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Objective: The aim of the present study was to compare symptoms of anxiety and depression among indigenous Sami and non-Sami youth in the Arctic part of Norway, and to examine the influence of perceived discrimination and ethnic identity on these symptoms. The relationship between ethnic self-labeling and native language competence on internalization symptoms was explored for Sami adolescents., Design: The Norwegian Arctic Adolescent Health Study was conducted among 10th graders in junior high schools in North Norway in 2003-2005. The sample consisted of 4449 adolescents, of whom 450 (10%) were indigenous Sami and 3999 (90%) were non-Sami. Anxiety and depressive symptoms were assessed using a short version of the Hopkins Symptom Checklist-10. Participants also completed The Multigroup Ethnic Identity Measure (MEIM) and a measure of perceived discrimination., Results: No differences were found among ethnic groups in internalization symptoms. Sami youth reported more discrimination than the non-Sami. Both MEIM and perceived discrimination were positively associated with internalization symptoms. Moreover, Sami youth who had not learned their native language at home were more vulnerable to experiencing internalization symptoms compared to Sami youth who had learned their native language at home., Conclusion: Culture-specific protective factors were discussed as potential explanations for the similarities between Sami and non-Sami youth. The present study documented a relationship between internalization symptoms and ethnic identity, perceived discrimination, and language loss. These findings could be understood as consequences of the recent colonial history and oppression of the indigenous Sami.

Objective: There is a paucity of knowledge about long-term outcome issues in the bladder-exstrophy-epispadias complex (BEEC). Adult male BEEC patients were investigated in respect of bladder and renal function, fertility, genital function and psychosocial facts., Patients and Methods: In a cross-sectional study, 17 adult male BEEC patients (mean age 23.4 years) from a single centre were evaluated with a questionnaire, renal and bladder ultrasound, blood tests, hormonal profile and semen analysis., Results: Phenotypically one patient had complete epispadias and 16 had classical bladder exstrophy. Five patients underwent a one-stage functional reconstruction as a primary and 12 as a redo procedure. After a mean follow-up of 19.4 years, 15 bladders were preserved with 12 voiding per urethram and 3 performing intermittent catheterization; 2 were secondarily diverted. Significant residual urine was present in 10; kidneys were normal in 14 patients. Sixteen patients proved ejaculations, 3 had normospermia, 7 oligoasthenospermia and 6 azospermia. In patients with only one single bladder neck procedure normospermia was statistically significant., Conclusion: After functional BEEC reconstruction, long-term bladder function is preserved with mostly normal renal function. The number of bladder neck attempts has a significant influence on andrologic outcome. Detailed analysis may detect multifactorial pathogenesis from the impaired sperm quality in the BEEC.

Background: This is the first population based study exploring health service use and ethno-cultural factors in indigenous Sami and non-Sami youth in North Norway. The first aim of the present study was to compare the frequency of health service use between Sami adolescents and their non-indigenous peers. The second aim was to explore the relationships between health service use and ethno-cultural factors, such as ethnic context, Sami self-identification, perceived discrimination and Sami language competence. Finally, we wanted to explore the relationship between use of health services and emotional and behavioural problems., Method: The Norwegian Arctic Adolescent Health Study was conducted among 10th graders (15-16 years old) in junior high schools in North Norway. The sample consisted of 4,449 adolescents, of whom 450 (10.1%) were indigenous Sami and 3,999 (89.9%) were non-Sami., Results: Sami and non-Sami youth used all health services with equal frequency. However, several ethno-cultural factors were found to influence health service use. Sami youth in more assimilated ethnic contexts used general practitioners more than non-Sami youth. Youth with Sami self-identification had a higher probability of using the school health service compared with other youth. Ethnic barriers to health service use were also identified. Sami speaking youth with a high degree of perceived discrimination had lower probability of using school health services than non-Sami speaking youth. Sami youth with conduct problems were less likely than non-Sami to use psychologist/psychiatrist. The present study demonstrated a relationship between health need and actual health service use., Conclusion: Culture-specific factors influenced the help-seeking process in indigenous youth; some factors acted as barriers against health service use and other factors increased the probability of health service use.

Objectives: Genital and reproductive function have a strong effect on the quality of life of adolescent and adult male patients with the exstrophy-epispadias complex (EEC). According to the limited available data, early exstrophy reconstruction, as well as recurrent infectious or operative trauma, have been responsible for the low fertility rates., Methods: We evaluated 21 adult male patients with EEC. Of the 21 patients, 17 had undergone single-stage reconstruction, 1 had undergone a staged approach, 2 had primarily undergone urinary diversion, and 1 had only undergone external genital reconstruction of epispadias. All were evaluated with a semistructured questionnaire, clinical examination, ultrasonography, and hormonal and semen analyses., Results: All patients reported erections, and 19 were sure about ejaculation. Of the 21 patients, 18 patients proved antegrade and 1 retrograde ejaculation; 2 patients were not able to retrieve their specimen. Fifteen patients had a regular testicular size, and four had unilateral and two bilateral small testes. Four had irregular intratesticular ultrasound findings. Of these 4 patients, 1 had a testicular intraepithelial neoplasia that was treated with radiotherapy. The hormonal analysis findings were normal for 17 patients and 4 had elevated follicle-stimulating hormone levels. The semen analysis showed normozoospermia in 3, asthenozoospermia in 5, oligo-asthenozoospermia in 6, and azoospermia in 5 patients. The seminal parameters included fructose 1441.8 microg/mL (normal 1200-4500), zinc 43.3 microg/mL (normal 70-250), and alpha-glucosidase 19.13 mU/mL (normal >20)., Conclusions: Single-stage reconstruction with consequent placement of the colliculus seminalis in the posterior urethra results in normal ejaculation in 94.1% of patients with EEC. Because of the severely impaired sperm quality and hormonal findings, patients with EEC should be offered adequate diagnostic and treatment options.

