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Cytomegalovirus (CMV) disease is a common complication of advanced human immunodeficiency virus (HIV) infection. Administration of oral valaciclovir, a valine ester of acyclovir, achieves sufficient plasma acyclovir levels to inhibit many clinical isolates. Acyclovir has been associated with enhanced survival in AIDS but not with CMV disease prevention. CMV-seropositive patients (1227) with CD4 cell counts <100/mm3 were enrolled in a randomized, double-blind trial. Valaciclovir, 8 g/day, was compared with acyclovir, 3.2 or 0.8 g/day, for CMV prevention; all three arms were compared for survival. The confirmed CMV disease rate was 11.7% among valaciclovir recipients and 17.5% in the pooled acyclovir arms, a 33% reduction in risk. Time to confirmed CMV disease was significantly longer for the valaciclovir group (P = .03). A trend toward earlier mortality for valaciclovir recipients was seen (P = .06). Toxicity and earlier medication discontinuation were more common in this group. Valaciclovir significantly reduces the risk of CMV disease. Further exploration of a better-tolerated dose is warranted.

The molecular pathogenesis of vestibular schwannoma has been investigated by determining the extent of chromosome 22 loss of heterozygosity in 77 tumors and relating these findings to clinical and immunohistochemical indexes of tumor behavior. Loss of heterozygosity was looked for at eight chromosome 22q loci. Clinical details were obtained in all 77 cases, and a clinical growth index was calculated for each tumor. The proliferative index was estimated in all tumors by using a monoclonal antibody to the proliferating cell nuclear antigen and by calculating the labeling index. Forty percent (31 of 77) of the tumors showed allele loss, and in each case this loss involved the region of the neurofibromatosis type 2 gene. No evidence was found that the presence of chromosome 22 allele loss was associated with the clinical growth index. On the log scale, however, an association was seen between the clinical growth index and the proliferating cell nuclear antigen labeling index p = 0.001). These results suggest that chromsome 22 allele loss is a frequent event in vestibular schwannoma. Tumor behavior, however, appears to be independent of the chromosome 22 mutation. It is proposed that chromosome 22 allele loss and neurofibromatosis type 2 gene inactivation is an early event, possibly involved in the initiation of tumorigenesis in vestibular schwannoma. Tumor growth appears to be independent of this mutation and is likely to be determined by other as yet undefined factors.

By April 1995, 302 cases of vertically acquired HIV infection had been reported through the British Paediatric Association Surveillance Unit. Over 50% of these children had developed an AIDS indicator disease, including nine malignancies (seven cases of non-Hodgkin's lymphoma (NHL) and two of Kaposi's sarcoma). There were two other malignancies that were not AIDS indicator diseases. In children less than 5 years of age the incidence of NHL was approximately 2500 times greater than expected in the UK child population. Three children presented with NHL as their AIDS indicator disease and four developed NHL at a median of 14 (range 10-19) months after the initial diagnosis of AIDS. Six of the seven children died at a median of 6.5 (range 2-14) months after the diagnosis of NHL. The seventh child responded to treatment and is alive nearly four years later. Histology was available in five cases, of which four were of B cell and one of T cell origin. Epstein-Barr virus was detected in all three patients with NHL where it was sought; all had B cell lymphomas. Although comparatively rare, malignancies occur in children infected with HIV and may be the presenting illness. Paediatricians now need to consider HIV infection as a predisposing cause of childhood cancer, especially NHL.

Effective primary prevention of congenital toxoplasmosis requires up to date information on locally relevant risk factors for infection in pregnant women. In Naples, risk factors for toxoplasma infection were compared in recently infected women (as assessed by detection of specific IgM in serum) and susceptible, IgG negative women. Recent infection was strongly associated with frequency of consumption of cured pork and raw meat. Eating cured pork or raw meat at least once a month increased the risk of toxoplasma infection threefold. This simple study design for determining locally relevant sources of toxoplasma infection is the first report of cured pork as a risk factor for infection. Further research is required to determine cyst viability in cured pork products. Our findings suggest that in southern Italy, cured pork and raw meat should be avoided by susceptible pregnant women.

