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In women with diabetes, SF may vary according to the phase of the menstrual cycle. Our recent study investigated SF in reproductive-aged DM1 women, compared these results with those of age-matched normally cycling healthy fertile women with an objectively assessed normal SF, compared the endocrine profile of both groups, and analysed the correlation between endocrine milieu and SF according to the phase of the menstrual cycle (85). The findings suggested that DM1 may affect several aspects of women's SF. In addition, the results emphasized that both psychosexual and endocrine parameters must be assessed according to the different phases of the menstrual cycle. Indeed, when comparing the FSFI scores recorded independently of the phases of the menstrual cycle, a significant impairment of the overall SF as well as lower values on the desire, arousal, lubrication, orgasm and pain domains were found in the DM1 group compared to the control group. In contrast, a menstrual phase-related analysis revealed lack of any significant difference between the two groups for each domain of the FSFI during the midfollicular phase, but decreased arousal and lubrication, decreased capability of reaching orgasm, decreased satisfaction, and increased sexual pain in DM1 patients during the midluteal phase (85). Sexual desire did not seem to be affected by diabetes according to the phase of the menstrual cycle, which is in accordance with Kolodny (86) but is contrary to other studies (25, 87).

The impairment of arousal, lubrication and orgasm observed in patients with diabetes is not exclusively related to psychosexual issues. A reduction in lubrication has been reported in

10-34% of the cases. Orgasmic difficulties are also frequently described, with a prevalence of

11-14% in women with diabetes (25, 26, 28, 33, 34). Interestingly, in our study (85), the major differences were found when comparing either the overall values of the sexual pain domain (independent of the specific phase of the menstrual cycle) or the midluteal-phase values. In the literature, pain or discomfort during coitus was reported by 10-12% of diabetic women (25, 26, 28, 33, 34).

Widom et al. (88) reported that the menstrual cycle may influence glucose metabolism in women with DM1. A subgroup of patients exhibits worsening premenstrual hyperglycaemia and a decline in insulin sensitivity during the luteal phase, and the deterioration in glucose uptake in this subgroup has been associated with a greater increment in estradiol levels from the follicular to the luteal phase. In our study, glycaemic control did not directly affect the different domains of FSFI. In fact, we did not find any significant correlations between HbA1c levels and the FSFI domains. This finding is in accord with previous reports (19) and confirmed that poor glycaemic control probably has a minor impact on SF in women. In contrast, a positive correlation was found between HbA1c values and both midfollicular-phase total testosterone and midluteal progesterone levels. This finding was contrary to those of Widom et al. (88), who reported changes in reproductive hormones not related to differing glucose uptake throughout the menstrual cycle.

Interesting results emerged from analysis of the endocrine profile of the DM1 women (85). Patients and controls showed similar circulating levels of follicle-stimulating hormone, luteinizing hormone and prolactin. As far as gonadotropins are concerned, our data were in line with previous observations of Bestetti et al. in diabetic rats (89). Other researchers, however, have shown that impairment of gonadotropin release in diabetic rats may be appreciated only after stimulation with gonadotropin-releasing hormone (90). This test was not performed in our study. However, according to previous reports (91-95), oestrogen levels during both the midfollicular and the midluteal phase were reduced in comparison with those of controls and the same occurred for progesterone during the luteal phase. A decrease in estradiol had a negative impact on mood profile scores, as defined by means of the Beck's Inventory for Depression (BDI) scores (96, 97), and we found a significant negative correlation between estradiol and sexual pain.

Both overall and midluteal total testosterone levels were higher in diabetes patients than in controls. However, the relevance of this result remained doubtful, because both the sex hormone-binding globulin and free testosterone levels were comparable in the two groups during all phases. The increased total testosterone levels might be related to a positive modulatory effect of exogenous insulin on the expression of the luteinizing hormone receptor in the granulosa cell of the ovaries (98), which differentiate into androgen-producing interstitial cells. High levels of circulating testosterone bring about follicular atresia and, lead to a loss of estrogen-secreting cells and the development of polycystic ovaries and hirsutism (99). Patients also showed an overall reduction in adrenocortical androgen production, as previously stated by Couch (100).

Of note was the finding of low triiodothyronine/thyroxine (T3/T4) levels during both the midfollicu-lar and the midluteal phase in DM1 patients (85). In addition, we found that the worse the glycaemic control, the more compromised the thyroid function. During the midfollicular phase, free triiodothyro-nine (fT3) was positively associated to sexual desire, lubrication, and sexual satisfaction. A higher rate of mood deflection was also related to lower values of fT3. We also found a significant association between fT3 and the FSFI full scale as well as the arousal, lubrication, orgasm, and sexual satisfaction domains during the midluteal phase. The fT3 plasma levels were also positively correlated with arousal, lubrication, orgasm, and satisfaction in controls.

Our findings suggested that DM1 reproductive-aged women are at an increased risk for SD, with an endocrine milieu characterized by reduced estrogenic tone, adrenocortical androgen production, and low T3/T4. The role of the endocrine milieu in the pathogenesis of SD related to diabetes remains to be clarified. Moreover, our findings highlighted that investigations of the sexuality of pre-menopausal women with diabetes mellitus require examination of all the parameters in relation to the different phases of the menstrual cycle (85).

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