Treatment of sexual dysfunction in diabetes mellitus

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)
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.
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.
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.
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.
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.
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.
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.