Note: Descriptions are shown in the official language in which they were submitted.
Administration of Growth Hormone (hGH) for Therapy of Sexual Functional
Disorders
This invention concerns the introduction of human growth hormone (hGH, GH) for
the
manufacture of medicaments for the treatment of sexual functional disorders in
both male
and female patients as well as the specific methods of treatment undertaken.
Symptoms indicating sexual functional disorders are, for example, lack or loss
of libido,
problems relating to orgasms, insufficient lubrication and erectile
dysfunction (ED). It could
be deduced from certain cases that the basic aetiologies leading to these
sexual functional
disorders were due to a number of different reasons. Apart from the cases of
mixed
aetiologies, vascular (arterial, venous), psychogenic, neurogenic,
medicamentous-induced
and cavernous sexual functional disorders are also differentiated.
Taking into consideration the nature of the underlying aetiologies, causal
therapy of the
sexual functional disorders is undertaken whenever possible. Up till now this
method of
therapy has only proved successful in the rare cases (e.g. by psychotherapy,
hormone
' treatment, a change-over of medication) so that the main methods of therapy
still remain
unspecific.
There are many different methods of therapy are available for males with ED
compared to
those available for females with sexual functional disorders. These include
oral, topical,
intracavernous, intraurethral and also a combination of drugs. These methods
do not
constitute a causal therapy, rather the aim is to achieve a direct or indirect
relaxation
(flaccidity) of the corpus cavernosum smooth musculature and the penile
arteries. Together
with an increase of blood circulation, penile erection is achieved.
Furthermore, the vacuum
pump, arterial shunt procedure, venous closure operations and penile
prosthesis
implantations are also methods used for therapy. Until the introduction of
sildenafil
(VIAGRA~), the most widely used form of therapy involved the administration of
intracavernous vasoactive substances. At the present time, sildenafil is used
as the so-called
"first line therapy" providing there are no known contraindications. The oral
phosphodiesterase type 5 inhibitor (PDES) does not provide a basis for causal
therapy. With
the inhibition of PDES, hydrolysis of cyclic guanosinmonophosphate (cGMP) of
an
intracellular second messenger is prohibited, resulting in relaxation of the
corpus
cavernosum smooth musculature. This effective mechanism is assumed beneficial
for the
increase of lubrication in women, however, recent studies have yet to prove
its effectivity.
The aim of this innovative breakthrough was to present a new therapy for both
males and
females suffering from sexual functional disorders.
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Surprisingly, it has been shown that the growth hormone (hGH) plays an
essential role in
sexual stimulation, as an enormous unexpected increase of this hormone was
seen to be
present at the onset of sexual stimulation.
The focal point of this breakthrough is therefore the use of hGH for the
manufacture of
medicaments for the treatment of sexual functional disorders in both males and
females with
e.g. lack or loss of libido, problems relating to orgasms, insufficient
lubrication and erectile
dysfunction and for the therapy of the aforesaid functional disorders.
A further issue is the use of hGH for the therapy of functional disorders in
synergic
combination with effective substances which result in GH stimulation, induce a
GH
analogous effect or promote IGF-I release.
The scientific results described are emphasized as follows:
Figure 1 shows the average values and standard deviations of the growth
hormone (hGH)
concentrations (ng/ml) in cavernous and peripheral blood samples taken from 35
healthy
probands during the four different phases of the penile erectile tissue
(flaccidity, tumescence,
rigidity and detumescence).
Figure 2 shows the average values and standard deviations of the growth
hormone (hGH)
concentrations (ng/ml) in the cavernous and peripheral blood samples during
the three
different penile phases (flaccidity, tumescence and detumescence) in 36
patients with
erectile dysfunction. Rigidity was not achieved due to disorder of patient.
The axis scale was
selected as in Figure 1 in order to demonstrate clearly the difference
(P<0.05).
Figure 3 shows the average values and standard deviations of the dose-
dependent decrease
in relaxation of 12 human corpus cavernosum strips after application of
recombinant hGH.
Figure 4 shows the average values and standard deviations of dose-dependent
increase of
cyclic guanosinmonophasphate (cGMP) of 3 human corpus cavernosum strips
respectively,
following incubation with recombinant hGH or sodium nitroprusside (SNP).
Incubation with
SNP was carried out using a concentration of 0.01 and 1 NMoI. For this reason,
no value for
SNP was achieved with 0.0001 NMoI.
In order to gain a better understanding of the physiology of a naturally
induced erection and
the pathophysiology of erectile dysfunction, a new method of investigation was
developed.
