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Background The prevalence of both vitamin D (VitD) deficiency and type 1 diabetes mellitus (T1DM) has increased worldwide over the last few decades. The objectives of this study were: (1) to evaluate the prevalence of VitD deficiency and insufficiency among Israeli youth with T1DM and (2) to assess the association between VitD status, seasonality and T1D glycemic control characteristics. Methods This was a multi-centered, cross-sectional study. VitD levels were routinely tested during the years 2008–2011 in T1DM patients aged up to 21 years. Medical records were reviewed for demographic, clinical and laboratory characteristics. Results The study population consisted of 199 participants (53% males), mean age 12.24±4.11 years, mean T1DM duration 3.77±3.43 years. VitD levels were within the normal range in 19.6%, insufficient (15–29 ng/mL, 37–72 nmol/L) in 62.3% and deficient ( Conclusions VitD insufficiency is largely prevalent among Israeli youth with T1DM, as is in Israeli youth in general. The VitD level is associated with seasonality, clothing habits and BMI.

Subacute sclerosing panencephalitis is a rare neurologic disorder of childhood and adolescence. We describe a 16-year-old boy who manifested the disease despite proper vaccinations. He was hospitalized because of bedwetting, involuntary limb movements, abnormal speech, and balance disturbances. Immunoglobulin G antibodies against measles were strongly positive, with a high relative cerebrospinal fluid/serum ratio. Polymerase chain reaction for measles produced negative results. Electroencephalography registered slow activity with high voltage discharges every few seconds, and with triphasic complex morphology. Magnetic resonance imaging revealed diffuse white matter changes, mostly around the posterior regions and lateral ventricles. Treatment with valproic acid, levetiracetam, carbamazepine, and intravenous immunoglobulin G was ineffective. Inosiplex and interferon-β-1a were also administrated. The patient became comatose, with generalized myoclonic jerks, and died 1 year later. An autopsy was not performed. This patient illustrates that subacute sclerosing panencephalitis should be suspected among young vaccinated subjects.

Background and Objective: Woodhouse-Sakati syndrome (WSS) is a rare autosomal-recessive disorder characterized by a combination of hypogonadism, alopecia, diabetes mellitus (DM), mental retardation and extrapyramidal signs, not described previously in Israel. Our aim was to study the clinical and genetic characteristics of the extended family of a 16-year-old female who presented with new-onset DM and had delayed puberty on physical examination. Methods: The primary physician’s medical charts of 9 members of the proband’s consanguineous Israeli-Arab family were reviewed. Hormonal, metabolic and antibody profile, imaging studies and molecular analysis were performed in 4 phenotypically compatible members, including the proband. Results: Four subjects, 2 females and 2 males, had DM, absent pubertal development and similar appearance. None had extrapyramidal signs. The patients were homozygous for a one-base deletion mutation (c.436delC) in the C2orf37 gene. Conclusion: We describe the first Israeli-Arab family with phenotype and genotype of WSS, imitating autoimmune DM with gonadal failure.

Objective To assess the association between hyperglycemia and electrical brain activity in type 1 diabetes mellitus (T1DM). Methods Nine youths with T1DM were monitored simultaneously and continuously by EEG and continuous glucose monitor system, for 40 h. EEG powers of 0.5–80 Hz frequency bands in all the different brain regions were analyzed according to interstitial glucose concentration (IGC) ranges of 4–11 mmol/l, 11–15.5 mmol/l and >15.5 mmol/l. Analysis of variance was used to examine the differences in EEG power of each frequency band between the subgroups of IGC. Analysis was performed separately during wakefulness and sleep, controlling for age, gender and HbA1c. Results Mean IGC was 11.49 ± 5.26 mmol/l in 1253 combined measurements. IGC > 15.5 mmol/l compared to 4–11 mmol/l was associated during wakefulness with increased EEG power of low frequencies and with decreased EEG power of high frequencies. During sleep, it was associated with increased EEG power of low frequencies in all brain areas and of high frequencies in frontal and central areas. Conclusions Asymptomatic transient hyperglycemia in youth with T1DM is associated with simultaneous alterations in electrical brain activity during wakefulness and sleep. Significance The clinical implications of immediate electrical brain alterations under hyperglycemia need to be studied and may lead to adaptations of management.

