapies. For these reasons, there is necessity of more efforts to create new non-invasive strategies that set a more accurate diagnosis and treatment of the causes of endometriosis-related CPP.