Unlinked anonymous HIV-1 testing of neonatal samples routinely collected for metabolic screening is now carried out in many parts of the United Kingdom. The purpose of this study was to assess the completeness of screening coverage in infants born to women known to be infected with HIV-1. Research nurses at family HIV clinics in three London hospitals searched for Guthrie cards from all infants born to known infected residents of North East, North West, and South West Thames regions over a 32 month period. If no card was found initially, mothers were approached for more information. Overall coverage was estimated to be 96.4% (94.6% in infants of African origin and 100% in white infants). These figures are similar to recent general population coverage estimates in inner London. We conclude that the anonymous newborn HIV testing programme is providing sufficiently accurate information on both absolute levels and time trends in maternal seroprevalence.

Objective: To estimate the reduction in the number of children infected with HIV that might be achieved by extending the provision of voluntary antenatal HIV testing. This effect would be mediated by increased numbers of women infected with HIV who receive an intervention to reduce the risk of vertical transmission (for example, zidovudine or caesarean section delivery), who use an alternative to breast feeding, or whose pregnancy is terminated., Setting: London, United Kingdom., Methods: Relevant data were derived from neonatal seroprevalence studies, obstetric and paediatric reporting schemes, and review of external information. Sensitivity analyses were performed for certain parameters., Results: Of 106,000 births annually in London, an estimated 169 are to women infected with HIV whose infection is not currently recognised before pregnancy. An estimated 28-33 children born to these women will be infected. Precise prediction of the number of paediatric HIV infections that could be prevented is difficult because of uncertainty in certain factors, particularly the uptake of antenatal testing and the efficacy and acceptability of interventions to reduce prenatal or perinatal transmission. If a testing programme detected 70% of infected women, none of whom opted for a termination but all of whom exclusively bottle fed and received an intervention which halved the risk of transmission, about 12-16 (42-46%) paediatric HIV infections would be prevented annually., Conclusions: The estimated cost of preventing each paediatric infection is high, but this should be seen in the context of the lifetime health and social care costs for a child infected with HIV. The feasibility of selective testing should be considered when formulating policies on antenatal HIV testing. Programmes that are introduced should be audited to obtain better estimates of costs and benefits.

Objective: To evaluate the extent to which antenatal HIV screening programmes identify HIV infected women who go to term., Design: Comparison of results of two surveillance systems. An anonymous neonatal HIV serosurvey was used to estimate the numbers of HIV infected women giving birth; reporting by obstetricians was used to assess the proportion who had been identified., Setting: Three Thames regions., Results: 729,105 neonatal blood samples were tested, of which 484 were HIV seropositive. Newborn HIV seroprevalence is increasing, at different rates, in inner London, suburban London, and in non-metropolitan districts. During the past four years the proportion of infected women who have been identified before delivery is 16.9%, but less than half of these were diagnosed during pregnancy. In 1993 only five of the 128 (4%) previously undiagnosed infected women delivering babies were identified by antenatal screening., Conclusion: Despite increased emphasis on antenatal testing for HIV in areas of higher prevalence the number of undiagnosed women delivering babies continues to increase. Consideration should be given to alternative strategies for offering antenatal HIV testing. Antenatal screening programmes should be monitored continuously by comparing anonymous neonatal seroprevalence with clinical reports from obstetricians.

