treatment of male fertility disorders
Haidl1, Frank-Michael Köhn2, Wolf-Bernhard
of Dermatology, University of Bonn, Germany
Asian J Androl 2000 Jun; 2: 81-85
AbstractDrug treatment remains an active domain in the therapy of male fertility disorders. Although there are only a few conditions that allow causal treatment, rational approaches are possible in many cases. Best results are obtained in cases requiring an anti-inflammatory treatment and in patients with an impaired sperm transport. High-dosage administration of FSH is a promising new development, aimed particularly at improving the disturbed sperm structures. A careful diagnostic work-up with elucidation of the underlying disease is essential to achieve a successful therapy.
the help of intracytoplasmic sperm injection (ICSI), unintended childlessness
can now be treated even in
cases of severe male infertility, which were beyond help until a
few years ago. However, milder therapeutic options should be preferred
to this costly method. Therapeutic drug approaches, which is still a domain
in the treatment of male subfertility, may be quite rational. Although
in most patients normal fertility and pregnancy cannot be achieved in
a natural way, it appears reasonable to improve impaired fertility so
that less invasive methods of artificial insemination can be applied,
e.g., intrauterine insemination instead of in vitro fertilization
or ICSI using ejaculated spermatozoa rather than those obtained by testicular
great number of papers published on the effectiveness or non-effectiveness
of medical treatment should be viewed on the ground of these considerations.
Many studies are merely based on symptoms, such as oligoasthenozoospermia
or idiopathic infertility, and are therefore (irrespective of their results)
of low value. If a therapy results in a change from azoospermia to high-grade
oligozoospermia or improvement of sperm concentration by some million
spermatozoa, which may allow simple intrauterine insemination, this can
be considered a success,
even though statistically verified effectiveness of such a measure can
never be proven.
any treatment is initiated, it has to be clarified whether spermatogenesis
is affected (e.g., due to inflammation) and can be restored, or whether
the damage is irreparable (e.g., because of genetic disturbances exhibiting
a high percentage of malformed spermatozoa). Frequently there are combined
disorders, such as varicocele orchipathy and inflammatory diseases of
the testes and/or accessory glands,
which require diagnostic work-up of the individual causes so that proper
treatment can be performed. Thus, rational therapy is determined by the
basic disorder rather than by insufficient number, reduced motility or
abnormal shape of spermatozoa. Under this aspect, therapeutic recommendations
from the literature become even more limited than they have already been.
In the following article, current methods of treatment and the use of
new drugs are discussed.
2 Drug treatment
are used for the treatment of male adnexitis-as a monotherapy of prostatitis
according to sensitivity tests, otherwise: tetracyclines, 1.5-2 g/day, doxycyclin,
200 mg/day, erythromycin, 1.5-2 g/day, cotrimoxazol (sulfamethodyzol 400
mg, trimethoprim 80 mg), and also gyrase inhibitors (ofloxacin, norfloxacin, ciprofloxacin,
0.8-1 g/day) are given for 2-3 weeks - in combination with
an antiphlogistic drug in inflammatory epididymal diseases (see below).
inflammatory epididymal diseases where macrophages are involved, nonsteroidal antiphlogistic
therapy is recommended in addition to the antibiotic treatment, in order
to prevent local occlusions and the induction of local immunity phenomena.
The indication for additional antiphlogistic therapy is supported by studies
with experimentally induced epididymal Escherichia coli infections
in rats. After a few days of therapy, no pathogens could be identified,
but numerous leukocytes and macrophages were found. Furthermore,
nonsteroidal antiphlogistic therapy is indicated in patients with inflammatory
testicular damage. Barkay et al observed improved
sperm count and motility after administration of indomethacin and ketoprofen
for 60 days. The antiphlogistic drugs diclofenac, indomethacin and aspirin
are used for 3-6 weeks[4,5].
a possible modulator and mediator of spermatogenesis, kallikrein has been
used for more than a decade in patients with idiopathic oligoasthenozoospermia.
Unfortunately, there are no selection criteria, apart from the exclusion
of inflammation where kallikrein is ineffective and may even cause deterioration
of semen quality. After previous reports on its beneficial effects, two
double-blind studies failed
to demonstrate any positive results in patients with idiopathic oligoasthenozoospermia.
Therefore, patients who might benefit from kallikrein therapy remain to
be defined more clearly.