The screening for additional human YjeF_N domain containing proteins beside the apolipoprotein A-I interacting protein (AI-BP), identified two other genes designated hYjeF_N2-15q23 (formerly human homologue of yeast edc3) and hYjeF_N3-19p13.11 comprising the human YjeF_N family. AI-BP is ubiquitously expressed, with a predominance of these tissues where the homologues were found to be restricted including brain, mammary gland, testes and ovaries. Immunohistochemistry of human testes and ovaries showed an expression of hYjeF_N3-19p13.11 only in Leydig cells and theca cells, respectively, indicating a role in steroid hormone metabolism. Interestingly, the protein was also strongly expressed in Leydig cell tumors and in thecofibromas. The identification of hYjeF_N2-15q23 in theca cells and granulosa cells in ovaries, in human spermatids of meiotic division part II and the apical membrane of Sertoli cells in testes suggest similar functions in oogenesis and sperm maturation which is strengthened by the identification of the spermatogenesis regulator HMGA1 as a conserved transcription factor. However, in contrast to AI-BP, both homologous proteins are unable to bind apoA-I. These results relate the human YjeF_N domain containing protein family to cholesterol processing and steroid hormone metabolism in spermiogenesis and oogenesis, and AI-BP may link this function to the HDL pathway.

The partial androgen deficiency in aging male (PADAM) has been of great interest to investigators and the public in the last few years. For males, androgens are said to be essential for the maintenance of quality of life (QoL) but there are no data available with respect to QoL and PADAM yet. In order to evaluate changes of individual well-being of males older than 50 years and with subnormal levels of free testosterone (FT) (<200 pmol l(-1)), these men were asked to fill in a questionnaire regarding QoL. The objective of this study was to compare age-matched males with androgen deficiency (group 1; n = 24) and normoandrogenic elderly men (group 2; n = 24) with respect to QoL and somatic indicators of the endocrine status. Participants suffered from benign prostatic hyperplasia (BPH) and were hospitalized for prostate surgery. Health-related QoL was assessed by the SF-12 Health Survey, including the physical health index and the mental health index. The SF-12 was enlarged by the scales 'vitality' and 'psychological well-being' of the SF-36. Additionally, patients were asked about social and clinical items. There were no statistically significant differences between the two groups regarding social and clinical parameters. The physical health index was reduced in group 1 (P < 0.05; effect size was medium (d = 0.57)) whereas the mental health index was similar in both groups. The correlation between the two health indices was very low and not statistically significant (r = 0.05, P = 0.72). Patients of group 1 described a lower vitality compared to group 2 (P < 0.05), but no differences could be observed regarding psychological well-being. Therefore, androgen-deficient patients seem to have the impression of a reduced physical ability. Our data emphasize that the subjective description of health-related aspects of QoL is a very sensitive methodological approach to discover psychological differences between patients. For the differentiation between androgen-deficient patients and those with normal testosterone levels the physical health index seems to be more sensitive than the mental health index. A question of interest is whether this difference remains detectable if testosterone is supplemented to androgen-deficient men. Whether testosterone supplementation is beneficial to these patients has to be carefully considered.

Background: Although considerable research has examined beliefs and learning outcomes (e.g. Schommer, 1990, 1993a, 1993b; Schommer & Dunnell, 1997), little has looked at the relationship between beliefs and the actual learning process., Aims: This research examines the relationship between beliefs about learning and knowledge, and reports of learning strategy-use relevant for successful text comprehension., Sample: Participants were 81 Norwegian university students who had studied from 1 to 4 years in a range of disciplines., Method: Students' beliefs about knowledge and learning were measured with the Schommer Epistemological Questionnaire (SEQ; Schommer, 1998b). Learning strategies particularly useful for text-based learning were measured with the Motivated Strategies for Learning Questionnaire (MSLQ; Pintrich, Smith, Garcia, & McKeachie, 1991). A correlational analysis between measures and full regression analyses of how beliefs influence strategy selection were performed., Results: Beliefs about how thoroughly knowledge is integrated in networks (simple) and how fixed the ability to learn is from birth (fixed) contributed significantly to reported strategy use: Simple to rehearsal and organizational strategies, fixed to elaboration and critical thinking strategies, and a combination of simple and fixed to strategies relevant to the thoughtful monitoring of learning tasks. Beliefs about how certain knowledge is (certain) and how quickly learning can be expected to occur (quick) were not found to contribute to reported learning- strategy use in any significant way., Conclusion: Some, but not all, beliefs about knowledge and learning offer insight into students' reported use of learning strategies relevant for reading course literature.

Objective: To evaluate the risk of testicular damage from testicular biopsies that are carried out for testicular sperm extraction (TESE) in infertile men., Design: Prospective controlled clinical study., Setting: Academic hospital., Patient(s): Forty infertile males with azoospermia. Examination of the clinical, endocrine, biochemical, and sonographic data in average after 18 months after TESE was performed., Main Outcome Measure(s): Measurements before and after TESE: hormone values, testicular size, morphologic characteristics, and power Doppler after scrotal sonography., Result(s): Comparison of preoperative and postoperative values of basal testosterone, FSH, LH, and estradiol levels did not reveal any differences. Twelve of 26 patients had subnormal testosterone values before TESE; 14 of 39 patients had subnormal levels afterward. Postoperative sonographic measurements showed no significant difference of the testicular volume as compared with the preoperative values. Results of power Doppler sonography revealed pathological conditions (n = 5) in patients with former iliacal or testicular operations., Conclusion(s): Endocrine testicular function and testicular size were not impaired after testicular biopsy when compared with preoperative data. However, patients with nonobstructive azoospermia seem to be at risk for androgen deficiency due to primary testicular failure after repeated testicular biopsies.

