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Assessment of sex hormones in organ transplant recipients suggests that sirolimus may impair testicular function. The aim of this study was to evaluate the frequency and severity of sirolimus-associated alterations in sperm parameters and their impact on fathered pregnancy rate. An observational study was carried out in male patients aged 20-40 years who received a kidney transplant during 1995-2005. Patients were sent a questionnaire by post, and sperm analysis was proposed. The fathered pregnancy rates according to the immunosuppressive regimen were estimated and compared using the Poisson model. Complete information was obtained from 95 out of 116 recipients. Patients treated with sirolimus throughout the post-transplant period had a significantly reduced total sperm count compared to patients who did not receive sirolimus (28.6 ± 31.2 × 106and 292.2 ± 271.2 × 106, respectively; p 0.006), and a decreased proportion of motile spermatozoa (22.2 ± 12.3 and 41.0 ± 14.5, p 0.01). Moreover, the fathered pregnancy rate (pregnancies1000 patient years) was 5.9 (95 CI, 0.8-42.1) and 92.9 (95 CI, 66.4-130.0) in patients receiving sirolimus-based and sirolimus-free regimens, respectively (p 0.007). Of six patients in whom sirolimus treatment was interrupted, only three showed a significant improvement in sperm parameters. Sirolimus is associated with impaired spermatogenesis and, as a corollary, may reduce male fertility.

Assessment of sex hormones in organ transplant recipients suggests that sirolimus may impair testicular function. The aim of this study was to evaluate the frequency and severity of sirolimus-associated alterations in sperm parameters and their impact on fathered pregnancy rate. An observational study was carried out in male patients aged 20–40 years who received a kidney transplant during 1995–2005. Patients were sent a questionnaire by post, and sperm analysis was proposed. The fathered pregnancy rates according to the immunosuppressive regimen were estimated and compared using the Poisson model. Complete information was obtained from 95 out of 116 recipients. Patients treated with sirolimus throughout the post-transplant period had a significantly reduced total sperm count compared to patients who did not receive sirolimus (28.6 ± 31.2 × 106and 292.2 ± 271.2 × 106, respectively; p = 0.006), and a decreased proportion of motile spermatozoa (22.2 ± 12.3% and 41.0 ± 14.5%, p = 0.01). Moreover, the fathered pregnancy rate (pregnancies/1000 patient years) was 5.9 (95% CI, 0.8–42.1) and 92.9 (95% CI, 66.4–130.0) in patients receiving sirolimus-based and sirolimus-free regimens, respectively (p = 0.007). Of six patients in whom sirolimus treatment was interrupted, only three showed a significant improvement in sperm parameters. Sirolimus is associated with impaired spermatogenesis and, as a corollary, may reduce male fertility.

Hyperandrogenism and ovulatory dysfunction are common in women with either polycystic ovary (PCOS) or ovarian virilizing tumor. However, contrasting with the numerous studies that have extensively described gonadotropin secretory abnormalities, principally increased LH pulse amplitude and frequency, few studies have concerned gonadotropin secretion in patients with ovarian virilizing tumors; low gonadotropin levels have occasionally been reported, but never extensively studied. The goal of the present study was to further evaluate the pulsatility of LH secretion in women with ovarian virilizing tumor compared with that of PCOS patients. Eighteen women with major hyperandrogenism (plasma testosterone level >1.2 ng/ml) were studied (5 women with ovarian virilizing tumor, 13 women with PCOS, and 10 control women). Mean plasma LH level, LH pulse number and amplitude were dramatically low in patients with ovarian tumors when compared to both PCOS (p<0.001) and controls (p<0.001). In case of major hyperandrogenism, LH pulse pattern differs markedly between women with ovarian virilizing tumor or PCOS, suggesting different mechanisms of hypothalamic or pituitary feedback.

