Treatment of sexual dysfunction in diabetes mellitus subjects using orally administered protodioscin and injection of vasoactive compounds A. Adimoelja Academic Hospital Dr. Soetomo, Airlangga University, Surabaya, Indonesia in Seminar of Erectile Dysfunction of Diabetes in Bandung, Indonesia (1997) SUMMARY Diabetes mellitus is a systemic metabolic disease which results in the destruction or weakening of many tissues and cell types. Here we conducted a preliminary clinical study to determine the level of dehydroepiandrosterone-sulphate (DHEA-S) in 15 diabetic males and 15 healthy controls. This study shows that the DHEA-S levels in healthy people are significantly higher than that found in diabetic subjects. A further study conducted with 30 male subjects with diabetes shows that those also suffering from erectile dysfunction (ED) have even lower DHEA-S levels than those without the dysfunction. Treatment of diabetic subjects with protodioscin in the form of tablets of Tribulus terrestris L extract (Libilov, 250 mg at 3 x 1 tablet daily for ten days) results in the increase of DHEA-S levels of these subjects, with the most gain experienced by those who also suffer from ED. Moreover, in this study we notice a significant increase (> 60%) in the frequency of successful sexual intercourse, as well as increased libido or sex drive in the diabetic male subjects. In this clinical study, we find no unwanted side-effects of administration of Libilov as examined by laboratory blood tests, as well as kidney and liver function tests. MALE SEXUAL DYSFUNCTION Erectile dysfunction (ED) or impotence, in addition to premature ejaculation, is the most common form of male sexual dysfunction. This form of dysfunction is also commonly found in subjects diagnosed with diabetes mellitus. Clinical research suggests that male subjects with this disease are more prone to ED compared to healthy males. Animal models of this form of diabetes show that hyperglycemia or abnormally high concentration of blood sugar can result in lowered androgen production, and lowered amounts of Leydig cells and Luteinizing hormone (LH) receptors. At first, insulin can successfully treat these deficiencies, suggesting that the lack of insulin is responsible for the sexual dysfunction of male diabetes mellitus subjects. This turns out not to be true, as later research revealed that insulin cannot successfully treat ED in these subjects. MECHANISM OF REGULATION OF CONTRACTION OF SMOOTH PENILE MUSCLES It is medically accepted that relaxation of the corpus cavernosum smooth muscle results in penile erection. First, the relaxation of the smooth muscle causes arterial blood to flow to tiny pool-shaped blood vessels called cavernous sinuses. The veins surrounding these tissues then are compressed shut by the pressure of the erectile tissues. The blood that pooled in the vessels are unable to flow out, thus resulting in penis rigidity. Destruction of the endothelium cells can directly result in ED. This is because relaxation of the smooth corpus muscle requires hormones and enzymes produced by these cells. For example, endothelium derived relaxing factor (EDRF) produced by these cells results in increased level of nitric oxide in the penis smooth muscles, which then results in tissue relaxation. In addition to EDRF, these endothelium cells also produce endothelin hormones, one of which is a strong vasoconstrictor. Furthermore, these endothelin hormones are similar to growth factors, in that they cause endothelium, fibroblast and smooth muscle cell production and development. By this mechanism, endothelin controls not only the structural development of blood vessels and smooth muscle tissues, but also that of the endothelium cells as well. Hyperglycemia and hypercholesterolemia associated with diabetes mellitus are two main causes of endothelial cell destructions, resulting in ED. OTHER VASOACTIVE ENDOTHELIN Prostaglandins are eicosanoids produced in corpus cavernosum which function in controlling smooth muscle contraction and tone. For example, PGF-2a, PGI-2 and thromboxane are prostaglandins that result in smooth muscle contraction, whereas PGE-1 results in smooth muscle relaxation. Indeed, injection of PGE-1 has been used as treatment for ED caused by diabetes mellitus. With well regulated diabetes management, injection of PGE-1 or other vasoactive chemicals such as papaverin and fentolamin can result in temporary erection. This palliative approach of injecting non-physiological vasoactive compounds, however, does not treat the underlying disease. Without injection, subjects will always experience ED. CURRENT TREATMENT OF ERECTILE DYSFUNCTION IN SUBJECTS WITH DIABETES MELLITUS In the past four years, treatment of 247 subjects with insulin-dependent (IDDM) and noninsulindependent (NIDDM) diabetes mellitus experiencing ED involve injection of PGE-1. These subjects, who have been diagnosed with diabetes mellitus for at least one year and have experienced at least six months of ED, are between 25 and 57 years of age, with an average age of 42.3 years. PGE-1 doses of between 5 and 30 mg, with average of 10 mg, are administered to these subjects twice per week for 3 months. Criteria for penile erection is determined by the 1993 NIH Consensus Conference on Impotence as published in Journal of American Medical Association 270, pp.83-90. 