The Impact of Thyroid Disease on Sexual Dysfunction in Men and Women.

BACKGROUND: Individually, thyroid disease and sexual dysfunction are common conditions that can have a detrimental effect on quality of life. Recent reports have documented an increased prevalence of sexual dysfunction among patients with thyroid disorders. As such, it is important for sexual medicine physicians to be primed on the presentation of patients with overlying sexual and thyroid dysfunction to allow for proper management. AIM: To review the available literature exploring the relationship between thyroid disease and sexual dysfunction in men and women. METHODS: A PubMed review of existing clinical and pre-clinical studies from 1978 through 2018 was performed. MAIN OUTCOME MEASURES: The prevalence, symptomatology, pathophysiology, diagnosis and management of patients with sexual dysfunction in the setting of thyroid disease were reviewed. RESULTS: The prevalence of sexual dysfunction in patients with hypothyroid (59-63% and 22-46% in men and women, respectively) and hyperthyroidism (48-77% and 44-60% in men and women, respectively) has been estimated in select populations. Both hypothyroidism and hyperthyroidism were strongly associated with erectile and ejaculatory dysfunction: hypothyroidism with delayed ejaculation, hyperthyroidism with pre-mature ejaculation. Hypothyroidism and hyperthyroidism have been reported to impair libido in men and women; however, evidence of hypothyroidism's impact on male libido is mixed. Hypothyroid and hyperthyroid women demonstrated impairments in desire, arousal/lubrication, orgasm, satisfaction, and pain during intercourse. Mechanistically, hypothyroidism and hyperthyroidism exert effects on circulating sex hormone levels through peripheral and central pathways and can indirectly provoke psychiatric and autonomic dysregulation that can impair sexual function. Correction to euthyroid state was associated with dramatic resolution of sexual dysfunction in both male and female patients with hypothyroidism or hyperthyroidism. CONCLUSION: By improving awareness of the link between thyroid disease and sexual dysfunction, sexual medicine physicians may sooner identify patients whose sexual symptoms may be remedied by treating an underlying thyroid disorder. Gabrielson AT, Sartor RA, Hellstrom WJG. The Impact of Thyroid Disease on Sexual Dysfunction in Men and Women. Sex Med Rev 2019;7:57-70.

Novel lipoproteoplex delivers Keap1 siRNA based gene therapy to accelerate diabetic wound healing.

Therapeutics utilizing siRNA are currently limited by the availability of safe and effective delivery systems. Cutaneous diseases, specifically ones with significant genetic components are ideal candidates for topical siRNA based therapy but the anatomical structure of skin presents a considerable hurdle. Here, we optimized a novel liposome and protein hybrid nanoparticle delivery system for the topical treatment of diabetic wounds with severe oxidative stress. We utilized a cationic lipid nanoparticle (CLN) composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and the edge activator sodium cholate (NaChol), in a 6:1 ratio of DOTAP:NaChol (DNC). Addition of a cationic engineered supercharged coiled-coil protein (CSP) in a 10:1:1 ratio of DNC:CSP:siRNA produced a stable lipoproteoplex (LPP) nanoparticle, with optimal siRNA complexation, minimal cytotoxicity, and increased transfection efficacy. In a humanized murine diabetic wound healing model, our optimized LPP formulation successfully delivered siRNA targeted against Keap1, key repressor of Nrf2 which is a central regulator of redox mechanisms. Application of LPP complexing siKeap1 restored Nrf2 antioxidant function, accelerated diabetic tissue regeneration, and augmented reduction-oxidation homeostasis in the wound environment. Our topical LPP delivery system can readily be translated into clinical use for the treatment of diabetic wounds and can be extended to other cutaneous diseases with genetic components.

Restoration of Nrf2 Signaling Normalizes the Regenerative Niche.

Chronic hyperglycemia impairs intracellular redox homeostasis and contributes to impaired diabetic tissue regeneration. The Keap1/Nrf2 pathway is a critical regulator of the endogenous antioxidant response system, and its dysfunction has been implicated in numerous pathologies. Here we characterize the effect of chronic hyperglycemia on Nrf2 signaling within a diabetic cutaneous regeneration model. We characterized the effects of chronic hyperglycemia on the Keap1/Nrf2 pathway within models of diabetic cutaneous wound regeneration. We assessed reactive oxygen species (ROS) production and antioxidant gene expression following alterations in the Nrf2 suppressor Keap1 and the subsequent changes in Nrf2 signaling. We also developed a topical small interfering RNA (siRNA)-based therapy to restore redox homeostasis within diabetic wounds. Western blotting demonstrated that chronic hyperglycemia-associated oxidative stress inhibits nuclear translocation of Nrf2 and impairs activation of antioxidant genes, thus contributing to ROS accumulation. Keap1 inhibition increased Nrf2 nuclear translocation, increased antioxidant gene expression, and reduced ROS production to normoglycemic levels, both in vitro and in vivo. Topical siKeap1 therapy resulted in improved regenerative capacity of diabetic wounds and accelerated closure. We report that chronic hyperglycemia weakens the endogenous antioxidant response, and the consequences of this defect are manifested by intracellular redox dysregulation, which can be restored by Keap1 inhibition. Targeted siRNA-based therapy represents a novel, efficacious strategy to reestablish redox homeostasis and accelerate diabetic cutaneous tissue regeneration.