Per Olov Lundberg
Neurotransmitters
and effects of neurally active drugs
on sexual function and dysfunction
P O Lundberg MD, PhD,
Authorized clinical sexologist NACS
Professor, Department
of neuroscience. Neurology, Uppsala University, Uppsala, Sweden, Phone +46186115026,
+4618309397 (home), +46186115027 (fax), e-MAIL PO.Lundberg@neurologi.uu.se
Original contribution, November 2010.
Reproduced here by permission of the author.
Contents:
The WHO data base on adverse drug reactions (ADRs)
Antihypertensive drugs and impotence
Alpha-adrenergic mechanisms and priapism
Alfa-adrenergic mechanisms and ejaculation
Local erectile mechanisms
Phosphodiesterase inhibitors and sexual adverse reactions
Nsaid and corticosteroids
Antidepressive drugs
Neuroleptic drugs
Antiepileptic drugs
Drugs for treatment of Parkinson's disease
Antibiotics and antimycotics
Cytostatic drugs
Drugs for treatment of gastrointestinal disorders
Insulin and antidiabetic drugs
Hormoners and antihormones
References
Under the auspices of the
WHO an international collaboration in monitoring adverse drug reactions (ADRs)
was started. The prime intention was – and remains – to establish and maintain
an effective method of detecting ADRs not revealed during clinical trials. This
programme started 1968 and now includes 70 countries. The Swedish government
assumed operational responsibility for the WHO programme in 1978 and the
Uppsala Monitoring Centre for international Drug Monitoring was created in
Uppsala. The centre has a review panel of some 30 scientists representing
different specialities. I have been a member of this panel for some 20 year and
have thus had access to the data base during this period. I have on a regular
basis reviewed the data base for my particular interest, sexual adverse
reactions (ADRs). I want to thank the Centre for giving me access to the data
base and all national centres for their willingness to let me use data from
them. However, the conclusions given in this lecture are my own. Since we are
dealing with a living material, the number of reports is to-day 5 millions and
new data are included on a regular basis no exact figures for each drug will be
given.
Antihypertensive drugs is a group ot drugs that very
often are reported to give sexual side-effects or sexual adverse reactions
(sADRs).This is of course partly dependent upon the fact that they are so
widely used, especially in elderly people. However, the mean age for this group
of reports in the WHO data base is just over 50 years of age. Impotence is the
most common adverse reaction among these. It has been reported with almost all
types of antihypertensive drugs, such as betareceptor blockers, calcium channel
blockers, ACE-antagonists, angiotensin II-antagonists as well as diuretic
drugs. Aldosterone antagonists are the only exception. Here gynecomastia is
the dominating sADR. The aldosterone antagonist spironolactone and/or its
metabolites compete with androgens for intracellular receptors. This mechanism
may also explain why digitalis has similar sADRs.
The only common mechanism explaining why these
antihypertensive drugs are reported with impotence is that they are lowering
the blood pressure and in such away may give a decrease in blood flow to the
penis. Very often there are also in these patients arteriosclerotic changes in
the blood vessels in question, as well as diabetes and smoking, thus acting in
the same way on local blood flow. Decrease in sexual desire is the second most
common sADR from antihypertensive drugs. The relation between the two types of
sADRs is for almost all hypertensive drugs around 1:4. This indicates that
there is no specific pharmacological mechanism explaining the combination of
impotence and loss of libido. The mechanism behind is instead believed to be
the fact that when a man looses his ability to perform sexually, the desire
also goes done. The observation that there are almost no reports at all about
sexual dysfunction in women in the form of vulvo-vaginal dryness –
corresponding to the erection in the male - in women taking antihypertensive
drugs also supports the mentioned mechanisms behind the sADRs. In women,
decrease in blood flow in the genitalia does not seem play a significant role
for normal sexual function.
Priapism
is not an uncommon sADR but there are only a few antihypertensive drugs that are
actually causing priapism. Here the mechanism is more well-known. Besides the
nerve fibres initiating erection there are also sympathetic nerve fibres having
an inhibitory effect. Among the antihypertensive drugs causing priapism we have
the alpha-receptor blockers (prazosin, doxazosin, terazosin) but also a few
antidepressive drugs, trazodone in particular and some neurolepic compounds
(clozapine, risperidone, olanzapine). The drugs in question that also are
alpha-adrenergic blocking agents are the drugs most often giving priapism...
