Rob F. A. Weber

Maternal and Paternal Risk Factors for Cryptorchidism and Hypospadias: A Case–Control Study in Newborn Boys

Little is known on environmental risk factors for cryptorchidism and hypospadias, which are among the most frequent congenital abnormalities. The aim of our study was to identify risk factors for cryptorchidism and hypospadias, with a focus on potential endocrine disruptors in parental diet and occupation. In a case–control study nested within a cohort of 8,698 male births, we compared 78 cryptorchidism cases and 56 hypospadias cases with 313 controls. The participation rate was 85% for cases and 68% for controls. Through interviews, information was collected on pregnancy aspects and personal characteristics, lifestyle, occupation, and dietary phytoestrogen intake of both parents. Occupational exposure to potential endocrine disruptors was classified based on self-reported exposure and ratings of occupational hygienists based on job descriptions. Our findings indicate that paternal pesticide exposure was associated with cryptorchidism [odds ratio (OR) = 3.8; 95% confidence interval (95% CI), 1.1–13.4]. Smoking of the father was associated with hypospadias (OR = 3.8; 95% CI, 1.8–8.2). Maternal occupational, dietary, and lifestyle exposures were not associated with either abnormality. Both abnormalities were associated with suboptimal maternal health, a lower maternal education, and a Turkish origin of the parents. Being small for gestational age was a risk factor for hypospadias, and preterm birth was a risk factor for cryptorchidism. Because paternal pesticide exposure was significantly associated with cryptorchidism and paternal smoking was associated with hypospadias in male offspring, paternal exposure should be included in further studies on cryptorchidism and hypospadias risk factors.

Occupationally related exposures and reduced semen quality: a case-control study☆

OBJECTIVE To determine whether there is an association between abnormal semen parameters and occupational exposures to organic solvents, metals, and pesticides. DESIGN Case-control study using three case groups based on different cutoff values for semen parameters and one standard reference group. SETTING University Hospital Utrecht and University Hospital Rotterdam, the Netherlands. PATIENT(S) Male partners of couples having their first consultation at the two infertility clinics (n = 899). INTERVENTION(S) Men provided at least one semen sample. Occupational exposure was assessed with use of job-specific questionnaires, a job exposure matrix, and measurements of metals and metabolites of solvents in urine. MAIN OUTCOME MEASURE(S) Standard clinical semen analyses were used to define case groups and controls. RESULT(S) An association between aromatic solvents and reduced semen quality was demonstrated, irrespective of the exposure assessment method used. The associations were stronger if the case definition was based on stricter cutoff values for semen parameters. Risk estimates were higher if the analysis was restricted to primary infertile men. Exposure to other pollutants at the workplace was not associated with impaired semen quality. CONCLUSION(S) The findings indicated an association between aromatic solvent exposure and impaired semen parameters.

In vitro fertilizing capacity of human spermatozoa with the use of zona-free hamster ova: interassay variation and prognostic value

The average fertilization percentage, with the use of zona-free hamster ova, of a donor group was 54% (range 11% to 100%). Nineteen sperm suspensions (24%) from a group of 79 infertile patients with semen abnormalities and 23 from a second group of 43 patients (54%) whose partner showed evidence of reproductive dysfunction, fertilized as well as spermatozoa from fertile donors. The interassay variation of the fertilization rates was found to be less than 20%. Spermatozoa from 10 patients with normal semen characteristics failed to penetrate. Six spontaneous conceptions were reported in the first group. Sperm from four of these patients had low fertilization percentages. This indicates that fertility prognosis cannot be made on the basis of a low in vitro fertilization percentage only. The fertilization rate negatively correlated with the duration of infertility. No positive assays were found after 6 years of infertility.