The effect of prolactin (PRL) on renal Na+K+-ATPase was investigated in 7-d-old neonatal rats. Animals were treated by bromocriptine (Br; a blocker of endogenous PRL secretion), and the enzyme activity was compared with that of untreated controls. Na+K+-ATPase was determined in renal sections in the medullary thick ascending limb of Henle's loop and in the distal tubule by cytochemistry. In the distal tubule, Na+K+-ATPase activity was significantly lower in Br-treated animals than in controls (330 ± 169 versus 558 ± 146 pmol inorganic phosphate/mm/h, respectively); values did not differ in the medullary thick ascending limb of Henle's loop between Br-treated and control animals (132 ± 74 versus 165 ± 113 pmol inorganic phosphate/mm/h, respectively). In vitro effects of PRL were investigated by determining the enzyme activity after incubation of renal sections from Brtreated and untreated animals with different concentrations of PRL. Results suggest that PRL may affect renal Na+K+-ATPase activity in the distal tubule in the neonatal period but do not support a major role of PRL in the enzyme maturation.

To test prolactin (PRL) action on osmoregulation in mammals, we evaluated in the rat the effect of this hormone on a major enzyme in renal regulation of water and electrolyte: renal Na-K-ATPase. Enzyme activity was determined by cytochemistry in medullary ascending limb (MAL) and distal convoluted tubule (DCT) from rats treated either by bromocriptine, or by PRL. Three hours after a bromocriptine injection (0.1 mg/100 g IP) a significant decrease of Na-K-ATPase activity is observed in both MAL (80% of control values,p<0.001) and DCT (78%,p<0.01). Reciprocally, a significant (p<0.001) increase in enzyme activity is induced 3 h after a single PRL injection (140 µg/100 g IM), in both segments (MAL: 165%, DCT: 172% of control activities) and persists 6 h after the injection (MAL: 130%, DCT: 118%). Na-K-ATPase activity was correlated to plasma PRL levels (r=0.78 in DCT,r=0.89 in MAL). A direct effect of PRL on the tubule is suggested by results from experiments in which PRL, at various concentrations, is added in vitro on renal slices before Na-K-ATPase activity measurements. The increase in Na-K-ATPase activity exhibits a log-dose dependency with PRL concentration (p<0.01) and is still observed when AVP antagonist is added before PRL incubation, ruling out the possible role of AVP contamination of PRL. These results suggest a direct effect of PRL on renal Na-K-ATPase in MAL and DCT.

ABSTRACT: The effect of prolactin (PRL) on renal Na+K+-ATPase was investigated in 7-d-old neonatal rats. Animals were treated by bromocriptine (Br; a blocker of endogenous PRL secretion), and the enzyme activity was compared with that of untreated controls. Na+K+-ATPase was determined in renal sections in the medullary thick ascending limb of Henle's loop and in the distal tubule by cytochemistry. In the distal tubule, Na+K+-ATPase activity was significantly lower in Br-treated animals than in controls (330 ± 169 versus 558 ± 146 pmol inorganic phosphate/mm/h, respectively); values did not differ in the medullary thick ascending limb of Henle's loop between Br-treated and control animals (132 ± 74 versus 165 ± 113 pmol inorganic phosphate/mm/h, respectively). In vitro effects of PRL were investigated by determining the enzyme activity after incubation of renal sections from Brtreated and untreated animals with different concentrations of PRL. Results suggest that PRL may affect renal Na+K+-ATPase activity in the distal tubule in the neonatal period but do not support a major role of PRL in the enzyme maturation.