Intracavernous
injection of alpha-adrenergic antagonists (phenoxybenzamine and phentolamine)
have in fact been used to treat impotence. Alpha-adrenergic agonists
(pseudoephedrine, phenylpropanolamine and metaraminol) can instead be used to
counteract priapism. Yohimbine, an extract from the yohimbe three, an old
nature medicine. given orally against impotence is another example of an
alpha-adrenergic blocker. Priapism may also result from an overdose of
therapeutic drugs such as alprostadil, sildenafil, tadalafil or vardenafil.
A
few of the antihypertensive drugs among the alpha-2-receptorblockers and
ganglieblockers have also been reported to give ejaculation failure. This is
probably dependent upon their capacity to block seminal emission and also to
counteract the contractions of the internal urethral sphincter. The sphincter
paresis results in a retrograde ejaculation which means that the ejaculate
passes into the bladder. Certain alpha-adrenergic agonists given orally have
been used to treat retrograde ejaculations.
The most important erectile neurotransmitters are
dopamine D2 and D3. In the hypothalamus oxytocin,
vasopressin and the melanocortins, derived from the proopiomelanocortin polypeptide
are working together with the parasympathetic nervous system. When the nerve
impulses reach the vessels in the cavernous bodies the enzyme NO-synthase
catalysis the production of nitric oxide (NO) from l-arginine and oxygen in the
vessel muscle cells. NO activates another enzyme, guanylcyclase. This enzyme
accelerates the production of cGMP (cyclic guanosine monophosphate) from GTP
(guanosine triphosphate). This opens the calcium channels in the muscle cells
leading to an outflow of calcium. This gives a relaxation of the muscle cells.
Through this relaxation an increase in intracavernouse pressure is achieved.
The venous outflow from the cavernous bodies is further surprised through
compression of the subtunical venules against the firm tunica albuginea
resulting in an erection.
High levels of cAMP (cyclic adenosine monophosphat) are
also important erectogen factors. Other neurotransmitters, such as VIP
(vasoactive intestinal polypeptide) and PGE1 (prostaglandin E1)
stimulates the production of cAMP from ATP (adenosine triphosphate) which
enhances the erection.
The phosphodiesterase- 5 inhibitor sildenafil was from
the beginning developed for treatment of pulmonary hypertension. However, it
was soon discovered that the drug had and important sADR, it enhanced erection.
Nowadays, this is the main clinical indication for this and a number of similar
drugs.
The enzyme PDE5 (phosphodiesterase-5) degrades
cGMP. This gives a contraction of the muscles in the penile vessels and the
erection subsides. If the PDE5 is inhibited the level of cGMP-stays
high and the erection continues if there is enough stimulation of the
proerectile nerve paths from the brain and spinal cord.
The non-steroidal
anti-inflammatory drugs (NSAID) have a series of important effects on the
cells. There is a number of reports of impotence in combination with treatment
with these drugs. The most probable mechanism seems to be antagonistic action
against prostaglandins. Prostaglandins have an important function in the
erection mechanism (see above). They are relaxing the muscles in the blood
vessels in the cavernous bodies in penis to make it possible for these cavernous
bodies to fill with blood.. Intracavernous injection of prostaglandin PGE 1 is
one important way to treat impotence.
The corticosteroids for topical or general use may give
dyspareunia and perianal pains as sADR. Systemic use may cause dyspareunia and
perianal pain probably through decreased local resistance against infections...
Antidepressive
drugs have rather complex mechanisms of action and are thus important for many
different systems in the brain. This group of drugs have for many years being
the group that counts for the highest number of all sADRs taken together. Since
they have very different pharmacological profiles their effects on sexual
functions are very different.
Nowadays
the selective serotonin reuptake inhibitors (SSRI) are most often used.
