Hormonal male contraception in men with normal and subnormal semen parameters.

Hormonal male contraception based on testosterone alone or on a combination of testosterone with a gestagen has been shown to suppress spermatogenesis effectively and to be fully reversible. However, clinical studies to date have only included volunteers with so-called 'normal' semen values by WHO standards. As a male contraceptive should be available to all interested men regardless of their semen parameters, we investigated how volunteers with subnormal semen parameters would respond to hormonal male contraception. During a 34-week treatment phase, the volunteers received injections of 1000 mg testosterone undecanoate in weeks 0, 6, 14 and 24. This was followed by a 24-week recovery and follow-up period. As it was not known whether men with subnormal semen parameters would recover to starting levels, cryopreservation of semen was offered to all subnormal volunteers. Twenty-three men with normal semen parameters and 18 with sperm counts below 20 million completed the trial. The normal volunteers showed the expected response with 17 suppressing sperm counts below 1 million/ejaculate (13 showing azoospermia) and six not-suppressing below 1 million sperm/ejaculate. By the end of the recovery period, all sperm counts had returned to the range of starting values. The subnormal group showed a similar pattern with 13 of 18 (= 72%) men suppressing below 1 million/ejaculate (8/18 = 44% showing azoospermia) and the remaining 5 of 18 (= 28%) not-suppressing sperm counts below 1 million/ejaculate. All sperm counts returned to the starting range. The study shows that in Caucasian men with normal sperm counts as well as in men with subnormal sperm counts, testosterone alone can produce azoospermia in about half and suppression below one million in about two-thirds of the volunteers. The same proportion of men in both groups appears to require an additional gestagen for full contraceptive protection. Most importantly, regarding suppressibility and reversibility, volunteers with normal and subnormal sperm counts display the same pattern.

New aspects on the pharmacokinetics of mitoxantrone and its two major metabolites.

In spite of its broad clinical application in the treatment of malignant disorders, the pharmacokinetics of mitoxantrone are still not fully understood and warrant further investigation. Information is also limited about interindividual differences in the plasma AUC infinity (area-under-the-curve concentration to time infinity) and renal elimination of mitoxantrone and its main metabolites, mono- and dicarboxylic acid. In the present study, the plasma concentration of mitoxantrone was measured by HPLC during 120 h after the end of a 30-min infusion of 10 mg/m2 in 18 patients undergoing combination therapy with mitoxantrone and high-dose cytosine arabinoside for acute myeloid leukemia. Plasma kinetics and renal elimination of mono- and dicarboxylic acid were analyzed in addition in eight of these patients, and in five cases with chronic lymphocytic leukemia receiving a 30-min infusion of 5 mg/m2 mitoxantrone weekly for 3 consecutive weeks. Fitting the results to a three compartment model, a substantial interindividual variation was observed for plasma and urine pharmacokinetics. Plasma AUC infinity for mitoxantrone differed approximately 13-fold between individual patients and varied between 80-1030 ngh/ml. The corresponding values for mono- and dicarboxylic acid ranged from 23-147 ngh/ml and 51-471 ngh/ml, respectively. The median terminal half-life for mitoxantrone was similar to that of the mono- and dicarboxylic acid and was 75 h. Cumulative renal elimination ranged from 670-1950 micrograms for mitoxantrone, from 366-852 micrograms for monocarboxylic acid, and from 792-3420 micrograms for dicarboxylic acid. Renal clearance of mitoxantrone reached a median level of 69 ml/min and for the total plasma clearance a median of 1136 ml/min was found. The corresponding values for the mono- and dicarboxymetabolites were 57 and 67 ml/min. In contrast to the great interindividual differences in pharmacokinetic results, a low intraindividual variability was observed upon repeated determinations of renal elimination of mitoxantrone and its metabolites at weekly intervals in five patients. These data provide new insights into the pharmacokinetic of mitoxantrone and its main metabolites revealing substantial differences in drug metabolism and elimination between individual patients. Further studies are needed to explore the potential impact on response and/or toxicity and the requirement of a pharmacokinetic directed adjustment of drug dosage in clinical trials.

Intramuscular testosterone undecanoate and norethisterone enanthate in a clinical trial for male contraception.