Mast cell blockers (ketotifen, tranilast)
a tricyclic benzocycloheptathiophene used for prevention and treatment
of allergic reactions of the respiratory tract and skin, has a stabilizing effect on the mast cell. Furthermore, ketotifen
blocks histamine (H1) receptors and inhibits the SRS-A (slow
reacting substance of anaphylaxis) as well as phosphodiesterase with increased
intracellular cAMP concentrations. In andrological indications, ius effect
is explained by inhibition of mast cells which are sometimes
increased in the testicular tissue of infertile men. The
daily dosage is 1 mg bid. An open study including 17 men with oligo- or
asthenozoospermia revealed its significantly positive effects on sperm
concentrations and motility, but not on pregnancy rates.
On the other hand, a placebo-controlled (non double-blind) study with
the mast cell blocker tranilast (300 mg/day for 3 months) in 50 men with
spermatozoa <5106/mL resulted in a pregnancy rate
of 28.6 % in the treatment group vs 0 % in the placebo group. Also, sperm
concentration and motility improved significantly.
salts are approved for treatment of zinc deficiency and a variety of non-andrological
diseases. Zinc hydrogen aspartate and zinc sulphate are used for andrological
indications. The effect of these
salts on spermatogenesis or cell functions is not clear. Zinc therapy
has been suggested for patients with testicular zinc deficiency caused
by increased exfoliation of spermatogenetic cells as well
as for those with secretory dysfunction of the prostate and seminal vesicles.
Marmar et al treated 11 patients with sperm concentrations
<60106/mL and decreased zinc concentrations in the seminal
plasma with 80 mg zinc sulphate tid for
at least 6 months. In this open, non-randomized study, a significant improvement
of total sperm count, motility and morphology was observed. The positive
effect on motility seems to be enhanced by combination of zinc sulphate
with an androgen. In another open, neither randomized nor
non-placebo-controlled study, a total of 101 infertile men with low seminal
plasma zinc concentrations were given 440 mg zinc sulphate daily for 2-24
months. Sperm motility was only improved in patients who had received
oral zinc after treatment of varicocele. Kynaston et
al observed a significant improvement of sperm motility
in 33 patients with idiopathic asthenozoospermia and/or oligozoospermia
after administration of 220
mg zinc bid for 3 months.
at a medium dosage (e.g., 40-60 mg methylprednisolone for 4-6 weeks) are
the therapy of choice in low-grade autoimmune orchitis, a clinical picture that
is determined by histological examination of tissue specimens. There
are various methods of treating antisperm antibodies; in most cases, short-time
administration of high doses of methylprednisolone has been recommended
(96 g per day for 7 days, 3
weeks prior to the calculated date of ovulation in the partner)[16,17].
However, other authors have questioned the effectiveness of steroids in
case of antisperm antibodies and have therefore recommended
in vitro fertilization. ICSI is considered to be
the method of choice.
in vivo and in vitro have shown that pentoxifylline, a methylxanthine
derivative, can increase the motility and number of spermatozoa.
The suggested mode of action is that pentoxifylline interferes with the
metabolism of cyclic AMP by inhibiting phosphodiesterase and thereby increasing
sperm cyclic AMP. The recommended oral dose is 400-600
mg tid for 3-6 months.
Alpha-sympathomimetics and anticholinergics
case of retrograde ejaculation or transport aspermia due to emission failure, e.g.,
as a result of retroperitoneal lymphadenectomy or diabetes mellitus, alpha-sympathomimetic
and anticholinergic therapy may be helpful; the following drugs can be
administered: midodrine, 5-15 mg iv, imipramine, 25-75 mg po, brompheniramine,
8 mg po three times a day. The duration of therapy is individually determined.
disorders due to hypogonadotropic hypogonadism are rarely observed by
the andrologist. In these cases, pulsatile administration of gonadotropin
releasing hormone (GnRH) has meanwhile been added to the well-established
substitution therapy with human gonadotropins or testosterone enanthate.
The following treatment schemes are used:
Human chorionic gonadotropin
2,500 IU HCG are administered im twice weekly for 4-6 weeks, thereafter
combination with 75-150 IU HMG im is given 2-3 times a week for 3-24 months.
