1 Introduction

With 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 biopsy.

 The 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.

Before 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

2.1 Antibiotics

Antibiotics 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^[1] - in combination with an antiphlogistic drug in inflammatory epididymal diseases (see below).

2.2 Antiphlogistics

In 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^[2]. 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^[3]. Furthermore, nonsteroidal antiphlogistic therapy is indicated in patients with inflammatory testicular damage. Barkay et al^[4] 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].

2.3 Kallikrein

As a possible modulator and mediator of spermatogenesis, kallikrein has been used for more than a decade in patients with idiopathic oligoasthenozoospermia^[6]. 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^[7]. Therefore, patients who might benefit from kallikrein therapy remain to be defined more clearly.

2.4 Mast cell blockers (ketotifen, tranilast)

Ketotifen, 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^[8]. 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^[8]. 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^[9].

2.5 Zinc salts

Zinc 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^[10]. Marmar et al^[11] 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^[12]. 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^[13]. Kynaston et al^[14] 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.

2.6 Corticosteroids

Corticosteroids 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^[15]. 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^[18] and have therefore recommended in vitro fertilization^[19]. ICSI is considered to be the method of choice^[20].

2.7 Pentoxifylline

Investigations in vivo and in vitro have shown that pentoxifylline, a methylxanthine derivative, can increase the motility and number of spermatozoa^[1]. The suggested mode of action is that pentoxifylline interferes with the metabolism of cyclic AMP by inhibiting phosphodiesterase and thereby increasing sperm cyclic AMP^[21]. The recommended oral dose is 400-600 mg tid for 3-6 months.

2.8 Alpha-sympathomimetics and anticholinergics

In 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^[22].

2.9 Hormone preparations

Fertility 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:

2.9.1 Human chorionic gonadotropin

Initially 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^[23]. 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^[24] 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^[24], Glander and Kratzsch^[25] 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 men^[26].

2.9.2 Testosterone

Testosterone deficiency is substituted by 250 mg testosterone enanthate im every 3-4 weeks or oral administration of 120-160 mg testosterone undecanoate daily^[23]. 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^[27].

2.9.3 Gonadotropin-releasing hormone (GnRH)

Pulsatile subcutaneous administration of approximately 50 ng GnRH per kg of body weight every 2 hours has been recommended^[28]. Hyperprolactinemia, which is extremely rare and may cause oligozoospermia, has been treated by oral administration of 2.5-10 mg bromocriptine per day^[29].

2.9.4 Antiestrogens

The 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^[30]. The recommended dosage of tamoxifen is 20 mg daily for 6-9 months. While some authors have questioned this kind of treatment^[31], others have achieved good results after tamoxifen therapy, especially in combination with testosterone undecanoate, at doses of 40 mg tid^[32]. 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^[33].

2.9.5 Aromatase inhibitors

Testosterone 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 further investigation.

2.10 Vitamin E

Vitamin 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^[35]. Suggested andrological indications for vitamin E (daily dosage of 300-600 mg is suggested) are asthenozoospermia and sperm dysfunction. Suleiman et al^[35] 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^[36]. 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^[37].

2.11 Other drugs

Concerning 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)^[38]. Another open, neither randomized nor placebo-controlled study demonstrated a positive effect of glutathione on sperm motility^[39]. 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.

2.12 Growth hormones

References