Biomedical subjects

Axel Kamischke

Publications and source records attributed to Axel Kamischke.

14 recordsLinked to original sources

PubMed2006

Elevated follicle-stimulating hormone levels and the chances for azoospermic men to become fathers after retrieval of elongated spermatids from cryopreserved testicular tissue.

OBJECTIVE: To assess individual chances for a live-born child in azoospermic men by performance of testicular sperm extraction (TESE) followed by intracytoplasmatic sperm injection (ICSI). DESIGN: A retrospective cohort study. SETTING: An academic fertility care center and research unit. PATIENT(S): Two hundred three couples who wished to have a child; all men had azoospermia. INTERVENTION(S): All men were operated for TESE; 112 men were found to have elongated spermatids (ES), and 209 ICSI cycles were performed in these men using cryopreserved tissue. MAIN OUTCOME MEASURE(S): Predictors for the chances to obtain live sperm and for probabilities of fertilization, clinical pregnancies, and live births. RESULT(S): Testicular volume, FSH, and inhibin B levels were predictors for the presence of ES. Intracytoplasmic sperm injection resulted in 23 pregnancies, leading to 20 live births. Despite the presence of ES and performance of ICSI in cases of FSH levels >or=20 IU/L, no pregnancy resulted in these men (n = 21). Receiver operating characteristics revealed FSH levels of >or=20 IU/L as cutoff for treatment success. The number of testicular tubuli containing ES served as a predictor for clinical pregnancy as well as for live birth. Cigarette smoking by the male partner exerted a significant negative influence on treatment success. CONCLUSION(S): The degree of completely maintained spermatogenesis within the biopsy appears to reflect intrinsic abilities of spermatozoa to induce normal embryo development. Charts based on regression models are presented for counseling patients before TESE; these explain chances of finding ES and probability of successful ICSI. Obtaining offspring is unlikely in cases of azoospermia and of FSH levels of >or=20 IU/L.

Adult↗

PubMed2005

Endogenous progesterone and the exogenous progestin norethisterone enanthate are associated with a proinflammatory profile in healthy men.

CONTEXT: Inflammatory processes are related to atherosclerosis. Identification of inflammation triggers may furnish new therapeutic pathways. In women, progestins can have a marked inflammatory capacity. OBJECTIVE AND DESIGN: We investigated the effects of progesterone in men within the setting of two independent trials. First, the relation of endogenous progesterone levels to inflammation markers was assessed in 67 healthy nonsmoking Caucasian men (age, 20-50 yr) on a cross-sectional basis. Second, in a longitudinal controlled trial (52 wk) involving 28 healthy men receiving i.m. medication, we determined the effects of an exogenous progestin (norethisterone enanthate 200 mg) in combination with a long-acting testosterone preparation (testosterone undecanoate 1000 mg) administered to avoid androgen deficiency caused by pituitary-hypothalamic feedback. Controls received testosterone plus placebo. RESULTS: In the cross-sectional study, progesterone levels were positively related to concentrations of IL-6 (r = 0.41; P < 0.001), C-reactive protein (r = 0.37; P = 0.007), soluble vascular cell adhesion molecule 1 (r = 0.28; P = 0.02), E-selectin (r = 0.45; P < 0.001), leptin (r = 0.42; P < 0.001), neutrophils (r = 0.62; P < 0.001), and serum protein fractions alpha-1 (r = 0.44; P < 0.001) and alpha-2 (r = 0.36; P = 0.002). During the pharmacological trial, the testosterone/progestin group exhibited a marked increase of IL-6 concentrations (P < 0.001), whereas these decreased in the testosterone/placebo group (P = 0.03). Antiinflammatory IL-10 levels decreased in the group receiving testosterone/progestin (P = 0.01) but did not change in the testosterone/placebo group. CONCLUSION: Progesterone concentrations correspond to an inflammatory profile in healthy men, and external progestins elicit a similar effect. Men receiving regimens for hormonal male contraception involving progestins should be monitored for inflammatory effects. Speculatively, testosterone treatment decreasing endogenous progesterone production may facilitate beneficial effects on inflammation profiles even in eugonadal men.

Adult↗

PubMed2005

Pharmacokinetics and pharmacodynamics of injectable testosterone undecanoate in castrated cynomolgus monkeys (Macaca fascicularis) are independent of different oil vehicles.