Recent trials for hormonal male contraception are based on gestagens or GnRH antagonists combined with oral or injectable testosterone substitution. However, the efficacy of most trials remained disappointing. Norethisterone enanthate (NETE) has been used as a long-acting injectable female contraceptive and has shown sustained suppression of spermatogenesis in male monkeys and prolonged suppression of gonadotropins in men. This study was designed to prove the efficacy of the long-acting testosterone undecanoate ester (TU) alone or in combination with NETE in a phase II clinical trial. Fourteen healthy men received injections of 1000 mg TU in combination with injections of 200 mg NETE every 6 weeks over a period of 24 weeks, followed by a control period of 28 weeks. Another 14 volunteers received TU alone. During the study semen variables, reproductive hormones, clinical chemistry and lipid parameters, well-being, and sexual function were monitored. Scrotal content and prostates were checked sonographically. During the entire treatment period mean testosterone serum concentrations remained within the normal limits. Marked suppression of gonadotropins in both treatment groups resulted in azoospermia in 7 of 14 and 13 of 14 volunteers and in oligozoospermia in 7 of 14 and 1 of 14 in the groups given TU only or TU/NETE, respectively. However, the highest azoospermia rate in the TU/NETE group was achieved 8 weeks after the end of the treatment period, and 1 volunteer with very high initial sperm counts (mean, 190 million/mL at baseline) remained oligozoospermic (10.2 million/mL). From week 20 to week 24 there was a significant, fully reversible maximum weight gain of 3.7 kg, on the average, in the NETE group. In the NETE and TU alone groups there were significant 26.6% and 11.5% maximum decreases in high density lipoprotein cholesterol compared with baseline values during the treatment period. A significant elevation of low density lipoprotein and a decrease in lipoprotein(a) were detected in the TU/NETE group. In conclusion, combination treatment with NETE showed suppression of spermatogenesis comparable with results using testosterone esters in combination with GnRH antagonists or cyproterone acetate, but had more favorable injection intervals and better efficacy. Because of its long-lasting, profound suppression of spermatogenesis and the absence of serious side-effects, the combination of TU and NETE can be considered a first choice for further studies of hormonal male contraception.

Inverse correlation between sperm concentration and number of androgen receptor CAG repeats in normal men.

Androgens are essential for the maintenance of normal spermatogenesis. Androgen action is mediated by the androgen receptor (AR), which in the testis is expressed by Leydig, peritubular, and Sertoli cells. The fact that sperm numbers range from 20 up to 300 million/mL in normal men without any indication of changed endocrine parameters led us to assume that genetic variability of transduction of androgen signaling could be important. We therefore compared the variable number of CAG repeats in the AR with sperm concentrations in men with normal ejaculate parameters (62 fathers and 69 volunteers participating in clinical trials). In multivariate analysis CAG repeat length did not differ between the volunteers (19.4 +/- 3.1) and the fathers (20.6 +/- 3.0), but was significantly correlated to sperm concentrations with a coefficient of -0.25. When compared with a group of infertile men with (n = 14) or without (n = 30) a family history of infertility, no such correlation was found. These results indicate that men with short CAG repeats have the highest sperm output within the normal fertile population. Polymorphisms of the AR contribute to the efficiency of spermatogenesis in normal men, but do not play a predominant role in male infertility.

Mutational analysis of the follicle-stimulating hormone (FSH) receptor in normal and infertile men: identification and characterization of two discrete FSH receptor isoforms.

In a search for pathophysiological causes of idiopathic male infertility we investigated the occurrence of mutations of the FSH receptor in 48 men with this disorder. The entire FSH receptor gene was analyzed by single stranded conformation polymorphism analysis (SSCP). A heterozygous point mutation without functional consequences, exchanging Val to Ala in codon 341, was found in one patient. SSCP analysis led to the identification of 2 polymorphisms in exon 10 associated in 2 discrete FSH receptor allelic variants, i.e. Thr307-Asn680 and Ala307-Ser680. The frequency and distribution of the two allelic variants was further analyzed in 86 proven fathers and 75 infertile men by SSCP (codon 307) and restriction fragment length polymorphism (codon 680). The 2 receptor isoforms showed similar Mendelian distribution in proven fathers and in infertile men. Serum FSH, inhibin B, and combined testicular volume did not differ between subjects with different receptor isoforms. Binding studies in transiently transfected COS-7 cells showed similar binding affinity for the two receptor variants. Moreover, the Ala307-Ser680 and the Thr307-Asn680 FSH receptors responded in vitro to FSH with comparable cAMP production. These data suggest that different isoforms of the FSH receptor with similar functional properties exist in normal and infertile men. We conclude that mutations of the FSH receptor or the FSH receptor genotype do not play a pathogenic role in male idiopathic infertility. The possibility that different FSH isoforms might interact differently with the 2 receptor variants remains to be investigated.