Attention-deficit hyperactivity disorder (ADHD) is the most common behavior disorder among children; methylphenidate is a drug frequently prescribed for the control of its symptoms. One of the potential side effects of methylphenidate that concerns parents is its impact on the growth of children, since the mechanism by which methylphenidate might influence growth is not known. As linear growth is associated with an increase in bone mineral density and turnover, this study was undertaken to evaluate bone mineral density by dual photon absorptiometry and bone turnover by measuring serum bone-specific alkaline phosphatase and the urinary deoxypyridinoline excretion rate in children treated with methylphenidate for 1 to 2 years as compared to a control group. There were no significant differences in bone mineral density at either the lumbar spine or femoral neck in the study group (0.662 ± 0.04 and 0.735 ± 0.07 g/cm2, respectively) as compared to the controls (0.675 ± 0.05 g/cm2 and 0.734 ± 0.07 g/cm2, respectively). Furthermore, there were no significant differences in serum bone-specific alkaline phosphatase in the study group (58 ± 22 U/L) as compared to the control children (71 ± 34 U/L) or in urinary deoxypyridinoline in the study group (34 ± 38 nM/mM), as compared to the control group (27 ± 12 nM/mM). In conclusion, our data do not support a significant effect of methylphenidate on bone mineral density turnover in children when used for 1 to 2 years. (J Child Neurol 2000;15:436-439).

Background: Active sodium absorption is the dominant mechanism of ion transport in airway epithelium, but its role in pulmonary physiology and airway host defense is unknown. To address this question, we studied the function of airway epithelial cells and determined the frequency of pulmonary symptoms in patients with systemic pseudohypoaldosteronism, a salt-losing disorder caused by loss-of-function mutations in the genes for the epithelial sodium channel. Methods: In nine patients 1.5 to 22 years of age who had systemic pseudohypoaldosteronism, we tested for mutations in the genes for the epithelial sodium channel, estimated the rate of sodium transport in the airway, determined the volume and ion composition of airway surface liquid, reviewed clinical features, collected laboratory data pertinent to pulmonary function, and, in three adults, measured mucociliary clearance. Results: The patients with systemic pseudohypoaldosteronism had loss-of-function mutations in the genes for the epithelial sodium-channel subunits, no sodium absorption from airway surfaces, and a volume of airway surface liquid that was more than twice the normal value. The mean (±SE) mucociliary transport rate was higher in the 3 adult patients than in 12 normal subjects (2.0 ± 0.7 vs. 0.5 ± 0.3 percent per minute, P = 0.009). Young patients (those five years of age or less) all had recurrent episodes of chest congestion, coughing, and wheezing, but no airway infections with Staphylococcus aureus or Pseudomonas aeruginosa. Older patients (those more than five years of age) had less frequent respiratory symptoms. Conclusions: Patients with systemic pseudohypoaldosteronism fail to absorb liquid from airway surfaces; the result is an increased volume of liquid in the airways. These results demonstrate that sodium transport has a role in regulating the volume of liquid on airway surfaces.

Digoxin and gentamicin are widely used in pediatric medicine, and therapeutic monitoring is mandatory because of their narrow margin of safety and wide interpatient and intrapatient pharmacokinetic variabilities. Saliva sampling may be of potential interest, especially in children, in whom blood sampling is often difficult. In 11 children treated with digoxin for various cardiac conditions, and in 24 children treated with gentamicin (14 patients were administered gentamicin three times a day, and 10 once-daily), drugs levels were measured in plasma and saliva. There was no correlation between plasma total or free digoxin concentrations and saliva levels, precluding the clinical use of the saliva test for digoxin. No correlation was found between plasma gentamicin concentrations and saliva levels when the drug was administered three times a day; however, good correlation was found when the drug was administered once-daily (r2 = 0.89, p < 0.0001). Saliva may be used as a noninvasive method of measuring gentamicin serum concentrations to guide dosage adjustments in patients administered the drug once-daily.

