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AM Andersson and NE Skakkebaek

There has been increasing concern about the impact of environmental compounds with hormone-like action on human development and reproductive health over the past decades. An alternative but neglected source of hormone action that may be considered in this connection is hormone residues in meat from husbandry animals treated with sex steroid hormones for growth promotion. Treatment of cattle with naturally occurring or synthetic sex hormones may enhance lean muscle growth and improve feed efficiency and is therefore a very cost effective procedure for cattle producers who have used it for decades in some Western countries, including the USA and Canada. The Joint Food and Agricultural Organisation/World Health Organisation (FAO/WHO) expert committee on food additives (JECFA) and the US Food and Drug Administration (FDA) considered, in 1988, that the residues found in meat from treated animals were safe for the consumers. We have re-evaluated the JECFA conclusions regarding the safety of estradiol residues in meat in the light of recent scientific data, with special emphasis on estradiol levels in prepubertal children. These levels are needed for estimates of the normal daily production rates of estradiol in children, who may be particularly sensitive to low levels of estradiol. In our opinion, the conclusions by JECFA concerning the safety of hormone residues in meat seem to be based on uncertain assumptions and inadequate scientific data. Our concerns can be summarized as follows. 1) The data on residue levels in meat were based on studies performed in the 1970's and 1980's using radioimmunoassay (RIA) methods available at the time. The sensitivity of the methods was generally inadequate to measure precisely the low levels found in animal tissues, and considerable variation between different RIA methods for measuring steroids exists. Therefore the reported residue levels may be subject to considerable uncertainty. 2) Only limited information on the levels of the various metabolites of the steroids was given despite the fact that metabolites also may have biological activity. 3) Reliable data on daily production rates of steroid hormones were and are still lacking in healthy prepubertal children. This lack is crucial as previous guidelines regarding acceptable levels of steroid residues in edible animal tissues have been based on very questionable estimates of production rates in children. Thus, even today the US FDA bases its guidelines on the presumably highly overestimated production rates in prepubertal children given in the JECFA 1988 report. 4) The possible biological significance of very low levels of estradiol is neglected. In conclusion, based on our current knowledge possible adverse effects on human health by consumption of meat from hormone-treated animals cannot be excluded.

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KM Main, IM Schmidt, J Toppari, and NE Skakkebaek

BACKGROUND: Patients with hypogonadotropic hypogonadism may be diagnosed shortly after birth because of micropenis and cryptorchidism, combined with subnormal LH and FSH concentrations during the postnatal period. OBJECTIVE: To investigate whether treating these patients with gonadotropins postnatally, to mimic the physiological development, would improve testicular growth and fertility potential later in life. DESIGN: Our patient presented with micropenis. Serum hormone concentrations were measured monthly after delivery: LH and testosterone were undetectable, and FSH and inhibin B were below the normal range (0.05-0.17 IU/l and 79-112 pg/ml respectively). METHODS: From 7.9 to 13.7 months of age, the patient was treated with recombinant human LH and FSH in doses of 20 and 21.3 IU s.c. twice weekly respectively. RESULTS: During treatment concentrations of LH, FSH, inhibin B and estradiol increased to values within normal limits (0.7-1.88 IU/l, 0.17-3.24 IU/l, 121-268 pg/ml and 40-55 pmol/l respectively), whereas serum testosterone remained undetectable. Penile length increased from 1.6 to 2.4 cm and testicular volume, assessed by ultrasound, increased by 170%. No significant adverse events were observed. CONCLUSIONS: Gonadotropin treatment in an infant with hypogonadotropic hypogonadism succeeded in inducing an increase in inhibin B and testicular growth.

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P Christiansen, AM Andersson, NE Skakkebaek, and A Juul