Testosterone undecanoate (TU) dissolved in soybean oil was developed in China to improve the pharmacokinetics of this testosterone ester in comparison with TU in castor or tea seed oil. As a pre-clinical primate model, three groups of five castrated cynomolgus macaques received either a single intramuscular injection of 10 mg/kg body weight TU in soybean oil, in tea seed oil, or in castor oil (equals 6.3 mg pure T/kg body weight for all preparations). Testosterone, estradiol, luteinizing hormone, and follicle-stimulating hormone as well as prostate volume, body weight and ejaculate weight were evaluated. After injection supraphysiological testosterone levels were induced. There were no significant differences in the pharmacokinetics of the three TU preparations for testosterone and estradiol. The gonadotropin levels showed a high individual variation. Prostate volumes increased equally in all groups after administration and declined to castrate level afterwards. The results suggest that TU in soybean oil produces similar effects as TU in the other vehicles. This study in non-human primates provides no objection to testing of this new preparation in humans.

Animals↗

PubMed2005

[Hormonal contraception for males--an option for adolescents?].

Although effective contraceptive methods are available, the incidence of teenage pregnancies and consecutive pregnancy interruptions remains high in industrial nations, including Germany. There are several reasons for this high incidence. Apart from earlier sexual maturation, the absence of contraceptive use or the use of inefficient methods contributes mainly towards this increase. Existing contraceptive methods for men either show unsatisfying efficacy (coitus interruptus, use of condoms) or problems of reversibility (vasectomy), which limits their broader use. Of the different experimental approaches towards male contraception, the hormonal approach is closest to practical implementation. Androgens are an essential part of all experimental approaches to hormonal contraception in males; they cause suppression of spermatogenesis through gonadotropin suppression. Previous clinical trials have validated the concept of hormonal contraception in men. However, the application modalities and the ineffectiveness of all self-administered androgen preparations have been unacceptable for practical use. Therefore recent developments focus either on androgen implants or on injectable, long-acting testosterone esters in combination with progestins, which also suppress gonadotropin secretion. Over the last decades various combinations of androgen preparations with different progestins or GnRH antagonists have been tested in clinical trials. Of these, testosterone with either depot medroxyprogesterone acetate, norethisterone, desogestrel or etonogestrel have shown promising efficacy in phase II clinical trials. However, whether hormonal contraception might be given to adolescent males remains to be elucidated. This will have to be assessed once a hormonal contraceptive for men has reached the market. Special attention will need to be given to bone maturation as androgens at the prescribed doses might induce premature closure of the epiphyseal joints.

Abortion, Induced↗

PubMed2005

Norethisterone enanthate has neither a direct effect on the testis nor on the epididymis: a study in adult male cynomolgus monkeys (Macaca fascicularis).

OBJECTIVE: Norethisterone enanthate (NETE) is evaluated in trials of hormonal male contraception. It has been speculated that progestins may exert their contraceptive effects not only by suppressing gonadotropins but also by direct effects on male organs. NETE was given to monkeys in which endogenous gonadotropin secretion was suppressed by a gonadotropin releasing hormone (GnRH) antagonist, and replaced by human follicle-stimulating hormone (FSH) and human chorionic gonadotropin (hCG). If NETE has a direct effect on spermatogenesis and/or epididymal function, some changes in testicular histology, sperm motility and/or morphology should occur soon after exposure to NETE. METHODS: Fifteen adult intact male monkeys were grouped and treated for a 38-day period. Group I received GnRH antagonist, FSH, hCG and NETE while group II received a regime identical to group I without NETE and group III received only NETE and vehicle. Ejaculates, body weight, testicular biopsies and volume, and hormones were evaluated. RESULTS: There was a similar pattern of serum FSH and testosterone in groups I and II. Testicular volume and the proportion of tubuli exhibiting spermatids was significantly decreased in group III. There were no significant differences between group I and group II in any parameters measured. The forward progression of sperm was not affected by NETE treatment. The consistently low percentages of grade c sperm indicated no sign of hyperactivation. No changes in the gross morphology of the acrosome were detected. CONCLUSIONS: Short-term NETE treatment has neither a direct effect on the testis nor on the epididymis in this nonhuman primate model and its contraceptive effects appear to be exerted exclusively through gonadotropin suppression.

Animals↗

PubMed2004

Progress towards hormonal male contraception.