We evaluated the prevalence, diagnosis, and treatment of dumping syndrome (DS) following Nissen fundoplication in 50 consecutive infants and children who underwent the operation for gastroesophageal reflux. Examination included a preoperative dietary assessment with emphasis on specific postprandial clinical symptoms and technetium scintigraphy to evaluate gastric emptying. In the immediate postoperative period, postprandial glucose levels were examined in all patients with symptoms clinically suggestive of DS. In the late postoperative period (6 months to 5.5 years), all patients with more than one specific clinical symptom of DS were further evaluated by glucose tolerance test (GTT), HbA1C levels, and gastric technetium scintigraphy. DS was diagnosed in 15 patients (30%). Five patients had immediate severe DS (SDS), and 10 in the late postoperative course had latent postoperative DS (LDS). In all patients with DS, preoperative and postoperative gastric emptying scan T1/2 did not show any statistical significance. High levels of HbA1C ranging from 7.9 to 9% (mean, 8.25 +/- 0.5) were found in only three patients. Treatment included parenteral nutrition in one patient. All the others were successfully managed with nutritional manipulation alone, using a combination of lactose-free formula and fat emulsion. In patients whose postprandial symptoms persisted, pectin 5-15 g/day divided into six doses was added to the diet. Following 6 months of dietary treatment, the postprandial normoglycomic response was restored. Eleven patients experienced complete resolution of symptoms (78.5%), and three patients (21.4%) showed significant clinical improvement. This study indicates that DS is a common complication following Nissen fundoplication. The GTT is the most reliable examination for establishing the diagnosis. Treatment is simple and effective. The technetium gastric emptying scan and HbA1C level do not play a significant role in the diagnosis.

Objective To evaluate the effect of intensive art therapy in youth with poorly controlled type 1 diabetes mellitus (T1DM). Methods A retrospective report of the characteristics and outcomes of all patients who were offered to receive individual art therapy sessions because of behavioral difficulties. Results The study population included 29 participants. The main behavioral difficulties were needle phobia and lack of compliance with nutritional recommendations or with insulin administration. The intervention group included 16 patients, with a mean age of 9.3±2.5 years, average intervention length of 0.77±0.41 years, and long-term data of 2.27±1.13 years. The control group included 13 patients, with a mean age of 9.3±3.4 years. Improvement was observed in 56% of the case group and in 23% of the control group. Art therapy was associated with a decrease in hemoglobin A1c in the intervention group compared with a similar control group (-0.79%, ±0.24%; r=0.17, p=0.025). Conclusions The addition of intensive art therapy for poorly controlled youth with T1DM may improve their glycemic control.

Pseudohypoaldosteronism is a hereditary salt-wasting syndrome usually seen in infancy with weight loss, dehydration, and failure to thrive. The patho-physiologic origin of Pseudohypoaldosteronism is unknown. The defect could be related to the unresponsiveness of target organs to mineralocorticoids resulting in hypo-natremia, hyperkalemia, and markedly elevated plasma aldostcrone and renin levels. Red blood cell Na+, K+-ATP-ase activity was measured in a pair of twins with pseudo-hypoaldosteronism, in an unrelated child with hypoaldos-teronism, and in an age-matched group of 50 healthy infants and young children. The enzyme was assayed by a method that couples ATP hydrolysis with NADH oxidation. Plasma renin and aldosterone levels were measured by RIA. Red blood cell Na+,K+-ATPase activity in the twins with Pseudohypoaldosteronism was very low at the time of diagnosis (3 wk). In both twins a time-related gradual increase in enzyme activity was observed during the 1st mo of life, reaching control values between 6 and 8 mo of age. This increase was associated with both a reduction in salt requirement and clinical improvement. Plasma renin activity and aldosterone levels were very high at the time of diagnosis. Plasma renin activity reverted gradually to normal values, whereas aldosterone levels remained high throughout the follow-up period. The child with hypoal-dosteronism had normal Na+,K+-ATPase activity at diagnosis and during follow-up.

The influence of maternal dexamethasone and ritodrine administration during pregnancy on cord blood cortisol and capillary serum glucose concentrations and on the incidence of respiratory distress syndrome (RDS) was studied in 30 premature infants (gestational age 27-36 weeks), and compared with a matched control group of 37 premature infants where no such medications were administered. RDS occurred less often in the treated group of infants (13.3%) than in the controls (35.1%, p < 0.01). The healthy treated infants had a significantly lower mean umbilical cord plasma cortisol concentration (5.5 +/- 1.8 ug/dl, mean +/- SD) than that observed in the controls (11.2 +/- 3.9 ug/dl, p < 0.01). Mean cord plasma cortisol concentrations increased with duration of pregnancy. No significant difference in the capillary serum glucose at 30 minutes post-delivery was found between the healthy, RDS, treated and non-treated infants. No adverse effects of steroid and ritodrine therapy were observed.