In order to review the clinical course, laboratory findings, and outcome of children with vertically acquired HIV infection and Pneumocystis carinii pneumonia, questionnaires were sent to paediatricians in the British Isles who had reported P carinii pneumonia and HIV infection through the British Paediatric Surveillance Unit (BPSU). Paediatric reports from the BPSU are linked to reports of pregnancies in HIV positive women and laboratory reports. P carinii pneumonia was the most frequently reported AIDS indicator disease at AIDS diagnosis, occurring in 22/56 (40%) children born in the British Isles; in a further two children P carinii pneumonia occurred after another AIDS indicator disease. The median age at P carinii pneumonia diagnosis was 4.1 (1.4-27.3) months and in 48% it occurred with other AIDS indicator diseases. Despite intensive treatment the three month survival was only 38%. The nine children surviving P carinii pneumonia subsequently developed further AIDS indicator diseases, in particular HIV encephalopathy and four have since died. P carinii pneumonia was present at AIDS diagnosis in 65% of children developing AIDS in the first year of life and caused 82% of infant deaths. Most children were not known to be at risk of HIV until they presented with P carinii pneumonia. Children with HIV infection develop P carinii pneumonia at an early age and have a poor outcome. Increased awareness of the condition is required to initiate early treatment. Prevention may be a compelling incentive for screening in pregnancy, but further study is required to quantify the risks and benefits of initiating early P carinii pneumonia prophylaxis as well as the impact this might have on life expectancy.

Study Objective: The purpose of this study was to investigate the relation between blood pressure at age 36, and birth weight and body mass index (BMI) in childhood, adolescence and adulthood., Design: Prospective longitudinal survey over a period of 36 years in England, Scotland, and Wales., Participants: A nationally representative sample consisting of 3332 men and women born in one week in March 1946. Altogether 82% of these subjects had complete data for the present analysis., Main Results: There was an inverse linear relation between birth weight and blood pressure at age 36. The relation between BMI and blood pressure at age 36 was initially inverse and became increasingly positive throughout life. Weight gain in childhood was positively associated with adult blood pressure, although less important than weight change in later life. The associations between blood pressure and birth weight, and blood pressure and adult BMI were independent, and together they accounted for no more than 4% of the variation in adult blood pressure. Both low birth weight (birth weight < or = 2.5kg) and high BMI at age 36 (BMI > 30kg/m2) were associated with hypertension (> 140/90mmHg), but the per cent population risk of hypertension attributable to low birth weight was less than 5%, and to high BMI less than 12%., Conclusions: Low birth weight and high BMI at age 36 were independently related to high blood pressure. A reduction in the percentage of low birthweight babies born in the fourth decade of this century would only have a negligible effect on the incidence of adult hypertension 30-40 years later.

Objective: To describe the epidemiology of vertically acquired HIV infection in the British Isles, the level of underreporting, the vertical transmission rate, and clinical spectrum of paediatric AIDS., Design: Confidential, linked registers based on reporting from obstetricians and paediatricians; anonymous unlinked neonatal HIV serosurveys., Setting: British Isles., Subjects: Children born to mothers with HIV infection., Main Outcome Measures: Trends in HIV infection and vertical transmission rate., Results: In Scotland and the Irish Republic, where most maternal HIV infection is related to drug misuse, the annual number of reports of children born to infected mothers has fallen since 1989. In England and Wales nearly half of maternal infections have been acquired overseas, and the number of children born to these women, and to women who became infected in Britain, is increasing. In south east England the proportion of live births to women whose infection was identified before delivery was only 17% (50/287), compared with 68% (26/38) in Scotland. The vertical transmission rate was 13.7% (23/168), and 23% of infected children developed AIDS in the first year of life. 41% (38/92) of children born to infected mothers who were ascertained after delivery were breast fed, compared with 5% (12/236) of those ascertained before delivery., Conclusions: The incidence of vertically transmitted HIV infection is increasing in England and Wales. More extensive antenatal testing would enable infected women to be counselled against breast feeding, which could prevent a substantial proportion of vertical transmission in some areas, and would increase opportunities for early diagnosis and treatment of infected children.