Clinical trial of transdermal testosterone and oral levonorgestrel for male contraception.

Approaches to hormonal male contraception are predominantly based on injectable testosterone (T) application. As most users would prefer an injection-independent modality, this study was designed to develop a self-applicable hormonal male contraceptive regimen by combining transdermal T with an oral gestagen. Eleven healthy men (23-40 yr old) were treated with oral levonorgestrel and transdermal T for 24 weeks. T was applied daily as a transdermal patch to be worn on the trunk. Levonorgestrel was taken orally at a dose of 250 microg daily up to week 12, followed by 500 microg to week 24 in those volunteers who had not become azoospermic by that time. Within 24 weeks, 2 of 11 volunteers had become azoospermic, and 3 of 11 showed sperm concentrations below 3 million/mL. The sperm concentrations of the remaining volunteers declined, but failed to reach the limit considered compatible with contraception by WHO. Treatment resulted in suppression of LH, FSH, and sex hormone-binding globulin, whereby the volunteers with lower sperm concentrations showed more pronounced suppression than the others. Mean T concentrations remained within the lower limit of normal and on occasions were below this level. There were no complaints of hypoandrogenism. Although mean levels of low density lipoprotein cholesterol, apolipoprotein B, as well as basal and postprandial insulin increased, high density lipoprotein cholesterol and apolipoprotein A-I decreased during the treatment phase. Changes in lipid parameters were normalized within 3 weeks after cessation of medication. Although only 5 of 11 volunteers reached the target sperm counts (<3 million/mL), the study shows that a self-applicable hormonal male contraceptive could be developed.

Gonadal protection from radiation by GnRH antagonist or recombinant human FSH: a controlled trial in a male nonhuman primate (Macaca fascicularis).

Chemotherapy and radiation often damage spermatogenesis irreversibly in oncological patients and various approaches to gonadal protection have been tested with equivocal results. In rats, hormonal protection of spermatogenesis can be achieved by blocking gonadotropin secretion. However, whether the same mechanisms can effect gonadal protection in primates remains questionable. To clarify this Issue we conducted a placebo-controlled trial in a preclinical animal model using macaques (Macaca fascicularis). Twenty adult male monkeys (five in each group) were randomized to receive either recombinant human FSH, GnRH antagonist or saline injections (two groups) for 36 days. On day 29 all groups except one saline-treated control group were exposed to a single testicular irradiation of 4 Gy. Every 2 weeks before, during and after the treatment, ejaculates, body weight, testicular Volume and hormones were analyzed until day 539. In addition, repeated testicular biopsies were performed. Testicular Volume and inhibin B decreased significantly in all irradiated groups compared with baseline and with the non-irradiated control group, followed by a gradual recovery of these parameters, which was, especially at the earlier time points, significantly better in the FSH-treated group compared with both other irradiated groups. Irradiation caused a drastic decrease of sperm parameters in all groups, followed by a partial recovery of sperm parameters, which was significantly slower in the early phases of recovery in the GnRH antagonist group compared with the vehicle group. Testicular histology showed a significant depletion on study day 261 in all irradiated animals. In conclusion, in clear contrast to rodent studies, GnRH antagonist treatment did not provide gonadal protection in this primate model. FSH treatment resulted in slightly better recovery of spermatogenesis, which appears to be of no or only little clinical relevance.

Is inhibin B a pharmacodynamic parameter for FSH in normal men?

