Treatment of sexual dysfunction
in diabetes mellitus subjects using orally administered protodioscin
and injection of vasoactive compounds
Academic Hospital Dr. Soetomo, Airlangga University, Surabaya, Indonesia
in Seminar of Erectile Dysfunction of Diabetes in Bandung, Indonesia
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
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 noninsulin-dependent (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.