BACKGROUND: Several studies have indicated that cryptorchidism is associated with degenerative changes in both Sertoli cells and germ cells. The gonadal peptide hormone inhibin B reflects Sertoli cell function. Low inhibin B levels are found in a large portion of formerly cryptorchid men who show compromised seminiferous tubule function. It is not known if inhibin B can be used to demonstrate early damage of seminiferous tubules in prepubertal boys with cryptorchidism. METHODS: We investigated the relationship between serum levels of inhibin B, testosterone, FSH and LH in 62 prepubertal boys with uni- and bilateral cryptorchidism. Furthermore, we investigated the changes in serum levels of inhibin B and the corresponding changes in serum levels of FSH, LH and testosterone during a short course (3 weeks) of human chorionic gonadotropin (hCG) injections in 18 of these cryptorchid boys. RESULTS: In the 62 prepubertal boys with uni- or bilateral cryptorchidism there were no significant differences in baseline levels (median and range) of inhibin B (88 (20-195) pg/ml vs 78 (35-182) pg/ml; not significant), LH (0.08 (<0.05-0.99) IU/l vs 0.06 (<0.05-1.61) IU/l; not significant) and FSH (0.60 (0.08-3.73) IU/l vs 0.85 (0.25-2.55); not significant) compared with 156 healthy prepubertal boys, and there were no differences in hormonal levels between boys with uni- or bilateral cryptorchidism. There was no correlation between baseline levels of inhibin B and FSH. In boys younger than 9 years, we found no correlation between baseline levels of inhibin B and LH whereas, in boys older than 9 years, baseline levels of inhibin B were positively correlated to baseline LH (Spearman rank correlation coefficient ((R(s))=0.58, P=0.03). Treatment with hCG (1500 IU intramuscularly twice weekly for 3 weeks) resulted in descensus of testes in 9 out of 18 patients. In all boys but one, irrespective of age, hCG induced a marked increase in testosterone into the adult range (from undetectable to 21.8 (7.0-35.4) nmol/l; P<0.001) and completely suppressed FSH and LH levels. Serum levels of inhibin B increased significantly from 116 (50-195) pg/ml to 147 (94-248) pg/ml (P<0.05), but not uniformly. The increase in serum levels of inhibin B was inversely correlated to baseline inhibin B (Rs=-0.52, P=0.03) and baseline FSH (R(s)=-0.59, P<0.01). CONCLUSIONS: We therefore suggest that, in the prepubertal testes, inhibin B is secreted from the prepubertal Sertoli cells following hCG, whereas early pubertal testes with more differentiated Sertoli cells are not able to secrete inhibin B in response to hCG stimulation, perhaps due to lack of germ cell-derived betaB-subunits. We found (a) normal inhibin B levels in prepubertal boys with uni- or bilateral cryptorchidism, (b) that hCG stimulated testosterone markedly and suppressed FSH and LH levels and (c) that hCG treatment stimulated inhibin B levels in the youngest cryptorchid boys. In the oldest prepubertal boys no hCG-induced changes in inhibin B were shown.

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EM Laursen, S Lanng, MH Rasmussen, C Koch, NE Skakkebaek, and J Muller

OBJECTIVE: The aim of the present study was to investigate whether patients with cystic fibrosis (CF) are GH resistant with increased GH release and decreased concentrations of IGF-I as a result of malabsorption, increased catabolism and impaired glucose tolerance. DESIGN: Twenty CF patients were included, ten with normal glucose tolerance (five male, five female, median age 25.5 years (range 20-31)) and ten with diabetes mellitus (five male, five female, median age 25.3 years (range 17-45). Twenty healthy individuals served as controls (ten male, ten female, median age 28.4 years (range 18-36)). METHODS: GH status was evaluated by 12h spontaneous GH release during the night time, arginine-stimulated GH release and the basal concentrations of IGF-I and insulin-like growth factor-binding protein-3 (IGFBP-3). Twelve hour spontaneous GH profiles were estimated using a constant blood withdrawal technique with sampling every 30min and the Pulsar method was used for the analysis of profiles. RESULTS: No significant differences were found in spontaneous and stimulated GH release in CF patients compared with healthy controls, whereas IGF-I and IGFBP-3 were significantly decreased in CF patients compared with healthy controls. The combination of reduced IGF-I and IGFBP-3 with normal GH release points to a relative GH resistance or a disturbance in the pituitary axis in patients with CF. The spontaneous GH release, the stimulated GH release and the basal concentrations of IGF-I and IGFBP-3 were not significantly different in diabetic CF patients compared with CF patients with normal glucose tolerance and the presence of diabetes mellitus was not consistent with increased GH resistance in CF patients. CONCLUSION: CF patients with normal glucose tolerance and diabetic CF patients had normal GH release and decreased concentrations of IGF-I indicating a relative GH resistance.