Belonging to this group are fluoxetine, sertraline, paroxetine, citalopram and
fluvoxamine. The most important and characteristic sADR for this group is
orgasmic problems in both sexes and ejaculatory failure in men. Almost as many
cases of loss of sexual desire have been registered in the data base and
impotence is also of high frequency. Interestingly there are also a large
number of reports about increase in libido and also priapism. In women is
galactorrhoea also common. The drugs in the SSRI group have very similar sADR
profiles. This indicates a common mechanism, an antiserotonin effect in the
cerebral centres for sexual desire and orgasm. The different drugs within the
group have varying number of reports. However, it is not possible to draw any
conclusions about the relative risk fro sADR since the actual number of
patients taking the drug in question is not known
Quite an other sADR profile can be observed for the
non-selective monoamine reuptake inhibitors such as amitryptiline, nortriptyline
lofepramine, desipramine and maprotiline. Impotence is here the most often
reported problem. Orgasmic problems and ejaculatory failure is reported with
one of these drugs, clomipramine. This drug has also SSRI-properties
Trazodon and nefazodon belongs to a further group of
antidepressive drugs Here the typical sADR is priapism. With trazodon priapism
is reported 10 times more often as impotence. This lead the use of trazodon in
the treatment of impotence during a period in the era before the
phosphodiesterase inhibitors.
Some further antidepressive drugs, such as mirtazapin,
moclobemid and mianserin have quite different pharmacological properties, So
far, these drugs have not so often be reported in connections with sADRs.
The observation that the SSRI drugs can give ejaculatory
failure have lead to the idea to use such drugs in the treatment of precocious
ejaculation. Now a particular SSRI drug (dapoxetine hydrochloride) have been
introduced. This drug gives vasovagal syncope as an ADR.
Persistent genital arousal disorder (PGAD) and persistent
sexual arousal syndrome (PSAS) are one or probably several different sexual
hyperfunctions in women. They have been described in several hundred patients.
There is a kind of physiological sexual arousal persisting for longer periods,
days up to months. The phenomena are not related to increased sexual desire and
do not disappear after orgasm. It may result in the women having many, up to a
hundred orgasms per day without reaching sexual satisfaction. The problem may
at first appear as agreeable but soon lead to suffering and frustration. The
mechanisms behind is not known but the fact that most of the women have
suffered from depressions and have taken SSRI-preparations has lead to the
hypothesis that the syndrome is caused by disturbed cerebral serotonin
metabolism.
It is quite obvious that serotonin plays an important
role in the regulation of sexual function. Why this regulation sometimes is is
going in one, let us call it positive direction, and sometimes is going in the
opposite, let us call it negative direction is not known. One explanation may
be the following. Two of the most studied molecules involved in regulating the
levels of serotonin are the serotonin transporter (5HTT) which transports
serotonin from the extracellular space into the cells and monoamino oxidase A
(MAOA), the key enzyme responsible for degrading serotonin the genes encoding
these proteins harbour genetic polymorphism that may affect the transcriptional
activity. This might also explain the difference in women compared to men.
Ordinary use of benzodiazepines and most anxiolytics is
rarely reported to give sADRS. However, abuse of these drugs may result in
severe problems in sexual behaviour. Benzodiazepines have been used in
treatment of decrease of sexual interest. Buspirone, an anxiolytic drug how is
a serotonin antagonist with serotoninagonistic effect; have in animal
experiments showed increase in sexual behaviour. In a few cases also positive
effects on sexual fucntions has been reported.
Neuroleptic
drugs can give serious sADRS. The phenothiazines, the largest group, give
impotence or priapism, a decrease or increase in sexual desire and rather often
also problems with ejaculation. Retarded ejaculation or anejaculation is common.
However, spontaneous ejaculations and/or painful ejaculations may also occur.
Priapism is more common than impotence. The profile priapism and retarded
ejaculation probably is explained by the fact that some of the phenothiaziens
have alpha-adrenergic antagonists (see above).
Most
reports of ejaculatory failure come from thioridazin. Thus, for that reason
this drug was used to treat precocious ejaculations in the era before the
SSRIs. However, there does not seem to be any reports of anorgamia in women
taking phenothiazines. A decrease in sexual desire may be explained by the fact
that many of these drugs also are dopamineantagonists and giving
hyperprolactinemia. If the drug in question has both dopamineantagonistic and
serotoninantagonistic effects the problems are more difficult to explain.
The new types of neuroleptics have other sADR profiles.
