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Urinary free cortisol (UFC) values in normal subjects have been determined for various age groups ranging from 4 mo to 50 yr. Mean values for UFC24 hr increased with age until approximately 20 yr, after which a relatively stable level of excretion was maintained. Correction of UFC for body surface area (per sq m), body weight (per kg), or muscle mass, i.e., creatinine excretion (per g creatinine), did not resolve the differences in all of the age groups studied. Regardless of the correction parameter used (surface area, etc.), a minimum in cortisol excretion was found in the 11–20-yr age group. Guidelines for the interpretation of cortisol production rate (CPR) and 17-hydroxycorticosteroid (17-OHCS) excretion in the same age groups are also provided. There was a significant positive correlation between UFC and both CPR (r = 0.71) and 17-OHCS (r = 0.87) during growth and maturation. Taking into account the variation in excretion of UFC with age, the data provides reference standards for the use of UFC in the diagnosis of adrenocortical disorders in children and adults.

Clinical staging of maturation in 487 white (232 male) and 239 black (166 male) youths was compared with serum gonadotropin levels. Gonadotropin patterns were similar in both male groups. Luteinizing hormone (LH) rose progressively with maturation. It is uncertain if LH plateaus in pubertal

Thirty normal males and 30 normal females who were between the ages 10–14 yr inclusive, who on careful physical examination ranged from prepubertal to adult sexual development (Tanner Stages I–V) were each studied by measuring serum FSH, LH, estrone (E1) and estradiol (E2). Prepubertal females (Stage I) had higher values for estradiol, 10 pg/ml than males, 5 pg/ml (p < 0.005). Estrone was not significantly higher in prepubertal females. At each subsequent stage of puberty, both E1 and E2 were significantly higher in the girls (p < 0.05). Both estrogens correlated significantly with stage of puberty, osseous maturation, and with chronologic age in males and females. A significant association (p < 0.05) was observed between levels of both gonadotropins and levels of both estrogens in males, and between both gonadotropins and E1 in females; E2 correlated significantly with LH (rs = 0.7), but poorly with FSH (rs = 0.13).

The patient was the fourth of affected male siblings. Cortisol (1.3 micrograms per cent), cortisone (9.6), and corticosterone sulfate (0.1) concentrations were low in cord blood. The larger amount of cortisone may have originated from maternal cortisol. Aldosterone was undetectable in cord blood, indicating lack of fetal secretion or maternofetal transfer. Unexpectedly normal concentrations of 11-deoxycorticosterone (DOC) sulfate in cord serum could represent maternal transfer of DOC, with subsequent fetal sulfurylation. Low estrone and estradiol concentrations in maternal and cord serum were consistent with absence of the fetal adrenals. Despite the low levels of the steroids, the propositus had a normal lecithin-sphingomyelin ratio at 38 weeks' gestation. Circulatory insufficiency developed within half an hour after birth and responded to gluco- and mineralocorticoid therapy. The three untreated siblings died between 14 and 67 hours of age. It is evident that early recognition of this condition may be lifesaving.

Subacute thyroiditis in a lateral, ectopic thyroid has been previously unreported. A 4 10/12-year-old girl had an enlarging mass in the left upper anterior neck. Initially, the serum concentration of T 4 was normal, T 3 was elevated, and TSH was undetectable without response to TRH. RAI uptake was 1%. The data were consistent with subacute thyroiditis. Twelve weeks later the serum concentration of T 4 was low and TSH was elevated; thyroid replacement therapy was given for 20 weeks. When this was discontinued, there was an initial increase and then a decrease in the TSH values accompanied by an increase in serum concentrations of T 3 and T 4 to normal during eight weeks. One must consider a lateral ectopic thyroid gland in the differential diagnosis of masses in the neck. Physicians must be aware that temporary hypothyroidism occurs during the course of subacute thyroiditis

Because of the limitations of existing methods for estimation of cortisol production rate (CPR), a micromodification of a previously reported technique based on measurement of the specific activity of

HCG3 stimulation of 5 endocrinologically normal boys was shown to cause a more prominent rise in testosterone than in the other testicular secretions, androstenediol, androstenedione, dehydroepiandrosterone (DHA) and dihydrotestosterone. There was no apparent difference in the testicular secretory pattern between 1 to 10 yr of age. The effect of hCG on children was similar to that reported in adults. However, the androstenediol-to-testosterone ratio after hCG seemed to be even lower than the 1:4 ratio recorded in adults. Previous studies have indicated that testosterone secretion is normal in pubertal boys with seeming hereditary deficiency of Δ5-3β-hydroxysteroid dehydrogenase (Δ5-3β-HSD), an enzyme necessary for testosterone biosynthesis. In 2 of 3 such cases we confirmed that plasma testosterone increased normally in response to short-term hCG stimulation. Nevertheless, the secretion of androstenediol was elevated relative to that of testosterone. The resultant uniformly abnormal ratio of plas...