Antenatal HIV screening policies throughout the British Isles were surveyed and results linked to data on HIV-infected pregnant women notified through the Royal College of Obstetricians and Gynaecologists. Units offering HIV testing to all pregnant women were compared with those offering it only to women considered to be at risk, and in both situations fewer than 50% of infected women were identified as HIV infected for the first time in antenatal clinics. Based on laboratory reports of HIV infection in women of childbearing age, paediatric reports of children born to HIV positive women and unlinked anonymous neonatal screening programmes, there was evidence of under-recognition of HIV infection in pregnancy, particularly in England and Wales.

To monitor the spread of human immunodeficiency virus (HIV) in the heterosexual population, residues of blood samples collected routinely on absorbent paper for neonatal screening (Guthrie cards) in NE, NW, and SW Thames Regions in England have been tested for antibodies to HIV-1 since June, 1988. 323,369 dried blood spots were analysed to end March, 1991. Prevalence of anti-HIV-1 in newborn babies has remained stable in outer London and non-metropolitan districts whereas prevalence in inner London has increased from 1 in 2000 in the 12 months beginning June, 1988, to 1 in 500 in the first 3 months of 1991. Either exponential or linear growth in the numbers of new seropositives could account for the results. That obstetricians were aware of maternal HIV infection in only 20% of infected pregnancies, indicates the extent to which HIV infection goes unrecognised in the heterosexual community.

The current working hypothesis on the pathogenesis of autoimmune disease focuses on the interactions between susceptibility genes and environmental stimuli. In Graves' disease it is postulated that aberrant expression of HLA class II antigens on thyroid epithelial cells permits the presentation of specific thyroid antigen to activated lymphocytes. Evidence suggests that thyrocyte HLA-DR expression is secondary to the production of cytokines by presensitized T-lymphocytes. A 20-yr-old woman and her 18-yr-old brother presented with classical findings of Graves' disease with ophthalmopathy within a year of each other. Diagnosis was confirmed by demonstration of elevated serum levels of T4 and T3, strongly positive titers of TSH binding inhibitory immunoglobulins, and histological examination after subtotal thyroidectomy. Eight years previously, acute life-threatening aplastic anemia in the brother led to therapeutic transplantation of bone marrow from his sister. After the procedure, 100% of his peripheral leucocytes were genotype 46,XX. HLA typing performed before transplantation and 2 months after thyroidectomy in the female indicated complete identity with her brother's leukocytes for class I and class II antigens. Thyroid autoantibodies at this time were weakly positive. Although the concordance of thyroid disease in these patients could be due to chance, the patients were of different sexes, the family history was negative, and neither the probands nor the first degree relatives bore the HLA-DR3/B8 antigens. We propose that the male passively acquired a clone of programmed or activated lymphocytes from his sister and that his hyperthyroidism was not primarily dependent on exposure to specific thyroid-derived antigen.

Gonadotropin-independent precocious puberty presents a challenge in diagnosis and management and in the elucidation of its pathophysiologic basis. Current therapeutic strategies reflect the fact that, irrespective of the underlying mechanism, the clinical and biochemical aspects of the disease process are consequences of gonadal autonomy. In MAS and in testotoxicosis, the most successful therapeutic maneuvers have focused on the local inhibition of steroidogenesis. Despite the positive reports on the use of MPA and cyproterone acetate, long-term experience with these preparations has been generally unsatisfactory, and there is a consensus that testolactone or ketoconazole represent optimal management. Although ketoconazole use, in our experience, has not been associated with any adverse effects either on liver function or on cortisol metabolism, the risk potential is always there. Nevertheless, its effects are dramatic in boys with testotoxicosis, and its mode of action allows for easy monitoring of its efficacy. Testolactone use in MAS, and in combination with spironolactone in testotoxicosis, appears to be relatively safe and reasonably effective. However, because serum testosterone levels are not lowered during treatment, assessment of efficacy depends largely on long-term evaluation of growth rate and of skeletal maturation. The etiology of these disorders remains unclear. The McCune-Albright syndrome is a multisystem disease and sporadic in nature. The organ involvement--ovary, thyroid, adrenal glands, bone, and kidney--is reminiscent of pseudohypoparathyroidism, ironically also bearing Albright's name (Albright's hereditary osteodystrophy, AHO). It is well established that in this syndrome, organ hypofunction associated with the AHO phenotype is caused by deficiency or dysfunction of the G-(or N) regulatory protein essential for production of intracellular cAMP and induction of specific protein kinases. The hypothesis that MAS is caused by abnormal regulation of the membrane receptor/kinase complex would seem logical. Despite its clinical similarity to MAS, the mechanism underlying testostoxicosis is clearly different. This disease is autosomal dominant and is expressed clinically only in boys. Its effects are confined to the production of gonadal autonomy. However, it is difficult to theorize how such autonomy could arise. The enzymatic reactions converting cholesterol to testosterone within the testis or adrenal gland are acquired typically through autosomal recessive inheritance, including the initial rate-limiting step of desmolase side-chain cleavage.(ABSTRACT TRUNCATED AT 400 WORDS)