Steroid 5alpha-reductase deficiency is a rare autosomal recessive disorder caused by mutations in the SRD5A2-gene, resulting in diminished dihydrotestosterone (DHT) formation and, hence, in a severe virilization deficit of the external genitalia in patients with 46,XY karyotype. The phenotype of affected individuals is variable and has been reported to range from completely female over genital ambiguity to normal male, depending on the type of mutation and its effect on enzyme activity. Here we report an adolescent 46,XY patient with predominantly female appearance, who had been gonadectomized in early infancy. Genital status revealed a urogenital sinus equivalent to Prader stage III. Molecular genetic analysis demonstrated a homozygous point mutation in exon 2 of the SRD5A2-gene, leading to a premature termination in codon position 111 of the 5alpha-reductase 2 enzyme, and not allowing formation of a functional 5alpha-reductase type 2 enzyme. This case demonstrates that even despite a complete loss of function of 5alpha-reductase type 2, marked virilization is possible, most likely the result of a testosterone (T) effect during foetal life.

Objective: To investigate the ICSI outcome of the patients who produced four follicles or less after ovarian stimulation using frozen-thawed surgically obtained spermatozoa., Study Design: The patient cohort of this study was composed of a carefully selected group of 20 men suffering from obstructive and non-obstructive azoospermia and in whom spermatozoa had been seen in their harvested epididymal aspirates and testicular tissues and the cryopreserved specimens had been used for subsequent ICSI cycles. This group of men represent those in whom the female partners produced only four follicles or less after ovarian stimulation., Results: For the cases of obstructive azoospermia with MESA (n=6) a total of nine cycles was carried out. Four couples went through one cycle, one couple underwent two cycles, one couple accomplished three cycles. Out of the nine cycles, seven went to embryo transfer. No pregnancy occurred in the MESA-ICSI group of patients. The mean+/-S.D. number of oocytes per cycle was 2.556+/-1.236, the mean+/-S.D. number of embryos per transfer was 1.444+/-1.014. Two couples did not have an embryo replacement because of absence of fertilisation. The mean+/-S. D. number of gonadotropin ampoules was 53.88+/-37.30 and the mean+/-S.D. duration of ovarian stimulation was 13.38+/-4.534 days. For the cases of non-obstructive azoospermia with TESE (n=14) a total of 16 cycles was carried out. Thirteen couples went through one cycle, one couple accomplished three cycles. Out of the 16 cycles, 11 cycles went to embryo transfer. One pregnancy occurred in the TESE-ICSI group of patients, which produced live offspring. The mean+/-S.D. number of oocytes per cycle was 3.00+/-1.211, the mean+/-S.D. number of embryos per transfer was 1.313+/-1.195. Five couples did not have an embryo replacement, four of them because of absence of fertilisation and one because of abnormal fertilisation (3 PN). The mean+/-S.D. number of gonadotropin ampoules was 81. 77+/-53.40 and the mean+/-S.D. duration of ovarian stimulation was 16.71+/-3.667 days., Conclusion: In our opinion, these data show that it is possible to achieve satisfactory fertilisation rates using frozen-thawed epididymal and testicular spermatozoa obtained from men with obstructive or non-obstructive azoospermia, but the limiting factor in reaching the stage of embryo transfer is the poor ovarian response to stimulation induction. It therefore seems preferable to cancel these cycles, in the hope that a better response might be obtained in a subsequent cycle, avoiding in this way financial and emotional implications.

Spermatozoa from seven healthy donors (two of whom had already fathered children) and five infertile patients taking part in the local programme of intracytoplasmic sperm-injection (ICSI) were investigated for the disomy rates of chromosomes 13/21, 18, X and Y as well as for the diploidy rates. Two- and three-colour fluorescence in situ hybridization (FISH) was applied after a donor-adapted decondensation pre-treatment: in a preliminary decondensation series the optimum fluorescence signals were individually determined by variation of the concentration of the decondensation reagents and the duration of incubation with these reagents. Strict scoring criteria were applied. The average disomy rates ranged from 0.10% (chromosomes 13/21) to 0.44% (disomy XY) in the infertile donors and from 0.07% (disomy XX) to 0.36% (disomy XY) in the controls. The average diploidy rates were 0.22% and 0.20% for the infertile donors and the controls respectively. There was no statistically significant difference between the two groups with respect to the disomy and diploidy rates. Within the two groups there were inter-individual differences which were partly statistically significant, indicating considerable inter-donor variation of the aneuploidy rates.

Abnormal human spermatogenesis is caused by a variety of genetic and acquired conditions. Because spermatogenesis is dependent on androgens, some males may have a minimal form of androgen insensitivity that does not inhibit virilization but impairs fertility. This has lead us to investigate the possibility of abnormalities in the androgen receptor (AR) gene in a large cohort of males suffering from infertility of unknown cause. We studied 180 males with variable impairment of spermatogenesis. In all patients, serum levels of testosterone and gonadotropins were analyzed to define an androgen sensitivity index (ASI). Single-strand conformation analysis and direct DNA sequencing of PCR-amplified blood leukocyte DNA were used to identify mutations within the whole coding region of the AR-gene. Endocrine and molecular investigations were compared with 53 normal males with proven fertility. In three infertile males, mutations in the AR were identified. Two unrelated males had the same variation within the first exon encoding for the transactivation domain of the receptor (Pro390Ser), whereas, in the third, a mutation in the hormone-binding region was characterized (Gln798Glu). All identified mutation carriers had a significantly elevated ASI. A proportion of males with idiopathic infertility carry relevant variations within the AR-gene. These males may be distinguished on the basis of hormone levels, calculating the ASI, although this index lacks specificity.