The hypothalamus-pituitary-testis axis in boys during the first six months of life: A comparison of cryptorchidism and hypospadias cases with controls

It is inconclusive whether the feedback mechanisms of the hypothalamus-pituitary-testis (HTP) axis are already established in the first 6 months of life, partly due to the dramatic changes in HPT-axis hormone levels over this period. Moreover, it is unclear whether these hormone levels are aberrant in boys with cryptorchidism or hypospadias, and therefore predictive for future fertility. We studied the regulation mechanisms of the HTP axis, and the effect of age, in boys 1-6 months of age. Secondly, we studied testicular function - as reflected by HPT hormones - in newborns with cryptorchidism or hypospadias. Sera from a population sample of infants with cryptorchidism (n = 43), hypospadias (n = 41) and controls (n = 113) were analyzed for inhibin B, anti-Müllerian hormone (AMH), testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH) and sex hormone binding globulin (SHBG). LH, testosterone, non-shbg-bound testosterone (NSBT), and AHM levels showed significant age-related trends. After age-correction, a negative correlation between FSH and inhibin B was observed (r = -0.43). The only significant group-differences were lower testosterone and NSBT levels in cryptorchidism cases, with a mean testosterone of 1.8 and 2.6 nmol/L and a mean NSBT of 0.48 and 0.70 nmol/L for cryptorchidism cases and controls, respectively. The higher levels of LH, testosterone, and NSBT in boys born pre-term or with a low birthweight indicate that abnormal prenatal development may determine postnatal testis function. Our results support the hypothesis that the inhibin B - FSH feedback loop is already functional before puberty. The lower testosterone and NSBT levels indicate that disturbed Leydig cell function can already be detected early after birth in cryptorchid boys.

LH-RH and Dopamine Levels in Hypophysial Stalk Plasma and Their Relationship to Plasma Gonadotrophins and Prolactin Levels in Male Rats Bearing a Prolactin- and Adrenocorticotrophin-Secreting Pituitary Tumor

The present study was concerned with the effects of a transplantable pituitary tumor secreting prolactin (PRL) and adrenocorticotrophin (ACTH) on the levels of LH and FSH in peripheral plasma and on the hypothalamic release of LH-RH and dopamine in the male rat. Male rats of the same age not inoculated with the tumor served as controls. Hypophysial stalk blood was collected from urethane-anesthetized rats 4-5 weeks after tumor inoculation to measure their LH-RH and dopamine content. A peripheral blood sample was withdrawn from the animals just before sectioning the hypophysial stalk to measure their content of LH, FSH and PRL. It was found that in the tumor-bearing rats the levels of PRL increased 17-fold, whereas plasma levels of LH and FSH decreased by 45 and 70% respectively, when compared with the control rats. In the tumor-bearing rats, the secretion rate of dopamine in hypophysial stalk plasma increased from 1.4 to 4.1 ng/h, whereas the secretion rate of LH-RH decreased from 122 to 61 pg/h. However, when at the time of tumor inoculation adrenalectomy was performed, the tumor did not decrease plasma levels of LH and FSH and the secretion of LH-RH into hypophysial stalk blood any longer. The effect of the tumor on hypothalamic dopamine secretion was, however, still present in the adrenalectomized rats. It is concluded that the effect of the PRL- and ACTH-secreting pituitary tumor on plasma levels of LH and FSH requires the presence of the adrenal gland and that this effect is mediated through an inhibition of the hypothalamic release of LH-RH. Furthermore, this tumor increases the hypothalamic release of dopamine independent of the presence of the adrenal gland.

Serum levels of sex hormone-binding globulin (SHBG) are not associated with lower levels of non-SHBG-bound testosterone in male newborns and healthy adult men

Objective   It is generally accepted that SHBG decreases the bioavailability and activity of testosterone (T). In in vitro experiments increased levels of SHBG will be associated with decreased levels of non‐SHBG bound testosterone (non‐SHBG‐T). However, in vivo SHBG can alter both production and clearance rates and thus plasma levels of T.