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NM Mol, N Sorensen, P Weihe, AM Andersson, N Jorgensen, NE Skakkebaek, N Keiding, and P Grandjean

OBJECTIVE: To determine whether prenatal exposure to polychlorinated biphenyls (PCBs) with possible hormone-disrupting effects is capable of affecting sexual differentiation in boys at the age of puberty. DESIGN: Following analysis for PCB in their umbilical cords, 196 boys from a Faroese birth cohort were examined for the development of puberty at 14 years of age. METHODS: Physical examination included determination of Tanner stages and testicular size. A morning urine sample was centrifuged and examined for the presence of sperm. Serum was analyzed for sex hormones. RESULTS: twenty boys (10.2%) had abnormalities in testicular development, mainly cryptorchidism. only three of them had a positive spermaturia test, but the level of exposure to pcbs in this group had not been increased. occurrence of spermaturia in 58 of the remaining 176 boys was also not associated with pcb exposure but showed highly significant associations with tanner stages and testicular size. serum concentrations of testosterone, fsh and lh were higher in boys with spermaturia, while sex hormone-binding globulin was lower and no difference occurred in inhibin b. serum hormone parameters showed only weak associations with the level of prenatal pcb exposure. CONCLUSIONS: These findings support the validity of spermaturia as a useful indicator of puberty, although a substantial rate of false negatives must be taken into account. Despite the wide range of exposure to PCB, the findings did not reveal any definite associations with the development of puberty. However, because of the limited size of the cohort, small effects cannot be excluded.

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HN Lim, E Raipert-de Meyts, NE Skakkebaek, Hawkins JR, and IA Hughes

OBJECTIVE: Testicular maldescent is important because it is a common congenital disorder that is associated with an increased risk of infertility and testicular cancer. Murine studies indicate that testicular maldescent can result from disruption of insulin-like factor 3 (INSL3) activity and that it may be more severe when there is concurrent undermasculinisation. Therefore, the INSL3 gene was screened for mutations and polymorphisms that may contribute to testicular maldescent in patients with undermasculinisation as well as those with isolated testicular maldescent. METHODS AND RESULTS: The patient groups consisted of individuals with isolated testicular maldescent (n=28) and patients with undermasculinised genitalia and intra-abdominal (n=24) or inguinal gonads (n=33). The three control groups were: normal males (n=15), males with undermasculinised genitalia and scrotal gonads (n=29) and females (n=82). SSCP/HA mutation screening detected eight variants, five of which were predicted to alter the protein sequence (A-1G, V19L, P25S, A36T, R78H). Three of the amino acid changes (A-1G, V19L, R78H) each occurred in a single control sample and one was identified in a male with undermasculinised genitalia and intra-abdominal testes (P25S). The A36T amino acid polymorphism was found in both patient and control groups at a similar frequency. CONCLUSIONS: The evidence suggests that INSL3 mutations and polymorphisms are not a major cause of testicular maldescent with or without associated undermasculinisation.

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M Lange, OL Svendsen, NE Skakkebaek, J Muller, A Juul, M Schmiegelow, and U Feldt-Rasmussen

OBJECTIVE: The insulin-tolerance test (ITT) is currently considered to be the gold standard for evaluating adults suspected of GH deficiency (GHD). The aim of this study was to determine factors that may influence nadir blood glucose (BG) when using a mean insulin dose of 0.1 IU/kg body weight. Furthermore, we wanted to evaluate the safety and GH-related aspects of the ITT. DESIGN: ITT was performed in 277 patients, of whom 255 (129 females) were eligible for evaluation. RESULTS: Multiple regression analysis, including the whole population, showed that the major determining factors for nadir BG were basal BG and body mass index (BMI) (P<0.02). No serious adverse event was recorded. Sixty-three percent of all patients tested had severe GHD with peak GH response to hypoglycaemia below 7.8 mIU/l. The positive predictive value for IGF-I was 0.82 and the negative predictive value was 0.47, using a cut-off value corresponding to -2 s.d. GH peak response to hypoglycaemia decreased with increasing numbers of other pituitary hormone deficiencies. CONCLUSIONS: When determining the dose of insulin based on weight, factors like pre-test BG and BMI should also be considered. We propose an algorithm stating that the dose of insulin should be 0.1 IU insulin/kg body weight minus 2 IU if pre-test BG is <4.0 mmol/l and minus 2 IU if BMI is <20 kg/m(2) in order to take these factors into account. Our findings furthermore support the concept that the low-dose ITT is a safe test in adults, when performed in experienced hands. It was confirmed that IGF-I is not sufficient when diagnosing GHD in adults, and reliable stimulation tests like ITT are required in the diagnosis.