Objective: To determine the feasibility of using frozen-thawed testicular spermatozoa for intracytoplasmic sperm injection., Design: Prospective clinical study., Setting: A university hospital., Patient(s): One hundred seventy-five azoospermic men participating in a routine intracytoplasmic sperm injection program., Intervention(s): The men underwent testicular biopsy for cryopreservation of tissue to be used in consecutive intracytoplasmic sperm injection treatment cycles. Their female partners underwent controlled ovarian hyperstimulation for conventional IVF treatment., Main Outcome Measure(s): Fertilization and pregnancy rates., Result(s): In 77% of the patients, spermatozoa could be harvested from the testis by an open testicular biopsy technique and used for intracytoplasmic sperm injection after freezing and thawing of testicular tissue. Histopathologic evaluation revealed a Sertoli cell-only pattern in 21%, maturation arrest in 60%, and hypospermatogenesis in 19% of the patients. In 2. 9% of the patients, carcinoma in situ or a germ cell tumor was detected. In all patients, viable spermatozoa could be visualized after the tissue samples were thawed. One hundred thirty-five intracytoplasmic sperm injection treatment cycles were performed, with a fertilization rate of 45% and a clinical pregnancy rate of 30% per oocyte retrieved., Conclusion(s): The use of frozen-thawed testicular tissue allows ovarian stimulation of the female partner to be timed and avoids cancellation of ovum pick-up when spermatozoa cannot be retrieved.

Supernumerary pronucleated stage oocytes (PN) are usually cryopreserved. PN are transferred in spontaneous, stimulated or artificial cycles. In this study, an artificial cycle with a transdermal therapeutic system was used for oestradiol release (Estraderm TTS 100) in combination with a targeted drug delivery system for vaginal progesterone release (Crinone 8%). Patients started transdermal 17beta-oestradiol treatment on cycle day 1. Only one clinical monitoring was necessary on day 14 for confirmation of satisfactory endometrial development and exclusion of ovulation by transvaginal ultrasound and endocrine determinations (oestradiol, progesterone and luteinizing hormone). Embryo transfer was performed on the third day of progesterone treatment (day 17). The first 25 cycles were recently completed in a prospective study; no cycles were cancelled due to ovulation or unsatisfactory endometrial development. In comparison with the previous protocol of embryo transfer in stimulated cycles in our clinic which required extensive ultrasound and endocrine monitoring, the pregnancy rate in these oestrogen- and progesterone-supplemented cycles was nearly twice as high (34.8%). Two pregnancies were even achieved with zygotes after micro-injection of frozen-thawed late spermatids extracted from testicular tissue (cryo-TESE). In these cycles, the Estraderm TTS 100/Crinone 8% protocol seems to be superior to stimulation protocols and even to other protocols reported so far for artificial cycles with exogenous oestradiol and progesterone treatment.

Microinjection is established as the method of choice in the treatment of severe male factor infertility as well as in azoospermic patients. Recent studies have shown that fertilization and cleavage can be achieved by injection of ejaculated as well as testicular elongated spermatids into oocytes. Here we report on the two first pregnancies worldwide resulting from elongated spermatid injection from frozen-thawed testicular tissue. Four patients with complete Sertoli cell-only syndrome (SCOS) and two with spermatogenetic maturation arrest were included in our microinjection programme. Tissues from open testicular biopsies were cryopreserved until the time of follicle puncture. A total of 67 oocytes were harvested. In the two patients with maturation arrest, cryopreserved elongated spermatids were successfully injected, while in two of the other four SCOS patients only cryopreserved round spermatids were available to be injected into the oocytes. Out of 18 injected oocytes, 10 were fertilized in the first group, while nine out of 49 injected oocytes showed fertilization and cleavage in the second group. Two clinical pregnancies were achieved with elongated spermatids from frozen-thawed testicular tissue, while no pregnancy was established in the case of round spermatids. This study confirms that fertilization, cleavage and pregnancy can be successfully achieved in cases with spermatogenetic maturation arrest by injecting cryopreserved elongated spermatids into oocytes. The literature on pregnancies following spermatid injection, as well as the problems using this technique and possible risks, are discussed.

The use of frozen-thawed testicular tissue as a source of spermatozoa for intracytoplasmic sperm injection (ICSI) in non-obstructive azoospermia yields favourable fertilization and pregnancy rates while avoiding both repetitive biopsies and unexpected cycle cancellations. Spermatozoa were obtained from frozen-thawed testicular biopsy specimens from 67 non-obstructive azoospermic men. Following fertilization, supernumerary two pronuclear (2PN) oocytes were frozen. After thawing, 17 cycles of embryo transfer were carried out with a mean number of 2.7 embryos and a mean cumulative embryo score (CES) of 18.3 per transfer. The clinical pregnancy and implantation rates per transfer in these cycles (23.5 and 8.3% respectively) were comparable to those of fresh embryo transfers (35.7 and 12.7% respectively) with a mean number of 2.7 embryos and a mean CES of 28.7 per transfer. Abortion rates, although higher with cryopreserved 2PN oocytes were not significantly different. With this approach, cryopreservation of supernumerary 2PN oocytes can be used to improve the cumulative pregnancy rates in a severely defective spermatogenetic population. To our knowledge, these are the first pregnancies reported which have been obtained by the transfer of cryopreserved pronuclear oocytes obtained from ICSI using cryopreserved testicular spermatozoa.