Renal function has been evaluated in 45 diabetic children (age 12.5±4 years) with a mean diabetes duration of 4.9±3.5 years. Glomerular filtration rate (GFR; inulin and creatinine clearances), renal plasma flow (RPF; PAH clearance), resting urinary albumin excretion (UAE) were measured and compared with indexes of metabolic control: Hb A1C and blood glucose values (mean, post-prandial and maximal excursion) on the same day. GFR (inulin clearance) and RPF were significantly increased in the diabetic group (171±31 and 778±172 ml/min per 1.73 m2) compared with controls (124±18 and 631±128 ml/min per 1.73 m2). Both parameters were strongly correlated (r=0.73;P<0.001). Creatinine clearance was not correlated to inulin clearance. Hyperfiltration (inulin clearance above 160 ml/min per 1.73 m2) was noted in 61% of the patients and was independent of diabetes duration. Five diabetic children had a UAE level above 15 µg/min. No relationship could be established between UAE and any of the metabolic indexes; GFR was weakly correlated to HbA1C (r=0.35;P<0.05), to mean (r=0.35;P<0.05) and post-prandial blood glucose (r=0.37;P<0.05). In contrast, there was a strong correlation between GFR and the maximal blood excursion (r=0.62;P<0.001). The study shows that renal abnormalities can be detected with a high frequency in diabetic subjects characterized by both an early onset and a short duration of diabetes and suggests the need for a more systematic evaluation of renal parameters in this population.

To gain insight into the role of transforming growth factor-beta 1 (TGF-beta 1) in the development of kidney pathology following fetal obstruction, we measured TGF-beta 1 gene expression, the active peptide, and the urinary concentration in a model of fetal bilateral urinary obstruction (BUO) in sheep. Fetal lambs underwent BUO at 60 (FO-60) or 80 days (FO-80) of gestation and were studied at 120 days. Independently of the onset or duration of obstruction, all fetuses developed type IV dysplasia (IV) associated with an arrest in the nephrogenesis or hydronephrosis. Fetal glomerular filtration rate was not significantly modified, whereas sodium tubular reabsorption was significantly decreased, and urinary TGF-beta 1 concentration was elevated in hydronephrosis but not in IV. Levels of TGF-beta 1 mRNA were increased in hydronephrosis compared with normal kidneys, and active TGF-beta 1 immunoreactivity was increased in both hydronephrotic and IV kidneys. In summary, TGF-beta 1 may play a role in the development of hydronephrosis and dysplasia in kidneys following fetal BUO. Its role in the arrest of nephrogenesis observed in the IV kidneys remains to be proved.

Using a prospective randomised double-blind crossover design, the effect of the angiotensin converting enzyme inhibitor enalapril compared to a placebo was studied in 18 normotensive, normoalbuminuric Type 1 (insulin-dependent) diabetic children. Each patient had a high normal or clearly elevated glomerular filtration rate (145 ml· min−1· 1.73 m2or higher) in the 6 months prior to the study. Enalapril, 0.5 mg·kg−1· day−1, was given for 4 weeks followed by placebo for 4 weeks, or vice versa. At the end of each period, glomerular filtration rate, renal plasma flow, blood pressure, plasma renin activity, and converting enzyme activity were determined. Enalapril caused significant reduction (p=<0.001) in blood pressure and converting enzyme activity and a rise in plasma renin activity. A slight but not significant rise in glomerular filtration rate and renal plasma flow without change in filtration fraction was observed. These data suggest that the renin angiotensin system is not involved in the glomerular hyperfiltration of Type 1 diabetes, and can be interpreted as showing no evidence for the presence of intraglomerular hypertension in these patients.

We compared plasma active and inactive renin (prorenin) concentrations and activities in infants and children, as measured with a newly available direct immunoradiometric assay kit for active renin and a widely used enzymatic renin assay (plasma renin activity). The study was performed in 57 healthy infants and children under steady-state conditions and in eight subjects after orthostatic stimulation. Our study; (i) reports concentrations for active and inactive renin determined by the immunoradiometric assay in normal infants and children; (ii) confirms, by use of the immunoradiometric assay, the previously described decrease in plasma active and inactive renin, as measured by the enzymatic assay, with increasing age; and (iii) shows close correlations between the results obtained by immunoradiometric and enzymatic assays for active and inactive renin in normal infants and children.