A five-year-old boy was evaluated for fever, abdominal pain, vomiting, and diarrhea lasting two days. Chest radiograph revealed a left bronchopneumonia. Metabolic work-up demonstrated phosphaturia, glucosuria, calciuria, proteinuria, profound hypophosphatemia, hypouricemia, borderline hypomagnesemia, and normoglycemia. Creatine phosphokinase values were elevated, a finding consistent with rhabdomyolysis. Serum pH was normal and urine pH was 5. Serum urea and creatinine levels were normal. The child was treated with ceftriaxone and azithromycin. Oral phosphate was administered, followed by a rapid normalization of its serum level. Re-evaluation one and three months after discharge, while being off any therapy, showed the resolution of all metabolic abnormalities. We believe that the metabolic disturbances in this child were due to an acute and transient tubular dysfunction, possibly secondary to inflammatory/infectious induced tubulointerstitial nephritis (TIN). TIN presenting with an isolated tubular functional impairment, in the absence of any evidence of functional glomerular impairment, does not appear to have been described before.

Pseudohypoaldosteronism type 1 (PHA1) is a rare inherited disorder characterized by salt-wasting due to target organ unresponsiveness to mineralocorticoids. PHA1 comprises two clinically and genetically distinct entities; isolated renal and systemic forms.The aim of this study was to investigate red blood cell (RBC) Na+,K+-ATPase activity and nasal potential difference (PD) in two pairs of unrelated dyzygous twins; one with the systemic form of the disease (PHA1-S) and the second with the isolated renal form (PHA1-R). Total and ouabain-sensitive ATPase activities were measured spectrophotometrically by a method that couples ATP hydrolysis with NADH oxidation. Maximal PD and response to amiloride perfusion were evaluated by a standard technique.In the twins with PHA1-S, persistently low activity of RBC Na+,K+-ATPase was found during a 6-year follow-up. Normalization of plasma renin activity (PRA) and plasma aldosterone was observed at the end of the first year of life. Maximal nasal PD was low and there was no significant response to amiloride. In the twins with PHA1-R, RBC Na+,K+-ATPase activity was very low at the time of diagnosis and normalized at the age of 6-8 months. PRA reverted gradually to normal values, whereas aldosterone levels remained high during the 6 years of follow-up. Maximal nasal PD and response to amiloride were normal.The observed differences in RBC Na+,K+-ATPase activity and nasal PD response to amiloride between the two pairs of twins support the contention of different basic pathogenic mechanisms in the two forms of PHA1.

Background: There is no satisfactory explanation why some individuals experience severe attacks of asthma, yet others, exposed to similar stimuli, have a milder form of the disease. Objective: We tested the hypothesis that children with more severe disease may have relative adrenal insufficiency compared to the children with milder disease. Patients and Methods: Sixteen children with chronic asthma aged 8-16 years old were studied. Adrenal function was evaluated by the 24-h excretion of urinary free cortisol (UFC) before and after ACTH stimulation, and by plasma cortisol levels before and 60 min after ACTH administration. The severity of bronchial hyperresponsiveness was evaluated by the methacholine provocation test. Results: Nine children had 20% fall in forced expiratory volume in 1 sec (FEV 1 ) after a provocative concentration (PC 2 0 FEV 1 ) of methacholine ≥2.5 mg/ml and were considered as having mild-moderate bronchial hyperresponsiveness (Group A). Seven children had a PC 2 0 FEV 1 of ≤1.25 mg/ml and were considered as having severe bronchial hyperresponsiveness (Group B). No significant difference was found between the peak plasma cortisol response to ACTH between the two groups (634 ′ 182 and 586 ′ 137 nmol/l, respectively). However, there was a significant statistical difference (p