Some examples: Haloperidol may give galactorrhoéa and amenorrhoéa in women and
impotence or priapism in men. Clozapine may give problems with ejaculation but
also priapism and in a few cases impotence in men. Olanzapine does not seem to
cause problems with ejaculation but instead priapism. Sulpiride causes
amenorrhoéa and especially galactorrhoéa. Risperidone gives often galactorrhoéa
and amenorrhoéa in women and ejaculatory problems and impotence or priapism in
men It should be recognised that in schizophrenia and paranoid psychoses,
which are the principal clinical indications for these type of drugs,
disturbances of sexual behaviour and dysfunctions are very common in it self.
Patients
with focal epilepsy from the temporal lobe do often suffer from impotence and
decrease in sexual desire interictally. Priapism may occur. This results
probably from the brain damage in itself. Such problems can be enhanced by
certain antiepileptic drugs, phenytoin, carbamazepine and valproat in
particular. Modern antiepileptic drugs can be tried instead to avoid these
problems.
Many antiepileptic drugs have hormonal effects such as
galactorrhoea, amenorrhoea, gynecomastia and hypertrichosis. Some antiepileptic
drugs may interact with the anticonceptive drugs because they increases the
protein binding of both synthetic and natural steroids.
There
are many observations indicating that dopamine is a transmitter in the nerve
tracts who are active where an increase in sexual desire is achieved.
Dopaminergic drugs (L-dopa, bromocriptine, pergolid and the MAO-B-inhibitor
selegilin) may give increase in sexual desire as a sADR. These drugs constitute
the only group of drugs where increase in sexual desire is reported more often
than decrease in sexual desire. Observations of this type are particularly
common among parkinsonian patients. The effects is hardly to be described as
hypersexuality, but instead more as a normalisation of the sexual desire in the
elderly Parkinsonian patient. He so to say recovers some of his young capacity.
However, this may cause problems if the treatment results are not so good as
regards the movement disorder in it self. Apomorfine, which is a short-acting
dopamine agonist is registered for treatment of
impotence. Quinelorane, a selective D2-agonist, have been used to treat
decrease in sexual desire. In a large study of the dopamine transporter gene
(DAT 1) in patients with premature ejaculation has shown an association between
polymorphism in this gene and the complaint. In animal studies it has been
shown that the neuronal activity in the paraventricular nucleus in the
hypothalamus stimulated by apomorphine administration varies with the oestrus
cycle. Thus, the effect of a pharmaceutical drug on sexual function can be
influenced both by internal hormonal variations and genetic polymorphisms.
It
is very rare that sexual problems are reported in patients treated with
antibiotics, one exception is tetracyclines and some other broad spectrum
antibiotics that may destroy the normal flora in the vagina/vulva and under the
fore-skin. This may lead to growth of Candida albicans and other fungi
resulting in dyspareunia.
Also the antimycotic drugs may, irrespective of the fact
that they may have good effects on the infection give local irritation and
pruritus. It is of course difficult to diagnose what are symptoms from the
original infection or the result of fungal growth or ADRs from the drugs in
question. The fact that the frequency of such reported observation varies very
much among different drugs may indicate that the symptoms results from the dugs
in themselves in a certain situation. Thus, miconazole represents 90 % of all
local irritations in the genitalia of treated women and all the other drugs
together only for the other 10%. This may depend on a local effect on the
sensory endorgans in the external genitalia.
There are rather few
reports were cytostatic agenst are suspected to give sADRs- Probably this is
an example of under reporting since we know that such treatment often
suppresses gonad hormone production. If this in itself is not the reason for
the treatment, the sADRs can be counteracted with hormone substitution. Thus
cytostatic drugs may give impotence and gynecomastia in men and amenorrhoea in
women. Gynekomastia sometimes is interpreted in such a way that the man
believes himself to be changed into women. Hence it is important to inform the
male patients in forehand. Cytostatic drugs may also in rare cases give rise
to a polyneuropathy which can result in impotence.
The
most important nerves giving erections, nn. erigentes, belong to the
parasympathetic nervous system. Thus, it would be expected that anticholinergic
drugs could case impotence. However, this is not the fact. In acute human
experiments it has been shown that parenteral atropine does not block erection.
There is a very weak effect. However, one particular cholinergic compound,
bethanecol, has been tried against impotence that has started during
treatment with tricyclic antidepressant drugs. These drugs have anticholinergic
properties.