Background: Patients with transfusion-dependent thalassemia major tend to have abnormal growth and sexual maturation at puberty, presumably as a result of pituitary iron overload. This study was designed to determine whether chelation therapy with deferoxamine before the age of puberty would ameliorate this problem., Methods: We examined 40 patients over 14 years of age with transfusion-dependent thalassemia major. The 19 patients in group A (mean [+/- SD] age at study, 17.0 +/- 1.5 years) had begun nightly treatment with subcutaneous deferoxamine before the age of 10 (mean age at start of treatment, 7.5 +/- 1.8 years). The 21 patients in group B (mean age, 24.1 +/- 3.8 years) had begun treatment after the age of 10 (mean age at start of treatment, 14.4 +/- 4.7 years)., Results: The abnormal findings were essentially confined to sexual development. The final height did not differ between groups or from the mean parental height in each group. Ninety percent of the patients in group A had normal sexual development, as compared with 38 percent of those in group B (P = 0.001). Outcomes were correlated with indexes of iron overload; the patients in group A had lower serum ferritin levels before chelation treatment (P = 0.01) and lower average serum ferritin levels during treatment (P = 0.005)., Conclusions: Beginning chelation treatment with deferoxamine before the age of puberty can help children with transfusion-dependent thalassemia major to attain normal sexual maturation.

Pregnant Rhesus monkeys treated with 131I at midgestation become hypothyroid and produce fetuses without demonstrable thyroid tissue. In an effort to prevent both maternal and fetal hypothyroidism, we treated 131I-treated pregnant monkeys with 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT), a thyroid hormone analog with structural changes which facilitate placental transfer. Five pregnant monkeys were treated with 131I (mCi/kg) at 83-87 days of gestation. One week later, three monkeys were started on treatment with DIMIT (10 micrograms kg-1 day-1, im) and two on im L-T4 (2 micrograms kg-1 day-1). Treatment was continued until delivery by Caesarian section at 152-157 days of gestation. None of the DIMIT-treated mothers became clinically hypothyroid, nor did they have elevated serum TSH concentrations despite low serum levels of T3 and T4. T4-treated mothers were also maintained clinically and biochemically euthyroid. At delivery, infants of DIMIT-treated mothers had normal respiratory function and skeletal maturation. Basal and TRH-stimulated TSH concentrations were suppressed in two of the three infants. By contrast, both T4-treated infants resembled untreated cretinous newborns and died soon after delivery from respiratory failure. Serum TSH concentrations were elevated and skeletal maturation was markedly delayed in these animals. We conclude that DIMIT administration to 131I-treated monkeys prevents clinical and biochemical hypothyroidism in the mother and prevents the major clinical manifestations of cretinism in the fetus.