OBJECTIVE: This study aims to investigate the pharmacodynamic effect of FSH on inhibin B serum levels in normal men in order to elucidate the physiological regulation of inhibin B secretion in more detail. DESIGN AND METHODS: Injections of 3000 IU recombinant, human FSH (rhFSH) were followed by single-blinded injections of placebo, 1000 and 2000 IU rhFSH spaced by at least 28 days between injections. RESULTS: After injection of 3000 IU rhFSH, inhibin B values were significantly elevated above baseline for 24, 96 and 120 h (maximal increase after 96 h, mean +/- s.e.m. 303+/-18 pg/ml). Injection of 2000 IU rhFSH led to a significant increase in inhibin B (maximum mean +/- s.e.m. 318+/-20 pg/ml) from 24 to 120 h. Injection of 1000 IU rhFSH led to a significant increase in inhibin B after 96 h (maximum mean +/- s.e.m. 300+/-16 pg/ml). The inhibin B areas under the curve after injection of 2000 and 3000 IU rhFSH were significantly higher than those following the placebo and 1000 IU rhFSH. In the 12 fertile men investigated, at baseline a strong diurnal rhythm of inhibin B parallel to that of testosterone was observed. CONCLUSIONS: Serum inhibin B can be considered only a partial pharmacodynamic parameter of FSH in vivo, since the integrity of the spermatogenic process appears to be a second fundamental component in the regulation of its secretion from the testis.

Screening for deletions of the Y chromosome involving the DAZ (Deleted in AZoospermia) gene in azoospermia and severe oligozoospermia.

OBJECTIVE: To evaluate the occurrence and prevalence of microdeletions of the Y chromosome involving the DAZ (Deleted in AZoospermia) gene in patients with azoospermia or severe oligozoospermia. DESIGN: Controlled clinical study. SETTING: University infertility clinic. PATIENT(S): Infertile men (n = 168) with nonobstructive, idiopathic azoospermia or severe oligozoospermia and normal LH. The control group consisted of proven fathers (n = 86). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Semen analysis; polymerase chain reaction amplification of the loci sY84, sY143, sY254, and sY255; serum FSH, LH, and T; testicular volume. RESULT(S): Deletions involving the sY254 and sY255 DAZ loci were found in three azoospermic patients and two men with sperm concentration < 1 x 10(6)/mL. Serum FSH was elevated in four patients and was normal in one. All five patients had decreased testicular volumes compared with controls. No deletions involving the sY84 and sY143 loci were found. The four loci were amplified normally in the control group. CONCLUSION(S): The estimated frequency of deletions involving the DAZ locus is 3% in azoospermic-severely oligozoospermic men consulting an infertility clinic. Polymerase chain reaction amplification of the DAZ locus is useful for the diagnosis of microdeletions of the Y chromosome. Deletions involving more proximal regions of the Y chromosome seem to be rare.

Sonographic testicular microlithiasis as an indicator of premalignant conditions in normal and infertile men.

Sonographic detection of multiple, small hyperechogenic lesions in the testis (testicular microlithiasis; TM) can indicate germ cell tumors. However, it has not been well established whether this finding signifies a risk factor for development of testicular neoplasm in all cases or whether it indicates premalignant changes only in those men with additional risk factors for germ cell cancer, such as infertility, a history of testicular maldescent, or the presence of an atrophic testis. In a retrospective analysis of 1701 consecutively performed scrotal sonographies of patients with (n = 1399) and without (n = 219) infertility or with contralateral testicular tumors (n = 83), the prevalence of TM was compared with that in 198 healthy men who volunteered for different clinical trials. TM was equally frequent in all groups (2.3% [32/1399] of infertile patients, 2.3% [5/219] of other patients without infertility, and 1.5% [3/198] of healthy men). Results of testicular biopsies were available for a subgroup of infertile men. Carcinoma in situ (CIS) was present only in cases with TM (2/11). In addition, sonographic follow-up examinations were performed in another 14 men with TM. Testicular tumors had developed in 2 patients, one whom was infertile and one in the control group. None of these patients had a history of testicular maldescent but all testes affected either by CIS or tumors were reduced in volume. We conclude that diagnosis of TM, especially if it is present in an atrophic testis, demands a diagnostic biopsy or at least sonographic follow-up examinations.

Estradiol and high-dose dihydrotestosterone treatment causes changes in cynomolgus monkey prostate volume and histology identical to those caused by testosterone alone.