The use of androgens is an essential part of all experimental approaches to hormonal male contraception and involves the suppression of gonadotrophins, leading to inhibition of spermatogenesis. Although clinical trials have proven the concept of hormonal male contraception, their modalities have been unacceptable for practical use for several reasons. Because the efficacy of all self-administered androgen preparations has been disappointing, recent studies have focused on either androgen implants or injectable, long-acting testosterone esters such as testosterone undecanoate. However, in contrast to East Asian men, only two-thirds of Caucasian men respond to such androgen-based regimens with the desired azoospermia (no sperm produced), and thus additional agents are required. Over the past decades various combinations of androgen preparations with different progestins or gonadotrophin-releasing-hormone antagonists have been tested in clinical trials. Of these, testosterone administered in combination with either depot medroxyprogesterone acetate, norethisterone enanthate, desogestrel or etonogestrel have shown promising efficacy.

Androgens↗

PubMed2004

Association of meiotic arrest with lack of BOULE protein expression in infertile men.

Spermatogenesis is a complex developmental process of mitotic and meiotic cell divisions that ultimately results in production of haploid spermatozoa. Recent studies in flies demonstrate that the BOULE gene encodes a key factor of meiosis in male germ cells, regulating the expression of twine, a cdc25 phosphatase, which promotes progression through meiosis. In this study, we investigated whether a common mechanism underlies the block of germ cell maturation observed in idiopathic and nonidiopathic azoospermic patients with meiotic arrest. We examined, by immunohistochemistry, BOULE and CDC25A phosphatase protein, the human homolog of twine, expression in 47 men with meiotic arrest, mixed atrophy, or normal spermatogenesis. The presence of genetic alterations within the BOULE gene was investigated by single-stranded conformation polymorphism. BOULE protein expression in men with complete spermatogenesis can be restricted to stages from leptotene up to stages of late spermatocytes, whereas CDC25A expression ranges from leptotene spermatocytes to elongating spermatids. Although spermatocytes were present in all testicular biopsies with meiotic arrest (28 testes), BOULE protein expression was completely lacking. In addition, in nearly all biopsies in which BOULE was absent, CDC25A was concomitantly lacking. However, no mutations or polymorphisms in the BOULE gene were identified, which could explain the lack of BOULE or CDC25A expression. These results indicate that a major group of infertile men with meiotic arrest lack BOULE protein and its putative target, CDC25A expression. The spermatogenic failure seems to arise from factor(s) upstream of BOULE, which are possibly involved in regulating transcription and/or translation of BOULE. Thus, the spermatogenic damage leading to meiotic arrest is independent of the etiology and indicates that BOULE is a possible fundamental mediator of meiotic transition in the human.

Adult↗

PubMed2003

Use of progestins in male contraception.

Hormonal male contraception aims at suppression of spermatogenesis to azoospermia or at least to severe oligoasthenozoospermia, incompatible with the ability to induce a pregnancy. The general principle of this approach is based on interference with the endocrine regulation of spermatogenesis, i.e. the suppression of gonadotropins. Since both FSH (through the Sertoli cell) and LH (through the Leydig cell and testosterone (T)) are required for normal spermatogenesis, both gonadotropins need to be suppressed as strongly as possible. In East Asian men this can be achieved with T alone (preferably in depot preparations such as T undecanoate) but only two-thirds of Caucasian men respond with adequate sperm suppression. Therefore, in Caucasian men additional substances such as GnRH antagonists or progestins are required to suppress the pituitary. Over the past 30 years many combinations of various T preparations with different progestins have been tested in clinical trials. Since self-applicable steroid combinations (e.g. oral levonorgestrel or desogestrel with transdermal T) showed low effectiveness, currently injections and implants are under clinical development. Long-acting intramuscular T esters (e.g. T undecanoate), T pellets or implants (e.g. MENT) are combined with injections of DMPA or noresthisterone enanthate or with implants containing levonorgestrel or etonogestrel. Acute side-effects of these combinations appear to be minimal and tolerable, long-term effects need to be investigated.

Asian People↗

PubMed2002

CAG repeat length in the androgen receptor gene and gonadotrophin suppression influence the effectiveness of hormonal male contraception.

