HYPOTHALAMUS-PITUITARY-GONADAL AXIS.

LH

FSH

ACTH

menopause and adrenopause

Estrogens, Androgens, DHEA

E,T

Androgen/receptors

DHEA

cellular growth, differentiation, proliferation, and apoptosis

CRISP-3 gene

sialadenitis

Normal minor salivary gland

SS minor salivary gland

Fig. 23.1 This figure shows the interaction of hypothalamus-pituitary-gonadal axis with CRISP-3 gen in normal minor salivary gland and SS syndrome salivary gland. In SS salivary glands the architecture of the intracrine enzymes producing active A is deranged. This dysfunction, together with low serum levels of DHEAS, may explain the local A deficiency seen in salivary glands of patients with SS. In consequence, glandular and salivary CRISP-3 of SS patients was very weak, indicating that the expression level of DHEA-regulated CRISP-3 is pathologically low in association with low salivary levels of DHEA

23.5Prolactin and Sjögren Syndrome

Hyperprolactinemia at serum concentrations between 20 and 40 ng/ml participates in the clinical expression of a variety of autoimmune rheumatic diseases, notably SLE. This hypothesis is based on several experimental studies that demonstrated prolactin’s role as a neuroendocrine hormone with immunostimulatory properties. In addition, controversial reports suggest an association between hyperprolactinemia and lupus activity [29, 30].

Gutierrez et al. [31] studied basal serum levels of prolactin in 11 patients with pSS (9 women). Prolactin levels were significantly higher in patients with pSS compared with normal controls [31]. These preliminary data demonstrated hyperprolactinemia in a subset of patients with pSS, supporting the hypothesis of immune-neuroendocrine dysfunction characterized by an increase in prolactin and a decrease in cortisol in patients with pSS. Another study reported hyperprolactinemia in 21% of women between the ages of 51 and 81 who had

anti-Ro and anti-La antibodies [32]. Some of those patients had clinical diagnoses of pSS, supporting an association between hyperprolactinemia and pSS [32].

Haga et al. [33] investigated the prevalence and clinical significance of hyperprolactinemia in 55 patients with pSS. Patients with pSS showed significantly higher prolactin levels than normal controls, and this difference was more striking in patients younger than age 45. Serum prolactin levels did not correlate with disease duration, serum immunoglobulin, autoantibodies, or focus score in biopsies from minor salivary glands, but did correlate with internal organ involvement. Two patients, both of whom had aggressive pSS with extraglandular manifestations, developed pSS 12 years after hyperprolactinemia was detected.

A recent study compares the level and relative ratio of estrogen, progesterone, and prolactin in postmenopausal (without hormone replacement therapy) patients with SS and healthy controls. A significantly higher level of prolactin in patients than controls was found with significantly higher prolactin/progesterone and estrogen/progesterone ratios [34]. Another study confirmed hyperprolactinemia in 16.3% of SS patients. Hyperprolactinemia was persistent after subgrouping the patients and the controls based on their menstrual history [35]. IgA-rheumatoid factor (RF), detected in the sera of 26% of the pSS patients and in 1% of the controls, correlated with serum prolactin levels [36]. As a whole, these studies suggest that hyperprolactinemia is prevalent in patients with pSS and that it correlates with internal organ involvement and the presence of autoantibodies. Primary SS may be preceded by hyperprolactinemia for many years.

Recently, Steinfeld et al. [37] investigated the role of prolactin in salivary glands of patients with pSS and normal controls. The investigators demonstrated prolactin receptors in the ductal epithelial cells of the salivary glands and increased synthesis of this hormone (prolactin of 16 and 60 kDa) by acinar cells among the patients with pSS. Furthermore, they found prolactin gene expression in the salivary glands and a positive correlation between the presence of prolactin in the acinar epithelial cells, extraglandular clinical manifestations, and positive anti-Ro and anti-La antibodies. Based on these findings and considering that diverse proteases are found in the minor salivary glands of patients with pSS, the same investigators studied the influence of prolactin on the expression of cathepsin B and D in the minor salivary glands of patients with pSS in comparison with normal controls. They found that under the direct influence of prolactin, patients had a significant increase of the proteases cathepsin B and D and their respective mRNAs [38].