Preliminary data have suggested that female infertility due to corpus luteum insufficiency may be caused by subclinical hypothyroidism [exaggerated thyroid-stimulating hormone (TSH) response to thyrotrophin-releasing hormone (TRH) stimulation]. L-Thyroxine supplementation has been recommended to achieve pregnancies in subclinical hypothyroid women. This controlled study was carried out in order to investigate the biochemical diagnosis of subclinical hypothyroidism as a possible infertility factor. Five infertile patients (aged 25-36 years) with subclinical hypothyroidism (n = 4, stimulated TSH >20 microU/ml) or primary hypothyroidism (n = 1) and five healthy controls (aged 22-39 years) with normal thyroid function (stimulated TSH <15 microU/ml), regular cycles and no history of infertility were studied in the early follicular phase. In the pre-study evaluation, eight of 23 volunteers (34.8%) had to be excluded because of subclinical hypothyroidism with stimulated TSH values (TSHs) >15 microU/ml. Cycle function of patients and controls was compared by the method of LH pulse pattern analysis. Therefore blood samples were drawn every 10 min during a 24 h period. Sleep was recorded from midnight to 7 a.m. Repetition of the TRH tests at the end of the 24 h blood sampling period confirmed the difference in stimulated TSH values of the two study groups. Pulse analysis for luteinizing hormone (LH), TSH and prolactin showed no differences between patients and controls for pulse frequency, amplitude, height, length, area under curve (AUC) and the 24 h mean. Even the hypothyroid patient had a normal LH pulse pattern. Additional measurement of melatonin in pooled sera every 30 min gave the well-documented diurnal profiles during day and night for both groups. Patients had significantly higher melatonin values at seven time points during the night. Peaks for LH, TSH, prolactin and cortisol were correlated with the sleep stages wake, rapid eye movement, 1 + 2 and 3 + 4. We concluded that corpus luteum insufficiency in female infertility cannot be explained by subclinical hypothyroidism and thus should not be treated with L-thyroxine for fertility reasons.

Among other factors contributing to male infertility, chromosomal anomalies are a frequent finding. Investigating 440 males with reduced sperm counts (< 20 x 10(6)/mL) we found 19 males with chromosome abnormalities (aneuploidies and translocations). This frequency of chromosomal aberrations (4.3%) is much higher than in the normal population. We were able to investigate sperm nuclei from seven out of these 19 men with molecular cytogenetic methods. There were two carriers of Robertsonian translocations, two had a constitutional reciprocal translocation and three were XYY males. In addition, one other man with a long history of infertility and a marker chromosome 15 was included. Using fluorescence in-situ hybridization, it was possible to investigate a great number of sperm nuclei in each case. Each translocation case showed a specific mode of chromosomal segregation; confirming the dependence on chromosomes involved and the individual segregation pattern in each patient. The well known elimination of the supernumerary Y-chromosome in XYY males during meiosis was confirmed in our study. Molecular cytogenetic investigations in sperm provide a more reliable risk estimate with respect to the possible injection of chromosomally unbalanced sperm during intracytoplasmatic sperm injection and can be valuable in genetic counselling.

Objective: To avoid multiple pregnancies caused by ovulation induction., Setting: Infertile couples treated in the Women's Hospital and the Institute of Reproductive Medicine of the University of Münster, Münster, Germany., Design: The outcome of ovulation induction in patients in whom supernumerary ovarian follicles were aspirated transvaginally was compared with the outcome in patients in whom this intervention was not necessary. In a second randomized prospective study, the efficacy of a low dosage of gonadotropins was compared with a higher dosage., Patients: Two hundred twenty-seven couples suffering from male infertility, unexplained infertility, incipient ovarian failure, and polycystic ovaries., Interventions: Aspirations were performed if more than three follicles were sized > 14 mm., Main Outcome Measure: Number of (multiple) pregnancies., Results: During 232 ovulation inductions, 127 aspirations of supernumerary follicles were performed (54.7%). The pregnancy rate (PR) in these cycles was similar to cycles in which aspirations were unnecessary (24.4% versus 21.9%). The efficacy of 75 units of FSH administered daily during the recruitment phase of follicular development was equivalent to 150 units of FSH (PR: 32.4% versus 31.6%), but supernumerary follicles were fewer (26.5% versus 76.3%). Six twins, two triplets (multiple PR: 10.4%), and no ovarian hyperstimulation syndrome occurred., Conclusions: Transvaginal aspiration of supernumerary follicles does not reduce the PR in ovulation induction. Supernumerary follicles can be avoided by low-dose administration of gonadotropins without compromising the PR.

Clinical symptoms of Cushing's syndrome were recognized in approximately 23 of 97 successive hirsute women attending the Endocrinological Department of the Women's Hospital. Endocrine and radiological examinations ultimately confirmed Cushing's syndrome caused by pituitary microadenomas (Cushing's disease) in only 2 women. In 17 of the remaining 21 patients suspected of having Cushing's disease hypercortisolism could not be diagnosed by classical endocrine tests. Thus further endocrinologial tests as corticotrophin releasing hormone (CRH)-tests (100 micrograms i.v.) and insulin tolerance tests were initiated including serum and stress-free salivary cortisol profiles during the day. Diurnal cortisol profiles showed higher values in the morning than during the night, but intermittent elevated cortisol concentrations could be detected. Finally, seven patients could be classified as suffering from a special form of pituitary ACTH-dependent hypercortisolism, named intermittent Cushing's disease (ICD). It is characterized by severe Cushingoid symptoms like marked central adiposity, purple striae, hirsutism and acne, intermittently increased cortisol concentrations, no cortisol response to hypoglycaemia, but preservation of some diurnal variation of serum or saliva cortisol. Three of these seven patients had diagnostic transsphenoidal neurosurgery and pituitary ACTH-producing microadenomas were removed in two women. Repeated determinations of the circadian rhythm of cortisol in saliva samples in combination with an overnight 1 mg dexamethasone suppression and an insulin stimulation test, are recommended to diagnose patients with suspicion on ICD even in an outpatient clinic.

During a polysomnographic (2 nights) sleep registration of 5 chronically stressed compared to 5 control persons 24 h blood cortisol values and salivary cortisol at daytime were measured and compared with measured stress vulnerability. While daytime cortisol levels were reduced under stress conditions, during night sleep combined with a significant change in sleep architecture cortisol excretion raised markedly compared to controls, and the cortisol response to CRF provocation is no more blunted but activated beyond controls, demonstrating the restitutive and protective effect of sleep.