A double antibody RIA was developed for the measurement of the long-acting GnRH agonist D-Ser(TBU)6EA10GnRH (buserelin). The antibody, raised in rabbits against a buserelin-hemocyanin conjugate, reacted with the intact molecule and also molecular fragments containing the C6-9 tetrapeptide sequence and permitted the measurement of buserelin activity in serum and urine. Natural GnRH, LH, and FSH did not cross-react in this assay system. The assay was applied to samples obtained from children receiving buserelin for the management of central precocious puberty either by once daily injection of 30 micrograms/kg or by nasal spray (in; 200 micrograms every 8 h). Urine and serum samples, chromatographed on Sephadex G-25, contained immunoreactive material corresponding closely in molecular size to [125I]buserelin. In unextracted serum samples taken at intervals after sc therapy in 11 girls, the peak immunoreactive buserelin levels of 52.2 +/- 14.8 ng/ml (mean +/- SEM) occurred at 30 min. The half-time of elimination was 74.9 +/- 36.9 min. Approximately 30% of the dose was detected in urine collected for 3 h after injection. Similar data were obtained in 3 normal adults given 10 micrograms/kg buserelin, iv. By contrast, after the administration of 200 micrograms buserelin by metered nasal spray, the mean peak serum concentration in 10 girls was 100-fold less (0.65 +/- 0.14 ng/ml), although the halftime of elimination was almost identical. Only 0.73% of the nasal dose was excreted by 3 h. Calculated relative bioavailability data indicated maximal nasal absorption of 6%. However, absorption after nasal administration varied greatly, and in 2 children, serum and urinary concentrations of buserelin after supervised administration were negligible. We conclude that in buserelin therapy, in the dose used in this study, does not represent optimal treatment for the initial management of patients with precocious puberty. The success of in therapy in sustaining initial effects of buserelin given by sc administration presumably reflects changes in receptor sensitivity induced by sc treatment.

The chronic administration of the long-acting LHRH agonist analog D-Ser(TBU)6-LHRH-EA10 (HOE 766, Buserelin) suppresses pituitary gonadotropin secretion. Since a similar analog was shown to be effective in the short term parenteral treatment of idiopathic precocious puberty in girls (10), we used Buserelin both intranasally and sc to treat patients of both sexes with idiopathic and secondary central precocious puberty to test its efficacy, safety, and potential for long term use. Six girls and two boys presented with advanced skeletal maturity, accelerated growth velocity, Tanner stage II-IV pubertal development, and pubertal levels of sex steroids and gonadotropins. Patients were treated for 6 months sc and up to 5 months intranasally. Optimal doses ranged from 10-20 micrograms/kg X day in girls and 30 micrograms/kg X day in boys, with marked individual variation. During sc therapy, there was significant suppression of growth velocity (P less than 0.001), serum gonadotropins (P less than 0.001), 17 beta-estradiol (P less than 0.005), and testosterone as well as clinical and behavioral improvement. The rate of bone maturation was reduced. All effects were reversed after discontinuation of therapy for 1 month in one girl. No reduction in efficacy was seen after changing four girls and one boy to intranasal therapy, but improved acceptability and compliance were reported by parents. Apart from withdrawal bleeding in one girl and transient acceleration of puberty in two patients during the initial phase of treatment, no serious unwanted effects occurred. Antibodies to native LHRH were not detected after 6 months of therapy. These results confirm the efficacy and safety of Buserelin by intranasal and sc routes in patients with sexual precocity and indicate a need for long term studies.