To evaluate the effects of testosterone (T), dihydrotestosterone (DHT), and estradiol (E2) on the regulation of prostate growth and tissue composition, the following study was conducted in a nonhuman primate model. Fifteen adult, long-term castrated cynomolgus monkeys were randomly assigned to receive implants filled with T (0.19 +/- 0.01 g), DHT alone (0.21 +/- 0.01 g), or (99%) DHT + (1%) E2 (0.21 +/- 0.01 g). Prior to and at 4-week intervals during the treatment phase of 252 days, prostate volumes (PV), body weight, ejaculate weight, hormone levels (of T, DHT, and E2), and red blood cell count were measured. Five adult, intact monkeys served as controls for prostate volume and histology. At the end of the study, histological analysis of an ultrasound-guided prostate biopsy was performed. T levels increased significantly in the T group compared with baseline (P < 0.01) and with the DHT and DHT + E2 groups (P < 0.05). Both groups receiving DHT showed higher DHT levels than did animals in the T group (P < 0.001). E2 levels in all groups increased over time (P < 0.05), although significant differences (P < 0.01) could only be detected between the DHT + E2 and the DHT group. Prostate volume in all groups increased (at baseline: T = 1.03 +/- 0.12 ml, DHT = 1.08 +/- 0.15 ml, DHT + E2 = 1.13 +/- 0.09; at day 252: T = 5.83 +/- 1.00, DHT = 4.72 +/- 0.9, DHT + E2 = 5.05 +/- 0.62) over time (P < 0.001), whereas no differences could be detected between the groups. Prostate biopsy could be performed successfully in 15 out of 20 monkeys. Prostate tissue evaluation between the treatment groups and the evaluated intact monkeys revealed no differences in the status of secretory epithelia, nuclear chromatin, excretory vacuoles, interstitial stroma, smooth muscles, and total functional status, whereas the prostate of a long-term castrated monkey showed severe atrophy. Thus, both androgens fully restored prostate volume and ejaculatory function. Highly supraphysiological DHT serum levels are not associated with abnormal volumetric or histological changes of the prostate. Comparing the DHT group with the DHT + E2 group, an additional stimulatory effect of normal or slightly elevated estrogens on the prostate cannot be found in the presence of highly supraphysiological DHT levels.

Direct analysis by small-pool PCR of MS205 minisatellite mutation rates in sperm after mutagenic therapies.

We have used small-pool PCR to analyse mutation in samples of sperm taken from men after mutagenic therapy. Small-pool PCR uses direct analysis of germline DNA at a highly unstable tandem-repeated "minisatellite" locus to measure rates of length-change mutation in individual sperm samples. The advantages of this approach are that the normal mutation rate is extremely high (about 0.4% per gamete at the locus analysed here), so that relatively small increases in mutation rate can be detectable in individual samples. It is known from work on sperm from untreated individuals that different alleles at this locus have different mutation rates. For this reason, we have analysed the germline mutation rates in sperm samples from two men, in each case comparing a post-treatment sample with a pre-treatment sample from the same individual. We find no evidence for altered mutation in the post-treatment sample, suggesting that the repopulation of the germ-cell compartment after treatment may be subject to stringent mechanisms for the detection and elimination of germ-cell damage.

Mosaic status in lymphocytes of infertile men with or without Klinefelter syndrome.

