Korean J Urol.  2009 Mar;50(3):211-223.

Diabetes Attenuates Female Genital Sexual Arousal Response via Disruption of Estrogen Action

• Traish AM
• Cushman T
• Hoyt R
• Kim NN

Abstract

PURPOSE: Diabetes profoundly and negatively impacts all domains of female sexual function, however, the underlying pathophysiological mechanisms remain unknown. To date, limited studies have been published on the effects of type 1 & type 2 diabetes on female genital sexual arousal and how this may impact overall sexual function. The aim of this review is to discuss the effects of diabetes on female sexual function and insights from laboratory studies on the underlying pathophysiology.
MATERIALS AND METHODS
Using PubMed, we reviewed and evaluated the literature published between 1970 and 2009 and data from our laboratories and others investigating the effects of type 1 and type 2 diabetes on genital sexual arousal responses.
RESULTS
Women with diabetes experience diminished genital arousal, reduced vaginal lubrication, vaginal atrophy, dyspareunia, and increased vaginal infections. Also, a number of studies using type 1 and type 2 diabetic animal models have reported reduced plasma estradiol levels and marked physiological, biochemical and histological changes in genital tissues. In animal studies, diabetes alters genital tissue structure and attenuates expression of the estrogen, progesterone and androgen receptors and alters vaginal and clitoral hemodynamics. Importantly, treatment of diabetic animals with estradiol in the face of persistent hyperglycemia can restore vaginal structure and sex steroid receptor expression.
CONCLUSIONS
Type 1 & type 2 diabetic complications produce significant structural and functional disruptions in genital organs and attenuate genital hemodynamics. In the type 2 animal model, estradiol treatment ameliorates diabetic-induced pathophysiological alterations in genital tissues, such as the vagina. This suggests that estrogen supplementation may be beneficial in restoring diabetes-induced genital pathology.

Keyword

Diabetes mellitus; Estradiol; Testosterone; Vagina; Clitoris

MeSH Terms

Animals
Arousal
Atrophy
Clitoris
Diabetes Complications
Diabetes Mellitus
Dyspareunia
Estradiol
Estrogens
Female
Genitalia
Hemodynamics
Humans
Hyperglycemia
Lubrication
Models, Animal
Plasma
Progesterone
Receptors, Androgen
Receptors, Steroid
Testosterone
Vagina
Estradiol
Estrogens
Progesterone
Receptors, Androgen
Receptors, Steroid
Testosterone

Figure

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  Fig. 1 Plasma estradiol and testosterone levels in control and diabetic mice. Plasma levels of estradiol and testosterone from control, diabetic (untreated) and diabetic animals treated with estradiol (E2) were determined by immunoassay at the Endocrinology Laboratory, Animal Health Diagnostic Center at the Cornell University College of Veterinary Medicine (Ithaca, USA), as described by Cushman et al.47,57 Note, that estradiol levels decreased in diabetic animals and testosterone levels increased in diabetic animals. This resulted in an imbalance in the testosterone to estradiol ratio (T/E) in diabetic animals. This ratio is normalized in diabetic animals treated with estradiol.

• 

  Fig. 2 Effects of type 1 diabetes on vaginal epithelial and muscularis morphology. Vaginal tissue sections from control and untreated diabetic were subjected to a Masson's trichrome staining protocol. The panels are representative sections from control (A) and untreated diabetic (B) animals. The 3 layers of the vaginal wall are labeled as epithelium (E), lamina propria (LP), muscularis (M). Scale bars represent 100 µm (magnification, ×200).

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  Fig. 3 Effects of type 2 diabetes and estrogen supplementation on vaginal epithelial and muscularis morphology. Vaginal tissue sections from control, untreated diabetic and diabetic animals treated with estradiol were subjected to a Masson's trichrome staining protocol. The panels are representative sections from control (A), untreated diabetic (B), and diabetic animals supplemented with estradiol (C). The 3 layers of the vaginal wall are labeled as epithelium (E), lamina propria (LP), muscularis (M). Scale bars represent 100 µm (magnification, ×200).

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  Fig. 4 Effects of type 1 diabetes on the density of neural nitric oxide synthase-immunopositive nerve fibers in vaginal tissue sections. Formalin-fixed and paraffin-embedded vaginal tissue sections from control (A) and untreated diabetic (B) animals were subjected to immunostaining procedures using anti-nNOS antibody and counterstained with Gill's hematoxylin (scale bar represents 100 µm, panels are at magnification, ×200). nNOS immunopositive nerve fibers are denoted by arrowheads. E: epithelium, LP: lamina propria, M: muscularis.

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  Fig. 5 Effects of type 2 diabetes and estradiol supplementation on the density of neural nitric oxide synthase (nNOS) immunopositive nerve fibers in vaginal tissue sections. Formalin-fixed and paraffin-embedded vaginal tissue sections from control (A), untreated diabetic (B), and estradiol treated diabetic (C) animals were subjected to immunostaining procedures using anti-nNOS antibody and counterstained with Gill's hematoxylin (scale bar represents 20 µm, panels are at magnification, ×400). nNOS immunopositive nerve fibers are denoted by arrowheads.

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  Fig. 6 Postulated effects of diabetes on estrogen production and signaling in the vagina. Diabetic complications may adversely affect vaginal health and function by altering sex steroid hormone production and/or steroid hormone receptor signaling (red triangles). Disruptions in ovarian function may lead to decreased production of estrogens. In addition, alteration of ERα expression or binding properties could lead to decreased binding of estrogens and/or attenuated receptor signaling, resulting in decreased expression or activity of estrogen-dependent proteins within the vagina. Direct interactions are represented by solid arrows, whereas indirect or multi-step processes are represented by dashed arrows. PKG: protein kinase G, PDE5: phosphodiesterase 5, cGMP: cyclic guanosine monophosphate, NO: nitric oxide, GTP: guanosine triphosphate, eNOS: endothelial nitric oxide synthase, nNOS: nitric oxide synthase, E2: estradiol (Adopted from Kim NN, J Sex Med 2009;6(Suppl 3):239-246).

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