The interaction between prolactin and cytokines is quite complex. IL-6 is a potent stimulator of both the synthesis and secretion of prolactin. The finding of elevated levels of IL-6 and prolactin in the cerebrospinal fluid of patients with SLE and CNS involvement supports the concept that these mediators may also participate in the pathophysiology of pSS [39].

Decreased serum levels of DHEA and DHEAS are perhaps the most important hormonal alterations observed in SS. DHEA and DHEAS (the major androgen products of the adrenal gland) inhibit IL-6 production and blunt the acute phase reaction. The mechanism of this effect is through the potentiation of an inhibitor of nuclear factor Kappa B [40].

23.6Hypothalamus-Pituitary-Thyroid Axis

The thyroid, salivary, and lacrimal glands are susceptible to immunological damage, which can be expressed as thyroiditis or as SS. Indeed, the histopathology of both diseases characteristically shows focal or diffuse T and B lymphocyte infiltrates. These findings suggest that SS and autoimmune thyroid disease could share pathogenic mechanisms and antigens, which might explain the frequent co-occurrence of these conditions. The most common thyroid disorder found in SS is autoimmune thyroiditis and the most common hormonal pattern is subclinical hypothyroidism [41].

Tanaka et al. [42] performed serological and histopathological examination of the thyroid gland in 89 cases of SS. Thyroidal microsomal and thyroglobulin antibodies were detected in 34.5% and 21.4%, respectively. A direct correlation between thyroidal microsomal antibody and histopathology of the thyroid gland were found. Approximately 30% of SS had chronic thyroiditis as a complication.

Alpha-fodrin, an intracellular organ-specific cytoskeleton protein that is known to serve as an autoantigen, may be relevant to both SS and autoimmune thyroid disease [43–45].

23.7Perspectives of Hormonal Treatment on Sjögren Syndrome

The main hormonal alterations in SS are hypofunction of the HPA axis and selective failure to produce DHEA-S. Based on these findings, several studies have proposed that pSS patients might benefit from DHEA supplementation. In a pilot study, 28 female pSS patients with severe fatigue and low serum DHEAS were treated with 200 mg of DHEA or placebo, (14 patients per group) during 24 weeks [46]. At the end of treatment, no significant differences were observed between both groups for dry eye symptoms, objective measures of ocular dryness, stimulated salivary flow, fatigue reduction, hypergammaglobulinemia, or ESR. Four DHEA and one placebo group patient dropped out because of adverse effects. However, a previous randomized, controlled trial had shown improvement of fatigue and well-being in the DHEA group [47].

Effects of 50 mg oral DHEA/day on changes in serum levels of DHEA and 12 of its metabolites, the relationships between steroid levels and disease characteristics; and the influence of DHEA on these parameters, were analyzed in a randomized, 9 month, controlled, double-blind crossover study. All metabolites increased during DHEA but not during placebo, with relief of symptoms as dry mouth during DHEA therapy [48].

Adiponectin is involved in the immune functions of several biologic systems. Its effect on the proliferation and apoptosis of salivary gland epithelial cells has been

investigated. Adiponectin treatment resulted in a Dose-Dependent suppression of proliferation of salivary gland epithelial cells in pSS and protected the cells from spontaneous and interferon-gamma-induced apoptosis [49]. Additional studies of this immunoregulatory hormone are indicated in pSS.

23.8Conclusions

1.Experimental and human studies suggest a dysfunction of immuneneuroendocrine system

2. The principal alterations in SS are hypofunction of the hypothalamus-pituitary- adrenal axis and the hyphothalamus-pituitary-gonadal axis

3.SS is characterized by androgen deficiency in salivary glands and defects in local processing of DHEA, with downregulation of CRISP-3 gene expression.

4. Prolactin and IL-6 may play a role in the pathogenesis of SS.

5. The treatment of SS with DHEA may be useful, but further investigations are required.

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