The histamine 2-receptor antagonists (cimetidine,
ranitidine, famotidine and nizatidine) are a group of drugs where impotence
often has been reported as well as decrease in sexual desire. These drugs can
also give gynecomastia in men and amenorrhoea and galactorrhoea in women.
Cimetidine, the original drug, gives gynecomastia 10 times more often than
decrease in libido and four times more often impotence than decrease in libido.
Decrease in sexual desire has thus a relatively low incidence and orgasm
problems are seldom reported. One probable mechanism is that these drugs bind
to androgen receptors.
Other antihistamines (cetirizine. terfenadine.
loratadine) taken against allergic problems have only been reported to give
impotence in a few patients. However, one should observe that these types of
drugs are usually not taken contiguously...
Proton pump inhibitors have about the same profile as the
histamin-2-receptor antagonists as regards sADR. However, it is not possible to
compare the two groups because the latter group has been on the market for many
more years. Acid binding drugs are rarely reported to have given sADRS.
Impotence is one of
the most common complications of diabetes mellitus, irrespective of type. About
every second man with diabetes type II has problems with the erection and every
fifth woman has problems with lubrication and /or orgasm. However, there are
few reports of sADR in patients taking insulin or antidiabetic drugs.
The nerve
cells contains enzymes which can metabolize hormones e g. testosterone testradiol
or 5a-reduced
metabolites. The synthesis of sex steroid does not only take part in the gonads
and suprarenal glands but also in the brain, irrespective of the production
from other parts of the body. These steroids are called neurosteroider in
analogy with the neuropeptides. These hormones affects neurotransmission in two
different ways.
1. They can function within nucleus of the
cell through induction of the genome. This lead to the production of substances
such as enzymes, receptors, structure proteins and neuropeptides. This is a
slow process.
2. They may act on receptors in the cellmembrane
which has a more direct and rapid effect.
Male
hypogonadism is most often caused by a decrease of testosterone. If the blood
levels of free testosterone are significantly lowered this will result in loss
of sexual desire. This is easily corrected by administration of testosterone.
Even men with normal serum testosterone values may get an increase of sexual
desire when they for other reasons are taking testosterone or anabolic
steroids. Thus, illegal use of such steroids may contribute to sexual behaviour
problems such as aggressively. Through the hypothalamo-pituitary negative feed
back mechanisms administration of high doses of androgens suppresses the normal
production of testosterone in the body. Thus, the end result in men abusing
androgens may be decrease in sexual desire, impotence and gynecomastia.
Women, especially postmenopausal, may get an increase in
sexual desire when taking testosterone or DHEA. However, this can not be used
as a treatment in fertile women because of the risk of masculinization of a
foetus. When its has been given on the indication of decrease in sexual desire,
the positive effects often subsides, probably because of the negative
hypothalamo-pituitary feed-back mechanism mentioned above. Anticonceptive pills
based on an estrogen/gestagen combination or gestagenes are rather often
reported to gives decrease in sexual desire as a sADR. Gestagens in high doses
may give amenorrhoéa, galactorrhoéa and hypertricosis.
Antiandrogen drugs such as cyproteronacetate or flutamide
as well as estrogener given to men result in decrease of sexual desire and
impotence. This may be a disturbing sADR in the treatment of for example
prostatic carcinoma but can be used in the treatment of sexual offenders.
Barker
JC, Harris SL, Dyer JE. Experiences of gamma hydroxybutyrate (GHB)
ingestion: a focus group study. J Psychoactive Drugs, 2007;39:115–29.
Buffum J. Prescription drugs and sexual function.
Psychiatr Med, 1992;10:181–98.
Buffum J, Moser C, Smith, D. Street drugs and sexual function.
In: Sitsen JMA, Money J, Musaph H. (eds.). Handbook of Sexology: the
pharmacology and endocrinology of sexual function V. 6. Amsterdam: Elsevier
Science Ltd. 1988 p. 462–77.
Csoka AB, Bahrick A, Mehtonen OP. Persistent sexual
dysfunction after discontinuation of selective serotonin reuptake inhibitors. J Sex Med,
2008;5:227–33.