Recently, therapy has been performed with pure and recombinant follicle
stimulating hormone (FSH) because of its higher specific activity. Its
action mechanism is identical to that of HMG. Acosta et al
have reported on the use of pure FSH in 24 men who failed to fertilize
in an IVF program (group 1) and 26 men with reduced ejaculate quality
(group 2). The patients received 150 IU pure FSH im 3 times a week for
at least 3 months. During this period, there were no significant
changes in the ejaculate quality; however, the average fertilization rate
in the FSH-treated group 1 increased from 2.2% to 54.4%, and in group
2 it was found to be 52.3%. These results implied effects of FSH therapy
on sperm functions. In accordance with Acosta et al,
Glander and Kratzsch did not observe
effects on sperm quality after 10 weeks therapy with pure FSH in 41 men with
idiopathic infertility. On the other hand, a significant increase in sperm concentration
and total motile sperm count was found in men who had shown lower FSH
secretion after injection of GnRH. Like urinary FSH, recombinant FSH in
combination with HCG seems to induce spermatogenesis in hypogonadotropic
deficiency is substituted by 250 mg testosterone enanthate im every 3-4
weeks or oral administration of 120-160 mg testosterone undecanoate daily.
Preparations for cutaneous application are also available nowadays. There
are several application techniques:
testosterone-coated membranes for scrotal application or, as an
alternative, testosterone patches which can also be applied outside
the genital skin region. In addition, a gel with 5-dihydrotestosterone is
available in the French market, which exerts its action as substitution
therapy of hypogonadism after extensive application to the integument.
Testosterone-containing membrane systems are affixed to the scrotal skin
because resorption at this site is about 40 times higher than e.g., on
the forearm. The skin should be clean, shaved and dry. The transdermal
system is left for 22-24 hours; peak serum testosterone levels being reached
within 2-4 hours. After the morning application, testosterone concentrations
achieved are similar
to the daily profile of physiological ones. Dihydrotestosterone levels
increase as testosterone in the scrotal
skin gets metabolized by 5-reductase.
Gonadotropin-releasing hormone (GnRH)
subcutaneous administration of approximately 50 ng GnRH per kg of body weight
every 2 hours has been recommended. Hyperprolactinemia,
which is extremely rare and may cause oligozoospermia, has been treated
by oral administration of 2.5-10 mg bromocriptine per day.
rationale for administering antiestrogens such as tamoxifen or clomiphene
is to indirectly stimulate
the secretion of follicle-stimulating hormone and luteinizing hormone
(LH) by blocking estrogen and testosterone receptors in the hypothalamus,
which results in increased release of GnRH. A direct effect of tamoxifen
in spermatogenesis by interfering wih testicular estrogen receptors has
also been discussed. The recommended dosage of tamoxifen
is 20 mg daily for 6-9 months. While some authors have questioned this
kind of treatment, others have achieved
good results after tamoxifen therapy, especially in combination with testosterone
undecanoate, at doses of 40 mg
tid. Tamoxifen should not be applied
in the presence of inflammatory symptoms. It has been suggested that determination
of serum inhibin B would serve as a better selection criterion than estimation
of FSH levels.
aromatase inhibitors, which block the conversion of testosterone into
estradiol and that of androstendione into estrone, have also been investigated.
The results of the available studies are controversial, demonstrating
either increased numbers of spermatozoa or no effect[21,34].
Meanwhile, new aromatase inhibitors are available. Preliminary
results ( Schlegel P, personal communication) seem promising and require
E (alpha-tocopherol) is a liposoluble vitamin, approved for treatment
of decreased vitality and
vitamin deficiency. In andrological indications, the action of vitamin
E is explained by a protective effect on lipid peroxidation in sperm membranes
through scavenging of free oxygen radicals. Suggested andrological
indications for vitamin E (daily dosage of 300-600 mg is suggested) are
asthenozoospermia and sperm dysfunction. Suleiman et al
have observed increased sperm
motility in a double-blind, randomized, placebo-controlled study in 87
men who received 100 mg vitamin E tid for 6 months. Furthermore, an open
study has demonstrated a positive effect on the fertilization rates in
an IVF program. Improved sperm function (sperm-zona pellucida
binding capacity) has been also achieved in a double-blind, placebo-controlled
crossover study in 30 healthy men who had increased concentrations of
oxygen radical species in the seminal plasma and were given daily doses
of 600 mg vitamin E for 3 months.
interferon alpha, reported case experience is limited to 4 patients who
had markedly higher sperm concentration and motility after injection of
interferon alpha (3 million units daily for 5 days every week for 8-12
weeks). Another open, neither randomized nor placebo-controlled
study demonstrated a positive effect of glutathione on sperm motility.
However, only 11 men were treated with this substance (600 mg daily for
2 months). The effect was thought to result from protective action against
damage by reactive oxygen species.
Schill WB. Established and new approaches in medical treatment of male
sterility (German). Fertilität 1986; 2: 7-17.
to: Prof. Dr. G. Haidl, Department of Dermatology, Sigmund-Freud-Str.
25, 53105 Bonn, Germany.