The "empty sella" (ES), a common entity in adults, is so named because a cerebrospinal fluid-filled arachnoid hernia fills the pituitary fossa and compresses the pituitary gland, creating the illusion of an "empty" sella. We report our experience of ES in childhood. Our four cases represent associations with ES that have not been previously described in childhood: case 1 was associated with central precocious puberty; case 2 with secondary ES resulting from shrinkage of a prolactinoma during bromocriptine therapy; case 3 with pseudotumor cerebri; and case 4 with no significant pathology. Together, they account for approximately 1 percent of cases of radiographically enlarged sella tursica investigated here. This brings the number of cases of ES reported in children to 27. Review of these 27 cases reveals seven with local skull dysplasia and/or a familial inheritance. The remainder lacked clinical homogeneity or similarity to the common adult variety of ES. Children with ES did not exhibit the higher female preponderance reported in adults with ES. They showed a higher frequency of secondary cases (4/27), and of associated endocrine (10/15) and visual (8/17) abnormalities than is seen in adults with the "empty sella."

The effects of electrical stimulation of the brain stem on ACTH and GH secretion were studied in pentobarbital-anesthetized dogs. Stimulations in or near the subcoeruleus area or ventral ascending noradrenergic pathway inhibited the stress-induced increase in ACTH secretion, while stimulations in other areas of the brain stem did not. No significant changes in GH secretion occurred following stimulation of the subcoeruleus area, ventral ascending noradrenergic pathway or adjacent regions of the canine brain stem. These results are consistent with the hypothesis that there is central noradrenergic input to the hypothalamus which can inhibit ACTH secretion. This input appears to be separate from the postulated noradrenergic input that may increase the secretion of GH.

A heterologous radioimmunoassay for canine prolactin was developed and used to study the role of catecholamines and indoleamines in the regulation of prolactin secretion in dogs. Females dogs were found to have a higher plasma prolactin concentration than male dogs. Thyrotropin-releasing hormone (TRH) increased plasma prolactin in male and female trained conscious dogs. L-Dopa blocked the increase produced by TRH, but this effect could be reversed by pretreatment with carbidopa, an inhibitor of the conversion of L-dopa to catecholamines outside the blood-brain barrier. The intravenous administration of the immediate precursor of serotonin, L-5-hydroxytryptophan (5HTP), caused an increase in plasma prolactin and growth hormone. The administration of the serotonin receptor blocker, metergoline, 18 and 3 h before 5HTP, significantly augmented the growth hormone response to 5HTP. In contrast, metergoline diminished the prolactin response to 5HTP. Pretreatment with carbidopa did not change the prolactin or growth hormone responses to 5HTP. These observations indicate that the dog is similar to other mammals in that females have greater plasma prolactin concentrations than males and TRH increases plasma prolactin. L-Dopa appears to act at a site outside the blood-brain barrier to prevent the prolactin response to TRH. The data suggest that 5HTP increases plasma prolactin via a serotonergic mechanism, whereas it increases plasma growth hormone via a different, nonserotonergic mechanism.

This study was undertaken to explore the physiological relationships between fasting glycemia, antecedent glycemic control and fasting growth hormone levels in pancreatectomized dogs. In contrast to other studies, we used continuous intravenous infusions of insulin in an attempt not only to normalize fasting plasma glycemia but also to eliminate the characteristic fluctuations of diabetes usually encountered in the postprandial and postabsorptive periods. For comparison, a similar group of healthy animals served as normal controls. In the healthy dogs, fasting growth hormone (GH) levels were stable and well within normal limits for this species, demonstrating an overall mean +/- SD of 2.50 +/- 0.46 ng/ml. In the pancreatectomized group as a whole, the fasting GH levels were significantly elevated (4.63 +/- 2.42 ng/ml, P less than 0.01) and significantly (P less than 0.001) more variable than in the controls. Multiple regression and analysis of variance confirmed the expected significant positive correlation between fasting GH and fasting plasma glucose levels, but also elucidated a heretofore unknown direct relationship between fasting GH levels and the preceding instability of glycemic control.

A female infant, younger than any other case in the literature, with ACTH-producing microadenoma of the pituitary is reported. She had full-blown symptoms and signs as well as laboratory evidence of Cushing's disease. The tumor was investigated by histology, immunocytology (avidin-biotin-peroxidase complex technique), and electron microscopy. The possibility that the tumor was derived from the fetal intermediate lobe is discussed.