OBJECTIVE: Nonuniformity in suppression of spermatogenesis induced by various hormones or hormone combinations has impeded the development of an effective hormonal male contraceptive. The basis for this heterogeneity in response remained unresolved to date; however, the presence of ethnic differences points to an involvement of genetic factors. PATIENTS AND MEASUREMENTS: In a retrospective analysis we investigated the impact of a CAG repeat polymorphism in the androgen receptor and polymorphic sites in the oestrogen and FSH receptor genes on spermatogenic suppression in 85 Caucasian men treated with different regimens of hormonal contraception. RESULTS: Failure to reduce sperm concentrations below 3 million/ml was significantly associated with insufficient suppression of gonadotrophins. The extent of gonadotrophin suppression was not explained by any polymorphism but was primarily pharmacological, resulting from addition of gestagens to testosterone. When LH and FSH suppression was rapid and persistent none of the polymorphisms studied explained why some men failed to achieve azoospermia. In cases with incomplete gonadotrophin suppression the chances of becoming azoospermic were 2.5 times higher in men having more than 22 CAG repeats. CONCLUSIONS: In summary, our analysis shows that in a subset of men, effective hormonal male contraception can be achieved even in the absence of complete gonadotrophin suppression.

Adult↗

PubMed2002

An effective hormonal male contraceptive using testosterone undecanoate with oral or injectable norethisterone preparations.

Suppression of spermatogenesis to azoospermia is the goal of hormonal male contraception based on T combined with gestagens. The combination of the long-acting T, ester testosterone undecanoate (TU), with norethisterone (NET) enanthate (E) showed high efficacy. In the present study, we tested the validity of this approach by varying the NET dose and mode of application. The aim of the study was to achieve high rates of suppression of spermatogenesis as reflected by sperm counts, monitor gonadotropins as well as other hormones, and evaluate any possible side effects. In a phase II clinical trial, groups of normal volunteers received: 1000 mg TU im at wk 2, 6, 12, and 18 combined with 200 mg NETE im at wk 0, 6, 12, and 18 (group I); 1000 mg TU im and 400 mg NETE im at wk 0, 6, 12, and 18 (group II); and 1000 mg TU im at wk 0, 6, 12, and 18 with daily oral NET acetate (NETA) from wk 0 to 24 (group III). In all groups marked suppression of gonadotropins resulted in a significant decrease of spermatogenesis and azoospermia in 13/14, 11/12, and 12/14 men in groups I to III, respectively. The remaining men all had less than 1 million sperm/ml. Reversible side effects included increase in body weight, erythrocytes, hemoglobin, and hematocrit and decrease in high-density lipoprotein cholesterol and alkaline phosphatase in all groups and increase in liver enzymes in the oral NETA group. This study documents the high efficacy of TU in combination with NET and confirms that this dose and mode of application (1000 mg TU im every 6 wk plus 400 mg NETE im every 6 wk or plus 10 mg daily oral NETA) is as effective as the previously reported regimen containing 1000 mg TU + 200 mg NETE im every 6 wk. The contraceptive efficacy of this combination of TU and NETE should be evaluated in further clinical trials.

Administration, Oral↗

PubMedDate not supplied

Cryopreservation of sperm from adolescents and adults with malignancies.

Although cryopreservation of sperm is performed routinely in adults, only a small amount of information is available on its feasibility in adolescent patients with malignancies. Of 936 patients who were candidates for sperm cryopreservation, 851 (111 adolescents and 740 adults) were eligible for this retrospective analysis after excluding patients with relapses of the original or secondary cancers, known bitesticular lesions, or an unknown diagnosis. In general, patients were seen before initiation of treatment for malignancies. However, unilateral ablation of the testis was performed in 61% of patients with testicular cancer before cryopreservation of samples. Patients were grouped according to primary diagnosis and age. Measurements included testicular volume, semen analysis, and serum hormones (luteinizing hormone [LH], follicle-stimulating hormone [FSH], and testosterone). The youngest patient with an ejaculate containing sperm was 13.5 years old. No significant differences in any investigated parameter could be detected for any diagnosis among the 111 adolescents (age, <20 years). In contrast, adult patients with testicular cancer showed higher FSH values and lower sperm concentrations than adult patients with lymphomas, leukemias, and bone cancers. Patients younger than 16 years had lower ejaculate volumes than men older than 25 years, and testosterone levels were higher in patients aged 20-29 years than in the youngest patient group. Cryopreservation of sperm can be performed in adolescent patients with overall success rates (defined as the observation of at least a single motile sperm after the thawing procedure) similar to those observed in adults and should be recommended even to oncological patients younger than 15 years, provided that these patients can produce a semen sample.

Adolescent↗

PubMedDate not supplied

Klinefelter's syndrome.