This involved detection of endogenous human neurotransmitters, neuromodulators
and
hormones which might have some connection with an erection or its sexual
function. These
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new methods of investigation aim to improve the diagnostics and therapy
(application of
endogenous substances and causal therapy) for those patients with sexual
functional
disorders.
Blood was taken simultaneously from the corpus cavernosum (cavernous) and the
cubital
vein (peripheral) in 35 healthy probands during the phases of flaccidity,
tumescence, rigidity
and detumescence. Audiovisual and tactile means were then provided to aid
sexual
stimulation (Figure 1 ). The procedure involving 36 patients with ED was
identical to that of
the healthy probands with the exception of blood withdrawal during the
rigidity phase, (this
penile erection phase cannot be achieved in patients with ED) (Figure 2). The
hGH
concentrations were determined with an immunoradiometric assay (IRMA). This
form of
investigation resulted in several new findings.
1. The highest increase of hGH concentration was found during tumescence,
namely the
point in time when sexual stimulation is at its peak.
2. The peripheral and cavernous hGH concentrations showed no significant
differences in
direct comparison with all penile phases. Peripheral blood withdrawal proved
sufficient.
3. When comparing the healthy probands with the patients, there were
significant
differences with regards to the hGH concentrations, in particular, a
significantly reduced
increase of the hGH concentration during the tumescence phase.
These data show for the first time the surprising causal connection of hGH
formed by the
hypophysis with sexual stimulation and the resulting penile erection. The
reduced expression
of hGH on sexual stimulation in patients is further proof for the significance
of this hormone,
the lack of which is connected with sexual functional disorders and erectile
dysfunction in this
study.
By means of extensive in vitro investigations using human corpus cavernosum
(CC) tissue
as well as the in vivo results described, important indications could be
deduced for the
possible physiological connections between hGH and penile erection.
1. Organ bath experiments (in vitro method to evaluate the relaxing properties
of
substances) with human CC were carried out to assess dose-dependent
relaxations
following application of hGH (Figure 3).
2. Incubation experiments (in vitro method to evaluate the content of cyclic
nucleotides in
tissues in response to drug exposition, in this case cGMP, after incubation
with various
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substances) with human CC were shown to have dose-dependent higher cGMP
concentrations after application of hGH than was the case after incubation
with sodium
nitroprusside (SNP), a classic NO donator (Figure 4).
Based on our human findings, it can be assumed that hGH plays a decisive role
in sexual
function (sexual stimulation), in particular, in penile erection. Furthermore,
it was shown that
the peripheral reaction of hGH induced an increase of cGMP, thereby
physiologically forming
a link between relaxation of CC with that of the ensuing erection. Due to the
anatomical
similarities in the structure of the penis and the clitoris and the
physiological conformities
regarding sexual stimulation (e.g. congestion of the genital organs mediated
by
neurotransmitter on relaxation of the smooth musculature), the described
reaction of hGH in
males must also apply to females too, since hGH is produced by the hypophysis
in both
sexes, therefore the same effect must also be evident in both sexes.
With reference to the effect of hGH, it is already known that hGH does not
focus on any
particular tissue and that the activity and metabolism (anabolic) is increased
in different
tissues in both men and women. The growth hormone stimulates, for example,
body growth
(substitution in insufficient hGH-caused hyposomia) and protein metabolism
(possible
indication in cachexia, severe burn injuries and also anabolic abuse). Under
the influence of
hGH, an insulin-like growth factor I (IGF-I) is formed mainly in the liver but
also in other
tissues. This polypeptide (IGF-I) plays a significant mediating role in the
process induced by
hGH (Merimee T.J. and Grant M.B.: Growth hormone and its disorders. In:
Principles and
Practice of Endocrinology and Metabolism. Edited by Becker, K.L.,
Philadelphia, J.B.
Lippincott Company, pp. 125-134, 1990).
The most recent findings in humans show that there is a systemic increase of
NO (nitric
oxide) and cGMP under a substitution of recombinant produced hGH (r-hGH) in
patients with
hGH deficiency (Roger R.H. et al.: Nitric oxide may mediate the hemodynamic
effects of
recombinant growth hormone in patients with acquired growth hormone
deficiency. J. Clin.
Invest. 98: 2706-2713, 1996). This NO-cGMP path presents a very important
positive
significance in achieving penile erection (Burnett A.L. et al.: Nitric oxide:
a physiologic
mediator or penile erection. Science 257: 905, 1993). Likewise, recent
findings derived from
animal experiments using rats were able to show that an increase of NOS
(nitric oxide
synthase)-containing nerves (generating NO) in CC and dorsal penile nerves
occurred under
substitution of hGH. This took place despite initiation of neurogenic damage
some weeks
before (Jung G.W. et al.: Growth hormone enhances regeneration of nitric oxide
synthase-
containing penile nerves after cavernous neurotomy in rats. J. Urol. 160: 1899-
1904, 1998).