Diamond
LE, Earle DC, Heiman JR, et al. An effect on the subjective sexual response
in premenopausal women with sexual arousal disorders by bremelanotide (PT-141),
a melanocortin receptor angonist. J Sex Med, 2006; 3:628–38
Eriksson T. Anti-androgenic treatment of
obsessive-compulsive disorder: an open-label clinical trial of the long-acting
gonadotropin-releasing hormone analogue triptorelin. Int Clin Psychopharmacol,
2007;22:57–61.
Griffits J, Lovick T. Withdrawal from progesterone
increases expression of alpha4, beta1, and delta GABA(A) receptor subunits in
neurons in the periaqueductal gray matter in female Wistar rats. J Comp Neurol,
2005;486:89–97.
Hines, M. (2008). Early androgen influences on human
neural and behavioural development Early Hum Dev, 2008;84:805–7.
Kennedy SH, Eisfeld BS, Dickens SE, Bacchiochi JR,
Bagby, RM. Antidepressant-induced sexual dysfunction during treatment with
moclobemide, paroxetine, sertraline and venlafaxine. J Clin Psychiatry,2006;
61:276–81.
Leiblum
S, Seehuus M, Goldmeier D, Brown C. Psychologial, medical, and
pharmacological correlates of persistent genital arousal disorder. J Sex Med,
2007;4:1358–66.
Lundberg PO. Priapism. A review. Scand J Sexol, 2000;3:13–24.
Lundberg PO, Biriell
C. Sexual dysfucntion as a suspected drugs reaction reported to the WHO
Collaborating Centre for International Drug Monitoring. Thèrapie
1993;48:457-459.
Lundberg PO, Biriell C. Sexual dysfunction as a
suspected adverse reaction to antidepressant drugs. Scand J Sexol,
1998;1:97–105.
Lundberg PO. Neurological disorders: female
neurosexology. In: Goldstein I, Meston CM, Davis SR, Traish AM (eds.) Women’s
sexual function and dysfunction: study, diagnosis and treatment. London: Taylor
& Frances. 2006, p. 650–7.
Lundberg PO, Osterman
PO. The benign and malignant form of orgasmic cephalalgia. Headache
1974;13:181-187.
Nordqvist
N, Oreland L. Serotonin, genetic variability, behaviour, and psychiatric
disorders. Upsala J Med Sci. 2010;115:2-10.
Park
K, Han HJ, Kim SW, et al. Expression of aquaporin water channels in rat vagina:
potential role in vaginal lubrication. J Sex Med, 2008;5:77–82.
Peeters M, Giuliano F. Central neurophysiology and
dopaminergic control of ejaculation. Neurosci Biobehav Rev,2008; 32:438–53.
Richards
N, Wayman C, Allers K. Neuronal activity in the hypothalamic paraventrcilar
nucleus varies across the estrus cycle in anethetized female rats. Effects of
dopamine receptor agonism. J Sex Med 2010;7:104-1115.
Sabol
SZ, Hu S, Hamer D. A functional polymorphism in the monoamino oxidase A gene
promotor. Hum Genet 1998;103:273-279.
Santilla
P, Jern P, Westberg L et al. The dopamine transporter gene (DAT1) polymorphism
is associated with premature ejaculation. J Sex Med 2010 Febr 5
Sitsen JMA. Prescription drugs and sexual function. In:
Sitsen JMA, Money J, Musaph H. (eds.). Handbook of Sexology: the pharmacology
and endocrinology of sexual function V. 6. Amsterdam: Elsevier Science Ltd.
1988 p425–61.
Sjöberg
RL, Nilsson KW, Nordqvist N et al Development of depression:sex and the
interaction between the environment and a promotor polymorphism of the
serotonin transporter gene. Int J Neuropsychopharmacol 2006;89:443.449
Taylor MJ, Rudkin L, Hawtorn K. Strategies for managing
antidepressant-induced sexual dysfunction: Systematic review of randomised
controlled trials. J
Affect Disorder,2005; 88:241–54.
Uvnäs-Moberg K, Arn I, Magnusson D. The
psychobiology of emotion: the role of the oxytocinergic system. Int J Behav
Med, 2005;12: 59-65.
Waldinger
MD, Zwinderman AH. Olivier B. Antidepressants and ejaculation: a
double-blind randomized, placebo-controlled, fixed-dose study with paroxetine,
sertraline, and nefazodone. J Clin Psychopharmacol, 2001;21:293–7.