In a patient, suffering of apituitarism after the surgical removal of a cranyopharyngeoma at the age of 14, was treated with various doses of human urinary gonadotropin preparations for in vitro fertilization and embryo transfer. The first five treatments were performed without the additional administration of recombinant growth hormone, but due to the administration of increasing doses of exogenous gonadotropins a pregnancy was finally achieved leading to the birth of a healthy girl. Later, as the couple desired a second baby, the treatment was repeated using a low dose of gonadotropins in combination with recombinant growth hormone. This combined treatment was immediately successful, leading to the birth of a healthy boy. The present communication offers a complete survey of the existing literature about the use of recombinant growth hormone in support of ovarian stimulation with gonadotropins. The ongoing controversy is caused by the lack of an established methodology for the diagnosis of growth hormone deficiency. Whereas the efficacy of the additional use of recombinant growth hormone in support of ovarian stimulation with gonadotropins is established in patients without any endogenous growth hormone secretion, its use in patients with less defined hormonal disturbances remains controversial.

The potential advantages of pulsatile s.c. administration instead of daily bolus i.m. administration of human urinary gonadotrophin preparations were tested after the administration of a long-acting gonadotrophin-releasing hormone (GnRH) analogue within a programme for in-vitro fertilization (IVF) and embryo transfer. First, the pharmacokinetic properties of human urinary gonadotrophins were analysed with immunological and biological methods, both during bolus i.m. injections and during pulsatile s.c. administration. Second, a prospective randomized controlled study was performed in 75 patients undergoing IVF/embryo transfer in whom the effects of pulsatile s.c. administration were compared with the effects of single daily bolus i.m. injections of the same gonadotrophin preparation. The results showed that neither method of gonadotrophin administration induced measurable changes in the serum concentration of luteinizing hormone (LH). Both oestradiol and androstenedione concentrations were slightly lower during pulsatile s.c. gonadotrophin administration, suggesting that this method of gonadotrophin administration results in less LH occupying the ovarian LH receptors. Pulsatile s.c. gonadotrophin administration resembles a continuous infusion of follicle-stimulating hormone (FSH). Significant fluctuations in the serum concentrations of FSH were observed during single daily bolus i.m. administration of human urinary gonadotrophins, but the pregnancy rate of IVF/embryo transfer per cycle after pulsatile s.c. administration was not significantly better than after the daily bolus i.m. injection of gonadotrophins (42.1 versus 37.2%). It is concluded that pulsatile s.c. administration of gonadotrophins instead of single daily injections does not improve the pregnancy rate in IVF/embryo transfer.

Individually adapted gonadotropin dosage is more successful than standardized schemes for ovarian stimulation prior to in vitro fertilization and embryo transfer. Unfortunately, differences in ovarian response can not be predicted reliably. In order to develop predictive parameters for ovarian response the data from 99 cycles in 69 patients were analysed retrospectively. Before initiating ovarian stimulation for in vitro fertilization, an untreated menstrual cycle was examined using a commonly used endocrinological screening protocol. The ovaries were then stimulated with exogenous gonadotropins after previous suppression of endogenous gonadotropin secretion using a long-acting GnRH-analogue. The predictive value of this endocrinological screening protocol for ovarian response was evaluated. Ovarian response was defined as the logarithmically transformed ratio of the serum estradiol concentration at ovulation induction, divided by the number of ampoules of exogenous gonadotropins administered. Comparison of the various hormone characteristics with ovarian response led to identification of two distinct groups of patients showing reduced ovarian response: those with elevated serum levels of FSH on the third cycle day (> 9 units/l, P < 0.0001), and those with elevated serum levels of estradiol on the third cycle day (> 190 pmol/l, P < 0.02). Patients with high serum levels of TSH in the TRH test responded poorly to ovarian stimulation (P < 0.05), but also showed significantly higher serum concentrations of FSH (P < 0.01). No parameter correlated positively with ovarian response.

In 118 successive infertile women (aged 22-40 years, median 30 years) with longstanding infertility from our infertility clinic we performed an endocrinological (TRH-test, TT3, TT4, TBG, antibodies) as well as a morphological thyroid examination (sonography and 99mTc-scintigraphy. The same endocrinological investigations except TRH-test and a thyroid sonography was performed in the control group (50 fertile women, aged 24-39 years, median 33 years). Two patients were hyperthyroid and one patient had primary hypothyroidism. Antibodies against thyroglobulin (TgAK) and thyroid peroxidase (TPO) or microsomal antibodies (MAK) were found in 19 patients (19%). The incidence of biochemical immunological thyroiditis was not significantly different from the control group. But thyroid volume was significantly higher in patients (21 versus 15.6 ml, p < 0.03). Goitre (> 18 ml) was diagnosed in 52% (n = 57) of the patients, although 43 had normal TRH-test results with delta TSH 2.5-12.5 microU/ml. So-called subclinical (latent) hypothyroidism (delta TSH > 12.5 microU/ml) was found in 29 patients; 18 of these infertile women had no goitre. Iodine avidity (99mTc-uptake) increased significantly with the increase in thyroid volume, but showed a tendency to lower values with increasing delta TSH-values and higher iodine avidity in women with thyroid enlargement (n = 109). During follow-up of 12-24 months 10 women with goitre conceived spontaneously after initiation of iodine and/or L-thyroxine 100 micrograms treatment. These data support recent studies, that factors other than TSH cause thyroid enlargement.(ABSTRACT TRUNCATED AT 250 WORDS)

Every year, a special federal program arranges for the arrival of about 12,000 educated women to Canada to work several years in private homes as housekeepers. However, in order to meet the needs of the employer and the Canadian economy, these women are denied their fundamental freedoms and are deliberately kept in a precarious situation material and psychologically and with respect to their status. Because it exposes these female workers to such factors of instability and to the negative effects of key experiences, this program carries the seed of mental illness.

