The effect of diabetes on women's SF is complex. Overall, the literature suggests that there is poor correlation between sexual difficulties and either duration of diabetes or diabetes complications (23). In this context, Enzlin et al.'s survey observed that women who reported SD were not significantly different in duration of diabetes (p = 0.36) and HbA1c values (p = 0.47). The subanalysis of women with or without diabetes complications also did not reveal significant differences for HbA1c values between those with and without SD (p = 0.052 and 0.29, respectively) (19).
Duration of diabetes is usually associated with a greater rate of diabetic complications. Neuropathy, vascular impairment and psychological complaints have been shown to be implicated in the pathogen-esis of decreased libido, low arousability, decreased vaginal lubrication, orgasmic dysfunction, and dyspareunia, but discrepancies exist among reports (25, 44, 45). In Enzlin et al.'s case-control survey (19, 26), the rate of women with diabetic complications (33%) - such as peripheral neuropathy, auto-nomic neuropathy, nephropathy, and retinopathy - who reported sexual problems was not significantly higher than the rate of their counterparts without complications (22%; c2 = 1.3, df = 1, p = 0.34). An overall comparison of the percentages of women reporting a specific SD showed that only decreased lubrication was more prevalent among women with diabetes complications (c2 = 6.5, df = 2, p = 0.04). A specific subanalysis revealed that the latter finding was due to the significant difference between the percentage of women with diabetes with complications and healthy controls (19, 26). In contrast, there was an association between the number of complications and the occurrence of SD: subjects with more complications were more likely to report greater SD (p = 0.002), for both the men and women enrolled in their survey (19, 26).
Likewise, Olarinoye et al. (41) observed a nearly significant association between the FSFI total score and the duration of diabetes (p = 0.05). In contrast, duration of diabetes was negatively correlated with lubrication (p = 0.03) as well as orgasmic function (p = 0.04). Glycaemic control and diabetic complications were not significantly correlated with any of the FSFI domain scores (41).
Few objective data are available on the pathophysiology of diabetic complications that underlie SD in women. Consequently, the effects of diabetes on genital tissue structure, innervation and function remain poorly characterized. Rutherford and Collier (21) conducted a comprehensive literature review as it pertained to the etiology of SD among diabetic women. An alteration in blood supply secondary to diabetes mellitus, also coupled with reduced vasocongestion due to lower nitric oxide, was hypothesized as a key factor in determining genital arousal difficulties in diabetic women (21). In a case-control study, Wincze et al. (23, 46) measured vaginal vasocongestion in response to erotic stimuli in women with diabetes, using vaginal photoplethysmography to measure the capillary engorgement at the vaginal wall, while subjects individually viewed counterbalanced erotic and nonerotic videotapes. Women with diabetes demonstrated significantly less physiological genital arousal to erotic stimuli than controls, whereas their subjective responses were comparable. Although they did not consider the more recently published clinical classification for female SD (7, 8), their objective, physiological findings supported the idea of a causal diabetes-related genital sexual arousal disorder. The psychometric profile revealed no difference in terms of subjectively experienced sexual difficulties in diabetic women as compared with the control group (46).
Peripheral and autonomic neuropathies have been frequently associated with and are considered an important cause of erectile dysfunction in diabetic men. With the specific aim to assess whether peripheral neuropathy may be causally associated with the development of sexual disorders among diabetic women, Erol et al. (44) experimentally evaluated the genital and extragenital somatic sensory system using biothesiometry. In this case-control survey of 30 premenopausal diabetic women and 20 healthy sexually active women, women with diabetes showed a mean FSFI total score significantly lower than that of controls (23.6 vs. 38.3; p < 0.0005). Moreover, for each genital and extragenital site, the mean biothesiometric values were significantly higher in diabetics, with the sensation at the vaginal introitus, the labium minora, and the clitoris the most deteriorated in diabetic women. A correlation was not found in women with diabetes, because the difference between women with or without SD was not significant in terms of biothesiometric values.
