Antenatal Diagnosis of Dizygotic, Monochorionic Twins Following IVF/ICSI.

Monochorionic twins are usually monozygotic and thus usually have the same sex. A case of monochorionic diamniotic twins following IVF/ICSI and laser treatment of the zona pellucida ("assisted hatching") is presented in which partial embryo amalgamation appears to have occurred. Discordant sex between the twins was suspected on detailed antenatal ultrasound at 13 + 3 weeks gestation and was confirmed on subsequent examinations. The sexual phenotype at birth was female for one twin and male for the other. Placental histology confirmed the monochorionic, diamniotic situation. Cytogenetic analysis of both twins was carried out postpartum on various tissues. On karyotyping of blood lymphocytes the male and female twins each had one mosaic of male and female cells. Oral mucosal cells showed normal male and female karyotypes respectively. Analysis of urothelium showed a normal result for the male infant, and a weak gonosomal mosaic with an XX and XY constellation for the female infant. At least for blood lymphocytes, a diagnosis of chimerism was proven.

Treatment of severe oligospermia with human chorionic gonadotropin/human menopausal gonadotropin: a placebo-controlled, double blind trial.

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.

Significance of mutations in the androgen receptor gene in males with idiopathic infertility.

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.

Experience with transvaginal ultrasound-guided aspiration of supernumerary follicles for the prevention of multiple pregnancies after ovulation induction and intrauterine insemination.

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.

Use of frozen-thawed testicular sperm for intracytoplasmic sperm injection.

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.

Indomethacin and oxaprozin lower seminal prostaglandin levels but do not influence sperm motion characteristics and serum hormones of young healthy men in a placebo-controlled double-blind trial.

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.

[MR findings in patients with idiopathic panhypopituitarism]. / MR-Befunde bei Patienten mit "idiopathischem" Panhypopituitarismus.

High-resolution MR imaging was performed in seven patients with pituitary dwarfism and panhypopituitarism. In five cases MR-findings included absence of the infundibulum and of the normal intrasellar posterior pituitary bright spot, and the presence of a small nodule at the median eminence. The absence of diabetes insipidus in these patients and the signal characteristics of the nodule at the median eminence suggest that the latter may represent a functioning ectopic posterior pituitary lobe. This complex of findings was only observed in patients with complications in the perinatal period (breech delivery) and appears to be the end result of an ischemic or traumatic injury of the infundibular stem. The infundibular defect would explain both the permanent hormone deficiency of the anterior pituitary gland through a disruption of the hypothalamic-hypophyseal portal system and the absence of diabetes insipidus through an ectopic regeneration of the neurohypophysis at the median eminence.

Predictive parameters for ovarian response to hyperstimulation with exogenous gonadotropins after suppression of gonadotropin secretion of the pituitary using a long-acting GnRH agonist.

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.

Outcome of ICSI cycles using frozen-thawed surgically obtained spermatozoa in poor responders to ovarian stimulation: cancellation or proceeding to ICSI?

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.

Transcranial magnetic stimulation: influence on plasma levels of hormones of the anterior pituitary gland and of cortisol?

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.

Early onset and high prevalence of gestational diabetes in PCOS and insulin resistant women before and after assisted reproduction.

OBJECTIVES: Polycystic ovary syndrome (PCOS) and/or insulin resistance (IR) are frequent conditions in women choosing assisted reproduction techniques (ART). However, infertility work-up has to include testing of insulin sensitivity to diagnose IR. It was the aim of the study to analyze the frequency of impaired glucose tolerance (IGT) or gestational diabetes (GD) in the first weeks of gestation after ART in women receiving metformin. DESIGN AND METHODS: This study included 107 women who were seeking ART under the pretreatment of metformin for PCOS, confirmed IR, recurrent spontaneous miscarriages (RSA) or other fertility disorders. They were examined for prepregnancy health parameters (weight, glucose tolerance). When pregnancy was confirmed a 75 g oral glucose tolerance test (OGTT) was conducted between the 5(th) and 7(th) week of gestation. RESULTS: A high rate of GD or IGT already was observed in the first weeks of pregnancy in our cohort under metformin treatment. The predominant risk factor for diagnosed early onset of IGT or GD (58 cases) was PCOS (p=0.014). The frequency of GD was the highest in the subgroup with prepregnancy confirmed IR not fulfilling the criteria of PCOS (55%); it was 40.6% in PCOS women and 26.1% in women neither exhibiting IR nor PCOS. CONCLUSIONS: Women seeking ART and being treated with metformin still show a very high rate of GD or IGT after achieving pregnancy by ART. Therefore in women undergoing ART screening for GD should be performed as soon as pregnancy is confirmed to avoid miscarriages due to overlooked uncontrolled glucose metabolism.

ApoA-I-binding protein (AI-BP) and its homologues hYjeF_N2 and hYjeF_N3 comprise the YjeF_N domain protein family in humans with a role in spermiogenesis and oogenesis.

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.

Quality of life in elderly men with androgen deficiency.

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.

Rational approach to genetic testing of cystic fibrosis (CF) in infertile men.

Male infertility as a result of isolated congenital bilateral absence of the vas deferens (CBAVD) is one primary genital form of cystic fibrosis (CF) and occurs in 1-2% of infertile men. Assisted fertilization in patients with CBAVD increases the risk of transmitting mutations in the CF gene. We developed a rational approach to genetic CF testing in infertile men. A total of 282 infertile male patients were screened for the most common CF mutations (DeltaF508, R117H, IVS8-5T). Clinical data including medical history, examination, semen analysis, sweat tests, karyotypes and hormonal values were analysed. We identified 23 patients carrying mutations in the CF gene (DeltaF508: 10 patients; R117H: six patients; IVS8-5T: 11 patients). Two patients were compound heterozygote for DeltaF508/R117H, two others for DeltaF508/IVS8-5T. Correlating these molecular analyses with the clinical data pertaining to serum follicle-stimulating hormone concentration, semen pH, sperm count and total testicular volume, we were able to develop a score with a high specificity (98.4) for the presence of a cystic fibrosis transmembrane conductance regulator (CFTR) mutation, but only with a low sensitivity (positive post-test likelihood: 62.5%; negative post-test likelihood: 6.3%). With regard to the low sensitivity and the high number of CFTR mutations found in this heterogeneous group of infertile men, we still recommend genetic CF testing before assisted fertilization.

Androgen receptor disorder in three brothers with bifid prepenile scrotum and hypospadias.

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.

[Does sperm penetration in bovine mucus provide additional information to the "classical" spermiogram and motility characteristics?]. / Liefert die Spermienpenetration in bovinen Mukus zusätzliche Information zum "klassischen" Spermiogramm und zu den Motilitätscharakteristika?

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.

Intra-individual variation of sperm velocity, linearity, lateral head displacement and beat frequency in healthy volunteers.

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.

Substitution therapy of hypogonadal men with transdermal testosterone over one year.

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.

Investigation of the cause of low sperm motility in asthenozoospermic patients by multiple quantitative tests.

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.

Transdermal testosterone substitution therapy for male hypogonadism.

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.