In this double blind cross-over study, 20 infertile men, who had sperm antibodies detected by the mixed antiglobulin reaction (MAR test) in the ejaculate and by the tray agglutination test (TAT) in serum, were treated with 40 mg/day prednisolone or placebo from days 1 to 10 of the partners' menstrual cycle. Patients were randomly allocated to different treatment groups. While group 1 started with placebo followed by verum for three consecutive cycles, group 2 began with verum and continued with placebo. All patients had regular intercourse (n = 19) or intra-cervical insemination at ovulation (n = 1). A post-coital test or a sperm penetration test was performed during verum and placebo regimes. Blood samples were drawn from the male partner at this time to control the efficacy of prednisolone treatment by checking the TAT titre. No pregnancy occurred during prednisolone or placebo treatment. In eight of 12 patients, post-coital testing showed little improvement and antibody titres decreased in seven of 16 patients. Side-effects from medication were reported by eight patients (seven verum and one placebo cycle) and caused treatment to be discontinued in two cases. Five patients' partners conceived at a later stage by intrauterine insemination with spermatozoa prepared by 'swim up' (n = 3) or by in-vitro fertilization (IVF n = 2). Thus high dose corticosteroid therapy was ineffective in achieving pregnancies induced by infertile men positive for antisperm antibodies. Since side-effects of corticosteroids should not be underestimated in otherwise healthy men, other reproductive techniques such as intrauterine insemination or IVF should be offered to such couples.

To assess possible side effects of transcranial magnetic stimulation on the release of anterior pituitary gland hormones three different examinations on 10 males were performed following a standardized protocol. Plasma levels of prolactin, FSH, LH, hGH and cortisol were determined before and after stimulation. Cortical stimulation had no specific influence on the plasma levels of the hormones examined.

Lead and copper concentrations were determined by atomic absorption spectroscopy in semen from 18 fertile and 172 infertile men. Significant correlations between copper concentrations in semen and sperm concentration (r = 0.32, P less than 0.001), percentage progressive motility (r = 0.23, P less than 0.005) and normal morphology (r = 0.22, P less than 0.005) were observed, while no such correlation existed for lead. However, semen copper concentrations of infertile men (194.99 +/- 5.70 micrograms l-1) and fertile men (183.39 +/- 14.37 micrograms l-1) did not differ significantly. Mean lead concentration in semen of fertile men was 11.18 +/- 0.62 micrograms l-1 and significantly higher than lead concentration in semen of fertile men (5.61 +/- 0.53 micrograms l-1, P less than 0.006). Reinvestigation of 18 infertile men after 2 years showed a significant drop of lead concentrations in semen from 17.31 +/- 1.41 to 6.94 +/- 1.32 micrograms l-1 (P less than 0.0002), which might be related to the decreasing use of leaded petrol in the Federal Republic of Germany.

Three brothers with congenital transposition of the penis, scrotal hypospadias, bifid scrotum, and bilateral undescended testes are described. Further signs of incomplete virilization, but no gynecomastia were seen. LH and FSH were elevated, whereas testosterone levels were reduced or in the normal range. Serum concentrations of 17-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, 5 alpha-dihydrotestosterone and estradiol measured in two affected brothers were in the normal range. Fibroblasts from scrotal skin biopsies performed in two patients showed normal 5 alpha-reductase activity (419 and 214 pmol.(mg protein)-1.h-1; normal greater than 1), whereas androgen receptors had reduced maximal binding capacity (Bmax 4 and 14 fmol.(mg protein)-1; normal greater than 18) and an increased equilibrium dissociation constant (0.7 and 1.26 nmol/l: normal 0.2 +/- 0.08) indicating a quantitative and qualitative androgen receptor defect. These patients represent a further variant of androgen insensitivity.

To evaluate the influence of indomethacin and oxaprozin on reproductive function in healthy young men, 34 volunteers with normal semen parameters were recruited. In a randomized double-blind design, 12 men were treated with placebo, 12 received 600 mg/day of oxaprozin and 10 took indomethacin 25 mg t.i.d. This treatment phase lasted for 14 days after which a follow-up period extended for another 10 weeks. Sperm counts, percentage of motile and normally formed sperm cells, sperm velocity, linearity, lateral head displacement and beat frequency were evaluated by computerized image analysis once before treatment and at weekly intervals during the rest of the study. Prostaglandin levels in seminal plasma were significantly reduced after 2 weeks of treatment and remained suppressed for at least 2 additional weeks. In spite of this long lasting impairment of physiologic prostaglandin concentrations, no changes in any of the measured parameters were detectable when compared with the placebo group. Basal levels of testosterone, estradiol, LH, FSH, TSH and prolactin were unchanged. The response of hypophyseal hormones to a combined GnRH/TRH test before, during and after the treatment also was not affected. Overall, no negative influence of indomethacin or oxaprozin treatment on male reproductive function could be found in healthy volunteers. Since the active treatment phase was only 14 days, one can only speculate about long term effects of the tested drugs on reproductive parameters in men.

In order to evaluate GnRH administration for the treatment of infertile men with elevated serum FSH levels we administered GnRH in pulses via portable electronic infusion pumps initially to seven patients with low sperm counts and high FSH values over 12 weeks and later to nine further patients over 24 weeks who also underwent testicular biopsies. Fifty microlitres containing 5 micrograms GnRH were infused subcutaneously for 1 min every 120 min in the short-term study and every 90 min in the long-term study. Although FSH levels could be lowered in both groups of patients, none showed any improvement in sperm count or other seminal parameters. Therefore, pulsatile GnRH treatment cannot be recommended for therapy of severe oligozoospermia with elevated FSH levels.

A transdermal therapeutic system (TTS) for administration of testosterone was tested in healthy and hypogonadal men. To ensure adequate absorption, a testosterone-loaded film was applied to the scrotal skin. The TTS was designed to last for 22 h; over this time serum testosterone levels in normal men were moderately increased, with concentration curves almost parallel to basal levels. Seven hypogonadal patients also responded to TTS testosterone; serum testosterone levels were in the normal range during a 12-week treatment period. There were no side-effects. TTS testosterone offers a new approach to androgen substitution therapy.