Thyroid function was systematically evaluated in 15 consecutive children (mean age 13.7 years, range 0.5 to 19.5 years) before and serially during treatment with amiodarone (Cordarone), a potent antiarrhythmic agent. Amiodarone is known to affect thyroid homeostasis by competitive inhibition of 5'-monodeiodinase, which converts L-thyroxine (T4) to triiodothyronine (T3) and reverse T3 (rT3) to 3,3'-diodothyronine (T2), and also by the direct effects of its high iodine content (37% by weight). Clinical and/or biochemical evidence of hypothyroidism occurred in three patients, two of whom required treatment with L-thyroxine. An additional patient had persistent hyperthyroxinemia but no clinical evidence of hyperthyroidism. Results from the patients who remained euthyroid showed characteristic alterations in serum thyroid function tests. These included significant increases in serum T4, rT3, basal thyroid-stimulating hormone and thyroid-stimulating hormone response to thyrotropin-releasing hormone testing. These changes were considered to be compensatory adjustments by the pituitary-thyroid axis to competitive inhibition of 5'-monodeiodinase by the amiodarone. Routine screening of thyroid function is needed to allow early detection of hypothyroidism when these compensations fail to occur.

Three boys, 5.0-7.4 yr of age, with clinical and biochemical features consistent with familial gonadotropin-independent precocious puberty ("testotoxicosis") were treated with the antifungal drug ketoconazole in a dose of 200 mg every 8 h. Serum testosterone levels fell significantly within 24 h in all three patients, with reciprocal changes in serum 17-hydroxyprogesterone, consistent with inhibition of C17-20 lyase activity. However, after 1-3 months of continuing treatment, an "escape" phenomenon occurred, characterized by progressive increases in serum LH, FSH, and testosterone concentrations. Furthermore, for the first time, a marked pubertal-type LH response was found after GnRH administration in contrast to the absent response consistently found in all patients before ketoconazole therapy. Combination treatment with ketoconazole and the GnRH analog buserelin resulted in restoration of pituitary and gonadal hormone concentrations to the upper range of normal for prepubertal children. We hypothesize that the advanced state of maturation of the boys in this study [mean bone age, 13.2 +/- 0.8 (+/- SE) yr] was the major contributing factor to this escape, with the set-point of the GnRH pulse generator (gonadostat) functioning at the adult level of sensitivity. Such escape may limit the successful use of ketoconazole alone. These data together with evidence of normal testosterone responses to hCG during ketoconazole therapy indicate that in testotoxicosis, pituitary and gonadal receptors are functionally intact, with appropriate negative feedback relationships.

Three boys 3.3 to 3.9 years old, who had precocious puberty that was unresponsive to an analogue of gonadotropin-releasing hormone, were treated with the antifungal agent ketoconazole for up to 12 months. Within 48 hours the serum testosterone concentration fell to normal in two boys and was significantly reduced in the third, paralleling major improvements in behavior. Reciprocal changes in serum levels of 17-hydroxyprogesterone suggested that C17-20 lyase was the principal site of drug action. Although there was evidence of a blunted cortisol reserve during the first week of treatment, the cortisol response to ACTH1-24 had returned to normal by one month of continuous treatment, and normal diurnal cortisol rhythm was preserved. No adverse clinical or biochemical side effects were noted during 9 to 12 months of continuing treatment. During that time, growth velocity was significantly reduced in all three boys, from a mean rate of 1.5 +/- 2.0 cm per year before treatment to 5.9 +/- 0.6 cm per year after ketoconazole therapy. There was a simultaneous retardation of the rate of skeletal maturation. The striking improvements in behavior were sustained for the duration of treatment. These preliminary data suggest that administration of ketoconazole may be a satisfactory treatment for precocious puberty in boys and possibly for other conditions characterized by androgen excess.