Several interesting basic studies assessing the impact of diabetes on SF have been conducted in animal models. To better understand the reduction in vaginal lubrication that is frequently reported by diabetic women in real-life clinical practice, Park et al. (47) studied the vascular impairment at the vaginal level in a streptozotocin-induced diabetic rat model. Their hypothesis was that reduced vaginal lubrication in diabetic women may result from structural changes of the vagina. They investigated the vaginal structures using histochemistry and the expression of transforming growth factor pi (TGF-pi) using immunohistochemistry. In the diabetic animals, vaginal tissue revealed reduced epithelial layers and decreased vaginal submucosal vasculatures as compared with the control animals. The collagen connective tissue in the submucosal area of the diabetic animals' tissue showed a dense, irregular and distorted arrangement. The TGF-pi immunoreactivity in the diabetic animals was prominent in the collagen connective tissue, fibroblasts and smooth muscle fibres, whereas no immunoreactivity was detected in the vaginal structures of the controls. Therefore, in the rat model, Park et al. concluded that diabetes mellitus may induce vaginal tissue fibrosis by TGF-pi expression, with a consequently reduced sexually driven local vasocongestion.
A recent study by Kim et al. (48) supported these findings. Indeed, they observed that in strepto-zotocin-treated female rats, the vaginal blood flow response to pelvic nerve stimulation was significantly reduced as compared with healthy controls. Moreover, the histological examination of vaginal tissue from diabetic animals showed reduced epithelial thickness and atrophy of the muscular layer. Diabetic animals also had reduced vaginal levels of endothelial nitric oxide synthase and arginase I, but elevated levels of cyclic guanosine monophosphate-dependent protein kinase (three key enzymes that regulate smooth muscle relaxation). These alterations were accompanied by a reduction in both estrogen receptor alpha and androgen receptor expression in nuclear extracts of vaginal tissue from diabetic animals. The authors reported that similar changes were also found previously in ovariect-omized animals; therefore, they hypothesized that diabetes may lead to multiple disruptions in sex steroid hormone synthesis, metabolism and action. These pathological events may cause dramatic changes in tissue structure and key enzymes that regulate cell growth and smooth muscle contractility, ultimately affecting the genital response during sexual arousal. In a different study of streptozotocin-induced diabetic rats (49), diabetes was confirmed to be associated with vaginal fibrosis, as evidenced by increased collagen, TGF-pi, plasminogen activator inhibitor, apoptosis, and by decreased a-smooth muscle actin. The increment of reactive oxygen species and the reduction of superoxide dismutase indicated oxidative stress in diabetic tissue, accompanied by inducible nitric oxide synthase induction and increased reaction between nitric oxide and reactive oxygen species.
Park et al. (50) also investigated the effect of diabetes on clitoral hemodynamics and structures in the alloxan-induced diabetic female rabbit. After having verified the development of diabetes, clitoral cavernous blood flow was measured with a laser Doppler flowmeter. Mean baseline flaccid and peak clitoral cavernous blood flow was significantly decreased in the diabetic group than in the control group (p < 0.05). Moreover, histology revealed diffuse clitoral fibrosis in the diabetic group, with a significant reduction of the clitoral cavernous smooth muscle (p < 0.05). The authors concluded that diabetes mellitus may produce significant adverse effects on the hemodynamic mechanism of clitoral engorgement and lead to diffuse clitoral cavernous fibrosis in the animal model, and this finding may be related with decreased sexual arousal in diabetic women.
Unfortunately, there are few human studies that have explored the sexually related functional vascular anatomy in women. Park et al. (51, 52) also demonstrated that the angiotensin (ANG) system is a potent modulator for the maintenance of smooth muscle tone of the rabbit clitoral cavernosum, as the clitoral cavernosum contracted dose-dependently by the addition of ANG I, ANG II, ANG III and ANG IV. More recently, they reported that the contractile responses to all four ANG peptides are significantly enhanced in the diabetic clitoral cavernosum (53). Enhancement of contractility in diabetic clitoral cavernosum may be related to the increased affinity to ANG II receptors for ANG pep-tides, which was the epiphenomenon of impaired clitoral vasocongestion in the analysed diabetic animals.
Giraldi et al. (54) characterized the effect of experimental streptozotocin-induced diabetes on neurotransmission in rat vagina. Diabetes was demonstrated to interfere with adrenergic-, cholinergic-and nonadrenergic, noncholinergic (NANC) neurotransmitter mechanisms in the smooth muscle of the rat vagina, leading to impairment in vaginal SF. Such an elegant demonstration is not available for diabetic women, where the actual potential impact of peripheral neuropathy is still not adequately studied and understood.
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