Human and bovine cervical mucus penetration tests (n = 57) were performed preceding IVF to test their prognostic value as sperm function tests for IVF. This evaluation also included results from conventional semen analysis and from a computerized sperm analysis system. The bovine cervical mucus penetration test was shown to be at least as valuable as the human cervical mucus penetration test in evaluating sperm function. The migration distance of the vanguard sperm (P less than 0.001) and the sperm density at a fixed migration distance in the mucus column (P less than 0.05) correlated most closely with the IVF results. A clear parallelism with the outcome of the 'swim up' technique was also found. Of the sperm parameters examined, only sperm motility in the ejaculate (P less than 0.05) correlated significantly with the results of IVF. It is concluded that the outcome of a bovine cervical mucus penetration test depends on the same sperm functions as required for IVF. Therefore, this test may be of predictive value in an IVF programme.

Current testosterone substitution therapy either by injectable or oral testosterone esters suffers from markedly fluctuating serum testosterone levels often far above or below the physiological range. Recently, a transdermal therapeutic system (TTS) for the delivery of testosterone was developed which, when applied to the scrotum, provides smooth serum testosterone levels. Here we report results from seven hypogonadal men treated with the TTS for 14 months by applying a new patch every day. In all patients serum testosterone and dihydrotestosterone (DHT) determined 3-5 h after applying a new patch increased significantly and remained within the physiological range during the entire treatment period. The DHT/testosterone ratio remained constant. In 4 of these patients and 2 others under TTS treatment serum testosterone and DHT were also determined over a 24-h period at regular intervals. In these patients serum testosterone levels in the physiological range were seen during the entire observation period, whereas an increase in the DHT/testosterone ratio occurred towards the end of the one-day treatment phase. All patients in the 14-month treatment study were clinically well substituted and responded with good compliance. Clinical chemistry showed no abnormalities during treatment. Thus, the TTS appears to be an effective and safe new modality for the treatment of male hypogonadism.

Multiple tests were done on the ejaculates of 10 asthenozoospermic patients and nine healthy normozoospermic volunteers in an attempt to identify individually the cause of low sperm motility in these patients. Possible defects in the sperm plasma membrane and the motility apparatus of sperm, and in epididymal function affecting the development of motility, were investigated. The presence of seminal sperm antibodies or any motility-inhibiting factors in the seminal plasma that could be removed by washing were also tested. Each test was positive in only one or two patients but axonemal dysfunction was identified in nine patients. Removal of seminal plasma from asthenozoospermic samples did not improve sperm motility to any greater extent than with donor ejaculates, and the motile sperm of these patients exhibited characteristics mostly similar to those of donors under various incubation conditions. Selection procedures are, therefore, required to obtain samples of good quality sperm from such asthenozoospermic ejaculates.

In an effort to evaluate the effect of hCG/human menopausal gonadotropin (hMG) treatment on semen parameters in normogonadotropic men suffering from oligospermia, a double blind, placebo-controlled study was conducted. After 2 basal examinations of seminal parameters and reproductive hormones, 39 men were recruited for the trial. Nineteen men, allocated randomly to the active drug group, received im injections of 2500 IU hCG twice a week in combination with 150 IU hMG three times a week for 13 weeks, while 20 men were treated, following the same injection schedule, with NaCl only. After the 13-week treatment period, follow-up examination was performed, followed by 3 additional examinations at 4-week intervals. Of those men receiving hCG-hMG, 2 induced pregnancies in their wives, while no pregnancies were reported in the placebo group. Sperm concentrations, the percentages of motile sperm, and the proportions of normally formed spermatozoa, however, were similar in the 2 groups at all times. It was not possible to predict the outcome of treatment based on results of GnRH and hCG tests performed before the treatment phase.

In vitro bovine cervical mucus penetration tests (Penetrak) were performed in 30 patients from our fertility clinic and in 33 healthy volunteers with normal semen characteristics. After 90 minutes maximum penetration by sperm (mm) was measured using a capillary filled with bovine midcycle cervical mucus. At the same time classical (sperm motility [%], concentration [mill/ml] and morphology [% oval heads] ) and computerized semen analyses (Cell Soft) were performed (mean velocity [micron/s], lateral head displacement [micron], beat frequency [Hz] and mean linearity). Multiple regression analysis of the depth of sperm penetration in cervical mucus (mm) yielded those semen parameters which allowed correct prediction of the penetration test in 54% of cases. Sperm concentration, morphology, motility and mean velocity alone accounted of 53% of the predictions. In 46% of cases the outcome of the cervical mucus penetration test could not be predicted, regardless of whether classical or computerized semen analysis was performed. This suggests that factors other than those described above must play a role in this aspect of sperm function.

In an effort to evaluate the intra-individual fluctuations of sperm motion parameters 12 healthy young men with normal semen parameters were recruited. Weekly semen analysis was performed for 13 weeks. Conventional semen parameters such as sperm concentration, percentage of motile and normally formed sperm were determined according to WHO guidelines, while sperm velocity, linearity, lateral head displacement and beat frequency were evaluated by computerized image analysis. Mean and standard deviations (SD) of all parameters were computed for each individual. Coefficients of variation were expressed as the ratio of SD/mean. On average the following coefficients of variation were found: total number of sperm 58 (+/- 5%); concentration of sperm 47 (+/- 4%); lateral head displacement 27 (+/- 4%); volume 24 (+/- 3%); velocity 19 (+/- 2%); linearity 17 (+/- 2%); percentage of motile sperm 12 (+/- 2%); beat frequency: 12 (+/- 2%) and percentage of normally formed sperm 9 (+/- 1%). The low variation of sperm motion parameters and the ease of their determination suggests that computerized motion analysis of sperm may be a valuable research tool to detect subtle effects e.g. of drugs and environmental toxins on reproductive functions in men.