We aimed to investigate, by means of dimercaptosuccinic acid (DMSA) scan, the relations between vesicoureteral reflux (VUR) and its degree, pyelonephritis during infancy, and renal parenchymal findings. Seventy-four infants with pyelonephritis, 44 girls and 30 boys (mean age at their first pyelonephritic episode 4.12 months, median 3 months), were enrolled in the study. Voiding cystourethrography (VCU) and ultrasonography (US) were performed within 6 weeks following the infection. DMSA was performed at least 4 months after the urinary tract infection (UTI). The renal parenchymal pathology was defined as focal or multifocal defects or as a split renal uptake of less than 45%. DMSA scintigraphy revealed that 19% (14/74) of the children had renal damage. Renal parenchymal findings were observed only when VUR was present, and its grade was above 3/5. No abnormality was found in 51 renal units without reflux, 9 with VUR grade 1/5, and 54 with grade 2/5. Renal pathology was observed in 9/24 renal units with VUR grade 3, 3/8 with grade 4, and 2/2 with grade 5. No correlation was found between renal parenchymal defects and clinical presentation of the pyelonephritis, type of the microorganism, presence of bacteremia, or the number of recurrent infections. In adequately treated infants, renal damage is probably due to a reflux-associated, preexisting, congenital renal parenchymal pathology and not to the inflammatory process. We suggest that DMSA scintigraphy should not be performed routinely in every infant with UTI and should be reserved primarily for children with VUR grade 3 and above.

To evaluate the efficacy and safety of intranasal midazolam in the treatment of autonomic crises in children with familial dysautonomia, intranasal midazolam was administered at the hospital to six patients during nine episodes of autonomic crisis. Treatment was successful in seven of nine episodes of autonomic crisis in five of six patients, with a mean interval to response of 9.25 +/- 1.25 minutes. The parents of five patients in whom the treatment was successful were instructed to use midazolam at home. At home, 16 additional episodes were treated by the parents, with successful control achieved in 14 (87%). The mean interval to response was 12.8 +/- 2 minutes. No significant side effects were observed at the hospital or at home after intranasal administration of midazolam. Midazolam, given intranasally, is effective and safe in the management of autonomic crises in patients with familial dysautonomia, either in the hospital or at home by the parents after appropriate instruction.

We previously reported that a decreased TCR mediated activity of the GTP-GDP binding p21ras protooncogene is associated with prediabetes in non-obese diabetic (NOD) mice. Furthermore, prevention of autoimmune diabetes is associated with reversal of the p21ras signaling defect in NOD T cells. Based on these animal studies we determined the activation of p21ras in PBMC from patients with Insulin Dependent Diabetes Mellitus (IDDM), Non-Insulin Dependent Diabetes Mellitus (NIDDM) and normal healthy controls. Stimulation by PHA induced a decrease of 3.7 +/- 1.4% and an increase of 2.44 +/- 2.3%, p < 0.02 and 2.6 +/- 1.6%,p < 0.003 in the basal unstimulated p21ras activity in the IDDM, NIDDM and normal control groups, respectively. Expression of p21ras and its regulatory elements, the GTPase activating protein p120ras-GAP and the guanine nucleotide releasing factor (GNRF) hSOS, was comparable in the three groups. The in vitro proliferative response to PHA was comparable in the IDDM and control groups: stimulation index (SI) of 8.6 +/- 2.5 and 9.4 +/- 3.5 respectively, p < 0.44. No correlations were found in the IDDM patients between the degree of p21ras activation and the mitogen induced in vitro proliferative response or the various clinical parameters including age, gender, disease duration, daily insulin requirements and metabolic control. Taken together these data indicate that PBMC from IDDM patients are characterized by a persistent impairment in the activation of their p21ras. They also suggest that p21ras stimulated activity is a sensitive and independent parameter of PBMC activation in these patients.

Forty-four nondiabetic patients with celiac disease (CD) were examined for the presence of insulin-dependent diabetes mellitus (IDDM)-related autoantibodies. Islet cell antibodies (ICA) were detected in 2 of 44 (4.5%). None of the 200 age- and sex-matched healthy controls was ICA positive (p < 0.05). Competitive anti-insulin antibodies (CIAA) were detected in 1 of 44 (2.5%) patients. First-phase insulin reserve (FPIR), stimulated insulin reserve (SIR), and glycosylated hemoglobin (GHB) levels were normal in the autoantibody-positive patients. Our data suggest that, like first-degree relatives of IDDM patients, CD patients are characterized by an increased prevalence of diabetes-related autoantibodies. Further follow-up is needed to determine whether the presence of these autoantibodies in nondiabetic CD patients predicts future IDDM.