231 subjects (93.5%) responded positively to injections, with optimal erection occurring approximately 20 to 90 minutes after injections. Subjects that fail to respond positively almost exclusively suffer from IDDM. Three months after treatment, 92 subjects (39.8%) do not require further PGE-1 injections. These subjects almost exclusively have NIDDM, suggesting that the erectile dysfunction caused by this form of diabetes respond well to treatments with injection of vasoactive compound. These results suggest that PGE-1 injections results in improvements of the endothelium cells that are damaged in subjects suffering from diabetes. CAN PROTODIOSCIN REPAIR DAMAGED CELLS? Protodioscin is the active ingredient in Tribulus terrestris L plant extracts. Tribulus is known as effective herbal medication for sexual dysfunctions in central European and Asian countries. Protodioscin's chemical structure is close to that of dihydroepiandrosterone (DHEA), a precursor to testosterone which circulates in the bloodstream as DHEA-sulphate (DHEA-S). DHEA-S has been shown to significantly activate the immune system. As diabetes mellitus is a systemic metabolic disease which results in the destruction or weakening of many tissues and cell types, we conducted a preliminary clinical study to determine the level of DHEA-S in 15 diabetes subjects and 15 healthy controls. Subjects suffering from diabetes were found to have an average of 50 mg/dl of DHEA-S, whereas healthy men had an average of 77.6 mg/dl (p < 0.01). This showed that the DHEA-S levels in healthy people were significantly higher than that found in subjects with diabetes mellitus. With this result, we conducted a larger study composed of 30 diabetes subjects that also suffered from sexual dysfunction. We found that these subjects had even lower level of DHEA-S of 11.9 mg/dl compared to 15 diabetes subjects that had no erectile dysfunction with DHEA-S level of 32.2 mg/dl (p < 0.05). To the diabetes subjects with erectile dysfunction, treatment with protodioscin in form of tablets of Tribulus terrestris L extracts (250 mg) was administered in form of one tablet three times daily for ten days. We found that this treatment successfully increased DHEA-S levels in these subjects by over 61% to 19.2 mg/dl. Treatment of diabetes subjects without erectile dysfunction with similar Tribulus dosage resulted in the increase of nearly 30% of their average DHEA-S level to 41.8 mg/dl (p < 0.005). Therefore, treatment with Tribulus extract can successfully increase the level of DHEA-S in diabetes subjects, with the most gain experienced by those who also suffered from erectile dysfunction. Moreover, from this study we notice a significant increase of more than 60% in the frequency of successful sexual intercourse, as well as increased sexual libido or sex drive in these male subjects. It is possible that the increased DHEA-S levels in these subjects promote healing of the membrane integrity of the endothelium, corpus cavernosum and cells in other penile tissues, as well as improved performance of the body's circulatory system. This hypothesis is well supported by previous findings that Tribulus supplements improve spermatozoa morphologies of infertile men, resulting in greater frequency of conception. Significant among the morphology improvements is the increased efficiency of enzymatic reaction of the acrosome. In all these clinical studies, including ours, there was no unwanted side-effects of administration of Tribulus extract as examined by laboratory blood, kidney function, and liver function tests. In exception of the desirable increase in DHEA-S level as mentioned above, we found no changes in the concentration of other hormones in the circulatory system. PGE-1, PROTODIOSCIN AND ERECTILE DYSFUNCTION IN SUBJECTS WITH DIABETES Insofar, PGE-1 is the drug of choice in treating erectile dysfunction or impotence in subjects also suffering from diabetes mellitus. As mentioned above, clinical research shows that treating erectile dysfunction by PGE-1 injections can result in improvement of sexual functions in 39.8% of subjects. In contrast, protodioscin treatment, which mode of action is presumed to involve increasing the level of DHEA-S in the bloodstream, has been clinically shown to significantly improve sperm morphology and the acrosomal enzymatic reaction. The increase in sexual libido in these men could also be the result of improved endothelium cells, among improvements in other cellular tissues. In turn, this increase in sex drive and the increase in successful sexual intercourse have positive effects in the sense of well being and self esteem of the subjects in this study. Therefore, the combination of PGE-1 injection and oral administration of protodioscin in form of Tribulus extract, should have an excellent prospect as improved treatment for diabetes subjects also suffering from erectile dysfunction or impotence. Lastly, further clinical research on the beneficial effect of protodioscin on the improvement of the endothelium cells, as well as its effect on general cellular aging process, should offer insight to the biological mechanism of such actions.