BACKGROUND: Gonosomal aneuploidies such as Klinefelter syndrome (47,XXY) are the most frequent chromosomal aberration in infertile men. Normally the chromosomal status of patients is detected by karyotyping of up to 20 metaphase spreads of lymphocyte nuclei, whereby low grade mosaicism may be overlooked. To test whether Klinefelter patients with 47,XXY karyotype or infertile men with 46,XY karyotype represent gonosomal mosaicisms, we performed meta- and interphase fluorescence in situ hybridization (FISH) on 45 men. METHODS AND RESULTS: A total of 400 interphase and 40 metaphase lymphocyte nuclei per patient were scored after hybridization with DNA probes specific for chromosomes X and Y, and chromosome 9 as a control. On the basis of conventional karyotype, hormone levels and clinical appearance, patients were subdivided into 18 Klinefelter syndrome patients with 47,XXY (group I), 11 Klinefelter syndrome-like patients with normal karyotype, 46,XY (group II) and six non-Klinefelter-like infertile patients with normal 46,XY karyotype (group III). Ten normal men (group IV) served as controls. Testicular volume in the Klinefelter group I was smaller compared with group II (P = 0.016), group III (P < 0.001) and group IV (P < 0.001). In addition, testicular volumes in group II were lower compared with group III and group IV (P < 0.004). No significant differences between the aneuploidy rate analysed by FISH in interphase nuclei and metaphases were found in either single patients or groups. Patients with Klinefelter syndrome, 47,XXY (group I) or with symptoms similar to those in Klinefelter patients 46,XY (group II) showed a similar aneuploidy rate (group I 7.1 +/- 4.0% and group II 4.6 +/- 3.4%) and two 47,XXY patients with a high prevalence for normal 46,XY lymphocytes had sperm in their ejaculate. However, in general, no correlations between FISH mosaic status and serum hormone parameters, nor with ejaculate parameters were found. CONCLUSIONS: The results suggest that 47,XXY patients with an increased incidence of XY cells (average of 4.2 +/- 2.3) may have a higher probability of germ cells as we found sperm only in the ejaculate of Klinefelter syndrome patients with mosaic 46,XY cells (6.0 and 7.0%). On the other hand, 46,XY patients with mosaic sex chromosome aneuploidies detected by FISH analysis more often show symptoms of hypogonadism phenotypically resembling Klinefelter syndrome.

Varicocele treatment in the light of evidence-based andrology.

Treatment of varicoceles became the most common treatment for male infertility merely on an empirical basis. However, in the age of evidence-based medicine it is surprising that only a few, and mainly recent, randomized controlled clinical trials with relevant outcome parameters have been published to allow adequate judgement of treatment effectiveness. Moreover, difficulties in study design could also be detected in most of these high-quality studies. Despite these difficulties and in contrast to the majority of uncontrolled studies on varicocelectomy, meta-analysis of these randomized controlled clinical studies involving 385 patients showed no significant treatment benefit and questions the common practice of varicocelectomy. Even the high-quality studies show conflicting results and therefore the topic of varicocele treatment will remain controversial and further randomized clinical trials should readdress this issue. For the time being, intervention by surgical or angiographic occlusion of the spermatic vein cannot be recommended.

Update on medical treatment of ejaculatory disorders.

Among the treatment modalities for ejaculatory disorders pharmacological treatment is the least invasive option. In this review, medical treatments for retrograde ejaculation (RE) and anejaculation (AE) are discussed systematically. Thirty-six studies dealing with patients with RE and 40 with AE evaluated the use of medical treatment and were included in this review. In addition four articles dealing with prostatic massage in anejaculatory patients were considered. Sperm quality in patients with retrograde and AE is often impaired. In patients with RE no differences in response to medical treatment could be detected between the different underlying diagnoses. Compared with ephedrine, imipramine and chlorpheniramine + phenylpropanalamine showed significantly higher reversal rates, while differences between the other treatments were not significant. Regarding the reversal of AE, the alpha agonistic drugs were significantly inferior to treatment with parasympathetic drugs. Of the different alpha agonistic medical treatments for the reversal of AE, milodrin showed significantly better rates than imipramine (p = 0.008), pseudoephidrine (p = 0.02) and ephedrine (p = 0.044), while all other treatments were not significantly different (p = 0.4). In conclusion, medical treatment for reversal of RE offers a realistic chance of conceiving offspring naturally and should be the treatment modality of first choice. In contrast, in AE, medical treatment cannot be recommended generally as treatment of first choice as it shows low overall success rates compared with electrovibration stimulation and electroejaculation. Under consideration of the mostly uncontrolled design of the majority of studies published, controlled clinical trials comparing different treatment options appear urgently warranted.

Treatment of retrograde ejaculation and anejaculation.

Treatment of retrograde ejaculation and anejaculation The various options for the treatment of retrograde ejaculation (RE) and anejaculation (AE) are discussed systematically in this review. A total of 88 studies dealing with patients with RE emphasize medical treatment for reversal of RE and retrieval of spermatozoa from urine. In 136 studies concerning patients with AE, the main emphasis is on medical treatment, electroejaculation (EE) and electrovibration stimulation (EVS) for the reversal of AE. Sperm quality in patients with RE and AE is often impaired. However, with the help of assisted reproduction techniques (ART) available today, both ejaculation disorders can be considered as treatable diseases. The major problem when analysing the studies was the uneven methodological quality of the original articles and the difficulties presented by different drugs and dosages, equipment and techniques, along with different criteria for success. In conclusion, controlled clinical trials comparing different treatment options appear urgently warranted.