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TK Jensen, M Vierula, NH Hjollund, M Saaranen, T Scheike, S Saarikoski, J Suominen, A Keiski, J Toppari, and NE Skakkebaek

OBJECTIVE: To assess differences in semen quality between similar populations from Denmark and Finland. DESIGN: Comparison of semen quality between 221 Finnish men (of whom 115 had no proven fertility) and 411 Danish men with no proven fertility in two follow-up studies among normal couples trying to conceive. METHODS: In Finland male partners of couples without experienced infertility attempting to conceive were recruited through advertisements in local newspapers from 1984 to 1986. From 1992 to 1995 Danish men who lived with a partner and who had not attempted to achieve a pregnancy previously were recruited through their union when they discontinued birth control. All semen analyses were performed in accordance with the World Health Organization guidelines. RESULTS: Median sperm concentration, total sperm count and the percentage of morphologically normal spermatozoa were significantly higher among the Finnish men without proven fertility (104.0 million/ml, 304.0 million and 58% respectively) compared with the Danish men (53.0 million/ml, 140.8 million, and 41% respectively). Sperm concentration was 105.7% (95% confidence interval (CI) 58.1%-167.6%) and total sperm count was 127.4% (95% CI 71.4%-201.6%) higher among Finnish men without proven fertility than among Danish men after control for confounders. CONCLUSIONS: Some, but hardly all, of the observed difference in semen quality may be explained by differences in recruitment procedures, selection of the men and by methodological differences in semen analysis between the two countries. Also a birth cohort effect may explain some of the differences between countries as the Finnish men were recruited 11 years before the Danish men. Therefore, follow-up studies with identical recruitment and selection of men from the two countries are needed.

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In a 7-year longitudinal study of 40 normal boys, initially aged 8.6-11.7 years, 24-h urine samples were collected every 3 months and analysed for LH and testosterone as well as for the presence of spermatozoa (spermaturia). Spermarche (onset of the release of spermatozoa) was estimated on the basis of age at the first observed spermaturia. Physical examination, including measurements of height and sitting height and staging of pubic hair (Tanner stage) was performed every 6 months. Spermarche occurred early in puberty when the median pubic hair stage was 2.5. Urinary testosterone did not reach maximum levels until approximately 2 years after spermarche. Peak height velocity occurred when urinary testosterone levels were low, 1-2 years before adult levels of testosterone were attained. Our results support the proposition that low levels of testosterone have a predominantly growth-promoting effect, whilst higher concentrations have an inhibitory effect on height spurt.

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M Lange, J Thulesen, U Feldt-Rasmussen, NE Skakkebaek, N Vahl, JO Jorgensen, JS Christiansen, SS Poulsen, SB Sneppen, and A Juul

OBJECTIVE: To evaluate the histomorphology of skin and its appendages, especially eccrine sweat glands, in patients with GH disorders, because reduced sweating ability in patients with growth hormone deficiency (GHD) is associated with increased risk of hyperthermia under stressed conditions. DESIGN AND METHODS: A skin biopsy was obtained from 17 patients with GHD treated with GH, five patients with untreated GHD, 10 patients with active acromegaly and 13 healthy controls. RESULTS: The sweat secretion rate (SSR) was significantly decreased in both the untreated (median 41 mg/30 min, range 9-79 mg/30 min) and the GH-treated (median 98 mg/30 min, range 28-147 mg/30 min) patients with GHD compared with that in controls (median 119 mg/30 min, range 90-189 mg/30 min; P=0.001 and 0.01 respectively). Epidermal thickness was significantly decreased in both untreated (median 39 microm, range 28-55 microm) and GH-treated patients with GHD (median 53 microm, range 37-100 microm), compared with that in controls (median 66 microm, range 40-111 microm; P<0.02). A statistically non-significant tendency towards thinner epidermis (median 59 microm, range 33-83 microm) was recorded in acromegalic patients (P=0.08) compared with controls. There was no significant difference in the area of the sebaceous glands in the biopsies between the three groups and the controls. The area of eccrine sweat gland glomeruli was significantly decreased in the untreated patients with GHD (median 16407 microm2, range 12758-43976 microm2) compared with that in controls (median 29446 microm2, range 13511-128661 microm2; P=0.03), but there was no significant difference between the GH-treated patients with GHD and controls. CONCLUSIONS: We conclude that GH, either directly or via IGF-I, may have both a structural and a functional effect on human skin and its appendages, and that patients with GHD have histomorphological changes in skin compared with controls. Importantly, these changes are not fully reversed despite long-term and adequate GH treatment in patients with childhood onset GHD.