Klinefelter's syndrome is the most common genetic cause of human male infertility, but many cases remain undiagnosed because of substantial variation in clinical presentation and insufficient professional awareness of the syndrome itself. Early recognition and hormonal treatment of the disorder can substantially improve quality of life and prevent serious consequences. Testosterone replacement corrects symptoms of androgen deficiency but has no positive effect on infertility. However, nowadays patients with Klinefelter's syndrome, including the non-mosaic type, need no longer be considered irrevocably infertile, because intracytoplasmic sperm injection offers an opportunity for procreation even when there are no spermatozoa in the ejaculate. In a substantial number of azoospermic patients, spermatozoa can be extracted from testicular biopsy samples, and pregnancies and livebirths have been achieved. The frequency of sex chromosomal hyperploidy and autosomal aneuploidies is higher in spermatozoa from patients with Klinefelter's syndrome than in those from normal men. Thus, chromosomal errors might in some cases be transmitted to the offspring of men with this syndrome. The genetic implications of the fertilisation procedures, including pretransfer or prenatal genetic assessment, must be explained to patients and their partners.

Anthropometry↗

PubMedDate not supplied

Contraceptive steroids influence the hemostatic activation state in healthy men.

Hormonal contraception for men requires administration of testosterone and gestagens. The effects of a long-acting testosterone ester and 2 different progestins on hemostatic activation parameters were studied in relation to cardiovascular risk. In phase 1, 7 healthy men aged 28-38 years received a single intramuscular injection of 200 mg norethisterone-enanthate (NET-EN) on Day 0. Plasma samples were obtained on Days 0, 14, 41, and 84. In phase 2, 3 groups of 14 healthy men aged 18-45 years received four injections (every 6 weeks) of 1000 mg testosterone undecanoate (TU), plus daily oral placebo or daily oral levonorgestrel (LNG, 250 microg); or four injections (every 6 weeks) of NET-EN. Treatment lasted 24 weeks. Plasma samples were obtained at weeks 0, 16, 24, and 52. All samples were assayed for levels of coagulation factors VIIc, VIIa, XIIc, and XIIa; prothrombin fragment F1+2 (F1+2); antithrombin; plasmin-alpha(2)-antiplasmin-complex (PAP); and fibrinogen. NET-EN alone led to a depletion of sexual hormones and a marked shift in hemostatic parameters with increasing levels of FXIIc, fibrinogen, antithrombin, and F1+2, whereas FVIIc and FVIIa levels decreased. PAP levels increased significantly. Opposite effects were seen in the TU/placebo group, with a significant down-regulation of fibrinolysis and the hemostatic turnover rate. Testosterone effects were attenuated by additional administration of gestagens. The effect of hormonal male contraception using long-acting testosterone esters with or without gestagens was significantly measurable within the hemostatic system. Down-regulation of the hemostatic system with testosterone alone may indicate an antithrombotic effect, whereas clinical consequences of an additional gestagen compound cannot be derived.

Adult↗

PubMedDate not supplied

Clinical and diagnostic features of patients with suspected Klinefelter syndrome.

Klinefelter syndrome, with an incidence of 1:600 male newborns, is the most frequent form of male hypogonadism. However, despite its relatively high frequency, the syndrome is often overlooked. To prevent such oversights, the clinical features should be better characterized, and simple screening tests should be used more frequently. In a cohort of 309 patients suspected of having Klinefelter syndrome, we evaluated the clinical symptoms as well as the diagnostic value of the Barr body test for screening procedures. On the basis of chromosome analysis, 85 patients (group I) were diagnosed as having Klinefelter syndrome, and 224 patients had a 46,XY karyotype (group II). Barr body analysis revealed a specificity of 95% and a sensitivity of 82% for the diagnosis of Klinefelter syndrome. General features (eg, reason for admission, age, age of the parents, body weight, and frequency of maldescended testes) were not different between the groups, except that group I had a higher proportion of patients with a lower educational background. Compared to group II, patients with Klinefelter syndrome were taller (P <.001); had smaller testis volumes (P <.0001), higher follicle-stimulating hormone (FSH) and luteinizing hormone (LH) values; and carried a tendency for less androgenic phenotype and secondary hair distribution. Testosterone, estradiol, sex hormone-binding globulin (SHBG), and prostate-specific antigen (PSA) serum levels as well as prostate volume were not significantly different between the groups. In patients who provided an ejaculate, azoospermia was found in 54% of the patients in group II and in 93% of the patients with Klinefelter syndrome. Although not exclusively characteristic for Klinefelter syndrome, the combination of low testicular volume and azoospermia, together with elevated gonadotropins, is highly indicative for a Klinefelter syndrome and should stimulate further clinical investigations. Barr body analysis provides a quick and reliable screening test, which, however, must be confirmed by karyotyping.

Adult↗