Conventional treatments of male infertility in the age of evidence-based andrology.

The field of reproductive medicine is characterized by the rapid development of assisted fertilization. Today, fertilization can be achieved by cytoplasmic microinjection of single spermatozoa or spermatids into oocyte cytoplasm. In view of these new reproductive techniques, conventional diagnosis and treatment of male infertility seem to be rather outdated and limited. However, the final goal of reproductive medicine should be to improve reproductive function in order to provide each couple with the chance of conceiving offspring naturally. In this paper we analyse the effectiveness of current conventional treatments of male infertility in the light of high-quality studies and emphasize that future therapies must be evaluated in properly conducted studies.

Analysis of medical treatment of male infertility.

Since the first injection of a single spermatozoon into the cytoplasm of an oocyte (intracytoplasmic sperm injection, ICSI), this method has become the most successful means of treating male infertility. Even for patients long considered untreatable, a chance of paternity has become reality. Using not only ejaculated but also testicular spermatozoa, pregnancies have been achieved in the partners of patients who had never had a chance previously, including even cases with Klinefelter syndrome. However, despite the tremendous success of ICSI, most couples would prefer to conceive offspring naturally. Therefore we review the effectiveness of current conventional treatments for male infertility and analyse the chances of infertile couples to conceive spontaneously.

Potential of norethisterone enanthate for male contraception: pharmacokinetics and suppression of pituitary and gonadal function.

OBJECTIVE: Gestagens are known to suppress gonadotrophins in women and are currently also under investigation for the development of hormonal male contraceptives. The aim of the study was to assess the potential of norethisterone enanthate (NETE) for male contraception. DESIGN AND MEASUREMENTS: The suppressive effect of a single injection of 200 mg NETE on serum gonadotrophins, serum testosterone, lipids, spermatogenesis, well-being and sexual function was evaluated in seven healthy men. RESULTS: In this single dose study treatment was well tolerated by all volunteers. NETE led to a rapid, profound and significant suppression of serum LH (day 6 - day 10), FSH (day 2 - day 29), testosterone (day 1 - day 29 and day 35) and SHBG (day 6 - day 35). At study end sperm counts were significantly suppressed. Numbers of spontaneous erections (day 17, 23 and 26), number of sexual fantasies (day 20 and 23) as well as libido (day 20 and 26) were significantly decreased compared to baseline. All other parameters including lipids, augmented glucose, testicular volume and well-being showed no significant alterations. CONCLUSION: Because of its strong, rapid and sustained suppression of serum FSH and testosterone norethisterone enanthate offers great potential for hormonal male contraception if combined with testosterone esters.

Imipramine for successful treatment of retrograde ejaculation caused by retroperitoneal surgery.

Retrograde ejaculation is a known complication following retroperitoneal lymph node dissection. Without further therapy, achieving paternity may be impossible. We evaluated the use of the tricyclic antidepressant imipramine in a new ovarian cycle-dependent dose regime for reversal of retrograde ejaculation in 11 patients desiring fertility. Ten patients with retroperitoneal lymph node dissection performed because of testicular cancer, and one with aortic surgery (thromboendarterectomy) were treated in an open, uncontrolled study with imipramine given at a daily oral dose increasing from 25 to 50 mg for 7 days prior to the planned ejaculation or the expected ovulation of the female partner. In all 11 patients, antegrade ejaculation could be induced (sperm counts: 3.9-276.0 x 10(6)/mL). Major side-effects were not observed, but half of the patients complained of minor degrees of dizziness, weakness, nausea or sweating during medication. Under treatment, two patients with normal sperm concentrations induced a spontaneous pregnancy. One ICSI cycle each was performed in 2 patients, with successful fertilization, out no pregnancy. In conclusion, temporary oral intake of imipramine is an effective and safe treatment to re-establish antegrade ejaculation in patients with retrograde ejaculation following retroperitoneal surgery, thus providing possibilities for paternity either through intercourse or by assisted fertilization.