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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, aswell 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
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.
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