In vivo Release of Dopamine, Luteinizing Hormone-Releasing Hormone and Thyrotropin-Releasing Hormone in Male Rats Bearing a Prolactin-Secreting Tumor

The present study was concerned with the effects of a transplantable prolactin-secreting pituitary tumor (7315b) on the hypothalamic release of dopamine, luteinizing hormone-releasing hormone (LHRH) and thyrotropin-releasing hormone (TRH) in gonadectomized, adrenalectomized male rats bearing subcutaneously a testosterone capsule and a corticosterone pellet. Similar male rats not inoculated with tumor served as controls. The rats were studied 3-4 weeks after tumor inoculation, while they were anesthetized with urethane. Compared to the controls, prolactin levels in the tumor-bearing rats had increased 70-fold, whereas the levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) decreased to 20 and 27%, respectively. In tumor-bearing rats, the secretion of dopamine into hypophysial stalk plasma increased from 2.3 to 4.9 ng/h (p less than 0.025), whereas that of LHRH decreased from 127 to 52 ph/h (p less than 0.005). Since the use of urethane anesthesia may change quantitatively and qualitatively the effects of hyperprolactinemia, it was decided to study these effects on the in vivo release of LHRH, dopamine and TRH in conscious rats by a push-pull perfusion of the median eminence-arcuate nucleus area. Using this technique, it was found that in tumor-bearing rats the secretion of LHRH decreased from 20.0 to 9.8 pg/15 min (p less than 0.005), whereas that of dopamine increased from 118 to 246 pg/15 min (p less than 0.025). The secretion of TRH was not altered by hyperprolactinemia (4.1 vs. 4.4 pg/15 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Long-Acting Somatostatin Analog (Somatulin) on Renal Hyperfiltration in Patients With IDDM

OBJECTIVE To investigate whether long-acting somatostatin (SMS) can suppress renal hyperfiltration in patients with IDDM. RESEARCH DESIGN AND METHODS A double-blind, randomized treatment of nine patients with IDDM was used. Selection criteria were renal hyperfiltration (glomerular filtration rate [GFR] ≥ 129 ml · min−1 · 1.73 m2) and absence of hypertension and macroalbuminuria. Treatment was either with a long-acting SMS analog (Somatulin, 30 mg) or with placebo, given by intramuscular injections every 10 days for 9 months. GFR, effective renal plasma flow (ERPF), IGF-I, and 24-h growth hormone (GH) profiles were used as evaluation parameters. RESULTS Five patients were randomized to Somatulin, four patients to placebo. One of the patients treated with Somatulin stopped after 3 months because of persistent abdominal discomfort after the injections. Somatulin treatment for 3 months lowered GFR and ERPF compared with placebo (P < 0.05). After 9 months, the differences were no longer significant. After 3 months, IGF-I concentrations were decreased in all Somatulin-treated patients. GH secretion tended to increase in the placebo group. CONCLUSIONS The administration of long-acting Somatulin to patients with IDDM and renal hyperfiltration leads to only a temporary reduction of ERPF/GFR.

Effect of BMI, insulin dose and number of injections on glycaemic control in insulin-using diabetic patients

BACKGROUND Strict glucose control is essential to the prevention of diabetic complications. The level of glycaemic control in insulin-treated patients with diabetes mellitus (DM) in a routine clinical setting is not known. METHODS In a cross-sectional survey comprising 8 hospitals in the Rijnmond area, The Netherlands, age, body mass index (BMI), insulin dose, number of injections, and HbA1c were scored in 712 patients with insulin-dependent DM (IDDM) and 462 patients with non-insulin-dependent DM (NIDDM). RESULTS In IDDM and NIDDM patients, respectively, age (mean +/- SD) was 40 +/- 17 and 65 +/- 12 years, BMI was 24.1 +/- 3.5 and 27.3 +/- 4.1 kg/m2, daily insulin dose was 49 +/- 18 and 44 +/- 18 U (P < 0.001). Intensive therapy (> or = 4 injections or continuous subcutaneous insulin infusion) was used in 59% of IDDM and 13% of NIDDM patients. HbA1c below the upper normal limit was achieved in 11% of the patients, and within 20% above the upper normal limit in 37%. Obesity was positively associated with HbA1c in NIDDM patients (P < 0.01). A higher insulin dose was associated with higher HbA1c in both IDDM and NIDDM patients (P < 0.01). CONCLUSIONS Good glycaemic control was established in 37% of our patients. Intensive insulin treatment and higher insulin dose did not improve glucose regulation. Obesity is a risk factor for poor glycaemic control.