A pair of non-identical twins with severe pseudohypoaldosteronism (PHA) were followed over a period of 4 years. The diagnosis was based on dehydration, hyponatremia, hyperkalemia, high urine sodium/potassium ratios, and high serum concentrations of aldosterone and renin. Sweat and saliva electrolyte concentrations were high, suggesting multifocal target-organ unresponsiveness to mineralocorticoids. No hydramnios was observed during pregnancy. Despite continuous treatment with sodium chloride and sodium bicarbonate (or = 20 g/day) and cation exchange resin (Kayexalate, sodium polystyrene sulfonate,or = 4 g/kg per day), the children had repeated episodes of dehydration, hyponatremia, and hyperkalemia. Growth velocity was normal in both twins. Catch-up growth was observed following infancy in the first twin. Normalization of plasma aldosterone, electrolytes, and renin concentrations was achieved at the age of 9 months.

Serum lipids were measured in children and their parents from 40 families in which the father had a myocardial infarction or coronary heart disease (CHD) before age 40 years. The relationship between physical activity and serum lipid concentrations in the children was also evaluated. Twenty six men had one or more abnormal lipid value (in mmol/l): total venous cholesterol (TVC) > 6.24, triglycerides < 2.55, low density lipoprotein cholesterol (LDL-C) > 4.42, or high density lipoprotein cholesterol (HDL-C) < 0.91. There were 15 spouses with significant hyperlipidaemia (values above). In the 107 children examined, TVC mean (SD) was 4.68 (1.17), triglycerides 1.4 (0.8), LDL-C 3.0 (1.0), and HDL-C 1.18 (0.28). Altogether 42% of the children had significant hyperlipidaemia. No significant correlation was found between the degree of physical activity of the children and their LDL-C and TVC concentrations. However, a significant positive correlation was found between the degree of physical activity and HDL-C and a significant negative one with triglyceride concentrations. It is concluded that screening the progeny of young CHD patients is highly productive in identifying young people at excessive risk for future CHD. The data also suggest that promoting high degrees of activity among these children may have a positive influence on risk factors for adult onset CHD.

Midazolam (Versed), the first water-soluble benzodiazepine, has had widespread acceptance as a parenteral anxiolitic agent. Its antiepileptic properties were studied in adult patients with good results. Midazolam was administered intramuscularly to 48 children, ages 4 months to 14 years, with 69 epileptic episodes of various types. In all but 5 epileptic episodes, seizures stopped 1-10 min after injection. These results suggest that midazolam administered intramuscularly may be useful in a variety of epileptic seizures during childhood, specifically when attempts to introduce an intravenous line in convulsing children are unsuccessful.

The aim of this study was to determine whether using air enema for acute intussusception is related to a higher rate of recurrence than other methods of treatment. A 10-y (1986-95) retrospective study was performed in a university-affiliated paediatric division. The overall recurrence rate for 97 patients with acute intussusception was 7.8% (10% of whom were treated non-surgically). There were no recurrences following the surgical treatment. In matched groups of patients, no risk factors were found for recurrence following air vs barium enema.

Four patients with severe pseudohypoaldosteronism caused by multiple end- organ resistance to aldosterone had frequently recurring lower respiratory tract infections and persistently elevated sweat and saliva electrolyte values. The increased saliva electrolyte values in these patients probably affect normal mucociliary function in the respiratory tract and facilitate the occurrence of frequent lower respiratory tract involvement. Patients with pseudohypoaldosteronism may require treatment similar to that for cystic fibrosis to prevent long- term respiratory complications. (J P EDIATR 1994;125:752-5)

The authors have compared the effects of treatment with weekly injections of human chorionic gonadotropin (hCG) with those of monthly testosterone (T) injections in males with hypogonadotropic hypogonadism. There was no significant difference in pubertal development as measured by progression through the Tanner stages, final height, or bone age, with the two treatment regimens. The final testicular volume in patients treated with 5,000 U/week of hCG (14.0 +/- 2.0 ml) was significantly greater than that in patients treated with 250-mg monthly T injections (4.3 +/- 1.8 ml) (P less than 0.01). This study shows that weekly injections of hCG are effective in achieving virilization in hypogonadotropic hypogonadic males, leading to a greater testicular growth than T preparations. Therefore, hCG treatment may have an advantageous effect on the eventual induction of fertility with human menopausal gonadotropin.