3.1.4. Sex Hormones Deregulation and X-Chromosome Linked Factors

Nine out of ten SS patients are women and generally during menopause [65]. The strong predisposition of women to develop SS clearly demonstrates the role of sex hormones as a risk factor of the disease. In a recent case-control study, pSS in women was associated with lower oestrogen exposure and lower cumulative menstrual cycling time compared to sicca controls. Conversely, an increasing oestrogen exposure was negatively associated with development of pSS [66]. Finally, an effect of X chromosome per se is also evoked since men with Klinefelter's syndrome have a higher risk of developing pSS—20 times higher—compared to healthy men, despite normal sex hormone levels [67,68]. Similarly, the association between pSS and mixed connective tissue disease has been reported in a 16-year-old Japanese patient with trisomy X [69].

Androgens suppress the inflammation and enhance the function of lacrimal glands in female SS mouse models (MRL/MpJ-Tnfrsf6lpr[MRL/lpr]) [70]. The androgens could help maintaining acini structure in healthy SG, while their reduction observed in SS patients could cause a decrease in integrin expression and probably a dysregulation of acini architecture [71]. SS patients present low levels of androgen hormones both in the bloodstream and in SG [72]. In Klinefelter's syndrome associated SS and SLE, correction of hypogonadism by testosterone therapy for 60 days leads to remission in one case-series report [73].

Healthy ovariectomized C57BL/6 mice display an exocrinopathy with autoimmune characteristics similar to SS including SG focal adenitis, lacrimal glands lesions, Ro/SSA, La/SSB and α-fodrin autoantibodies [74]. Similarly to ovariectomized mice, both mice rendered deficient in aromatase, an enzyme important in the biosynthesis of oestrogens, as well as mice that received an aromatase inhibitor develop a lymphoproliferative autoimmune disease resembling SS [75,76]. How oestrogen deficiency promotes autoimmune lesions remains unclear. However, one putative explanation could be that oestrogen deficiency stimulates SGEC to secrete IFN-α and IL-8, and to express MHC class II, enabling them to act as antigen-presenting cells. Oestrogen deficiency is responsible for RbAp48 overexpression, which induces p53-mediated apoptosis in exocrine glands [77]. In another study, transgenic mice overexpressing RbAp48 develop SS-like exocrinopathy characterized by an increased propensity to apoptosis and the acquisition of an active immunocompetent role by epithelial cells, producing IFN-γ and IL-18 [78]. In primary cultures of human SG cells, pre-treatment with 7β-estradiol impede IFNγ-induced upregulation of ICAM-1 in control group but not in pSS group. These data suggest a protective role of oestrogens on epithelial activation and the existence of a deficient estrogenic responsiveness in pSS [79]. Not surprisingly, the use of aromatase inhibitors in the treatment of breast cancer is associated with arthralgia or even authentic SS [80–82].

Humans and other primates, secrete large amount of sex steroid precursors, such as dehydroepiandrosterone (DHEA) and DHEA-sulphate precursors, metabolic intermediates in the biosynthesis of androgens and oestrogens. According to tissue needs, the prohormones are directly processed within tissues. DHEA is present in low concentrations in patients with SS as compared to age-matched healthy controls [83]. Several studies have shown that human MSG possess an organized intracrine machinery capable to convert DHEA(-sulphate) pro-hormone to its active metabolites, dihydrotestosterone (DHT) and 17β-oestradiol [84] (Figure 3). However, the non- functionality of this enzymatic machinery in MSG from SS patients could account for the diminished local concentrations of DHT and androgen-regulated biomarker Cysteine-Rich Secretory Protein 3 (CRISP-3) in SS patients [85].

**Figure 3.** Intracrine steroidogenic machinery in healthy acinar cells. The figure shows the conversion of dehydroepiandrosterone (DHEA) to active sex steroids. STS: steroid sulphatase, SULT2B1: sulfotransferase 2B1, HSD: hydroxy steroid dehydrogenase, 5-α-R: 5α-reductase, TEST: testosterone, DHT: dihydrotestosterone. DHEA-S: DHEA-sulphate.

Taken together, these data suggest that women affected by SS at menopause, when the levels of testosterone produced by the ovaries has already declined, may be particularly vulnerable to androgen deficiency because the only source of DHT in SG is dependent on local conversion of DHEA. Whereas in men, the level of systemic androgens produces by gonads may satisfy the specific needs of SG, not requiring the intermediate metabolite.