The patent W098/42361 (Human erectile dysfunction and methods of treatment)
stems from
these results and describes the indication of hGH therapy for the prevention
and treatment of
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neurogenic erectile dysfunction of different aetiologies (condition following
extensive pelvic
operations or pelvic trauma, diabetes, alcoholism and aging process).
Our findings on human models show for the first time a positive causal
connection between
sexual stimulation, increase of hGH and penile erection. The reduced (often
totally lacking)
increase of hGH in patients with ED emphasizes the importance of this hormone.
The in vitro
data conclude that the NO-cGMP path is activated by hGH, leading to relaxation
of the CC,
thus resulting in penile erection.
The appropriate therapy for all patients (both sexes) with sexual functional
disorders includes
peripheral blood sample to determine the basal hGH concentration. This form of
therapy is
undertaken independent of the underlying aetiology(ies). Following this, a
further blood
sample is taken under sexual stimulation (audiovisual, tactile) in order to
detect the
stimulated hGH concentration. In cases of insufficient or no reaction at all
to sexual
stimulation (e.g. lubrication, penile erection) and inadequate increase of hGH
concentration,
a continuous, strictly controlled therapy with hGH should ensue for a certain
period of time
(e.g. 2 - 6 months).
Suitable pharmaceutical preparations for therapy include solid or liquid forms
of
administration for oral intake, such as tablets, capsules or emulsions,
parenteral forms of
administration for injection or non-invasive application or transdermal
topical systems, such
as plasters, creams, gels, lotions or transdermal films. The administered
amount for
successful therapy lies between 0.01 and 500 mg per dosage unit; recommended
is between
0.1 and 100 mg.
Improvement of therapy outcome can be achieved by administration of a
combination of
medicaments containing, besides hGH, a synergic combination of substances
which lead to
GH stimulation, induce a GH analogous effect or promote IGF-I release.
These substances do not have to be combined into one particular medication,
but can be
administered in separate suitable galenic preparations to be taken at the same
time or taken
separately according to the specific course of therapy. It is essential that
the specialist
instructs and informs the patient with regards to the suitable dosage or in
which combination
the medicaments should be taken, likewise which substance should be
administered to
ensure the best possible therapy outcome. Furthermore, it is permissible to
combine several
of the named substances to treat the individual patient accordingly.
The suitable substances to be used as a combination therapy in order to
achieve GH
stimulation are familiar to the specialist. For example, arginine, alpha 1 and
alpha 2-agonists,
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such as clonidine, norepinephrine or salbutamol, glucagon, pyridostigmine,
galanine, GH-
releasing hormone, NPY (neuropeptide Y) and dopamine agonists, such as
apomorphine,
quinpirole or cabergoline.
Suitable substances which induce a GH analogous effect include, for instance,
GHRP
(growth hormone, releasing hexapeptide, hexareline), GH releasing peptide 1,
2, 6 and non-
peptidergic agonists of growth hormone releasing peptide such as MK 0677, EP
51389 (2-
methylalanyl-2-methyl-D-tryptophyl-2-methyl-D-tryptophanamide), L 692429 (3-
amino-3-
methyl-N-[(3R)-2,3,4,5-tetrahydro-2-oxo-1-[(1 H-tetrazol-5-yl)[1,1 '-biphenyl]-
4-yl]methyl]-1 H-1-
benzazepine-3-yl]butanamide], or L 692585 (3-[[(2R)-2hydroxypropyl]amino]-3-
methyl-N-
[(3R)-2,3,4,5-tetrahydro-2-oxo-1-[[2'-(1 H-tetrazol-5-yl)[1,1 '-biphenyl]-4-
yl]methyl]-1 H-1-
benzazepine-3-yl]-butanamide).
Suitable substances which promote IGF-I release include, for example,
cannabinoide such
as e.g. HU-210 (3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-
dimethyl-6H-
dibenzo[b,d]pyran-9-methanol) or serotonine receptor agonists such as e.g. 8-
OH DPAT (8-
hydroxy-2-dipropylamino)tetraline), or SC 53116 (4-amino-5-chloro-N-[[(1
s,7aS)-hexahydro-
1 H-pyrrolizine-1-yl]methyl]-2-methoxy-benzamide).
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