Altered carbohydrate metabolism associated with fibrosarcomas and chondrosarcomas has been well-documented in past literature. This report describes abnormal carbohydrate metabolism in 2 osteosarcoma patients, and abnormalities in growth hormone and somatomedin serum levels. Experimental evidence is presented showing in vitro suppression of osteosarcoma tumor cell proliferation by 17 beta Estradiol. Estrogen inhibition of linear bone growth, cartilage proliferation, and somatomedin is discussed with reference to possible estrogen therapy in osteosarcoma.

Six girls, aged 5 to 15 years, presented with thyroid masses in otherwise nonpalpable thyroid glands and with normal serum thyroxine levels. Scintiscanning before and after TSH stimulation confirmed the presence of autonomous nodules in the four adolescents, of whom two had elevated T 2 levels. Surgical exploration revealed adenomatous thyroid hyperplasia in three of the girls and papillary adenocarcinoma in the fourth. Scans in the other two girls revealed absence of the left lobe. One of them proved to have agenesis of the left lobe with enlargement of the right lobe because of lymphocytic thyroiditis. The other girl had an ectopic thyroid with chronic inflammation. A thorough diagnostic evaluation of single or multiple functioning thyroid masses in children and adolescents is essential in establishing the correct diagnosis. The possibility that carcinoma can occur in autonomous nodules as well as in hemiagenesis and ectopic thyroid tissue is discussed. An approach to the management of functioning thyroid masses in the pediatric age group is proposed.

The relationship between age at beginning therapy and subsequent intelligence quotient was studied in 31 patients with congenital hypothyroidism. Those patients treated before three months of age had a significantly higher average I.Q. than those treated after three months. Because the clinical symptomatology before three months of age is often obscure, and the diagnosis is often missed, a neonatal screening program could be beneficial.

We have observed the association of transient hypoglycemia, temporary ACTH deficiency, and elements of “maternal deprivation” or parental neglect in three children. Since reversible pituitary deficiency has been documented in the syndrome of “maternal deprivation” and since hypoglycemia can be the manifestation of ACTH and/or growth hormone deficiency, we suggest that recognition of hypoglycemia in the pediatric population may sometimes lead to the discovery of an adverse environment.

Although the finding of antithyroglobulin antibodies has been considered the mostuseful diagnostic procedure for nonbiopsy diagnosis of chronic lymphocytic thyroiditis, we found titers

Extract: High levels of unconjugated estrone ((E1) 3-hydroxyestra-1,3,5(10)-triene-17-one) and estradiol ((E2) estra-1,3,5(10)-triene-3,17β-diol) were found at term in maternal venous, umbilical vein, and umbilical artery plasma. For estrone the respective values in nanograms per milliliter ±SD were 12.8 ± 5.9, 25.1 ± 6.5, and 13.2 ± 7.7. For estradiol the respective values were 17.3 ± 9.2, 8.1 ± 4.0, and 5.1 ± 3.2. For estrone, levels for umbilical vein were higher than those in the paired maternal and umbilical artery; estradiol was higher in maternal vein than in the paired umbilical vessels. Absence of the fetal adrenals was associated with low levels of estrone and estradiol for maternal and umbilical vessels, whereas, in anencephaly, only the maternal levels were markedly diminished. An initially rapid, and then a slower decline in both estrogens was found in normal infants during the first 72 hr of life.

An attempt was made to determine whether increased cortisol production contributes to the pathogenesis of juvenile diabetes mellitus. Cortisol secretion rates (CSR) were estimated by the in vivo isotope dilution method in 10 children with newly diagnosed diabetes, who were not acutely ill and whose venous blood pH was 7.33 and plasma CO 2 content was 20 mM. per liter. The mean and range of their cortisol secretion rates were no different from those of normal control children. Hyperadrenocorticism apparently plays no role in the pathogenesis of juvenile diabetes mellitus. However, newly diagnosed diabetic children who were acutely ill in diabetic acidosis (venous blood pH ⪯7.30 and plasma CO 2 content ⪯19 mM. per liter) had elevated cortisol secretion rates.

The abuse of amphetamines has become a problem of international significance. Japan was the first country to recognize this problem, and by 1954 there were an estimated 500,000 to 600,000 abusers in Japan. More than ten years ago Japan banned the use of amphetamines. The United Kingdom restricted distribution of amphetamines to hospital pharmacies in 1968. Sweden categorized amphetamine as a narcotic in 1944 because of abuse; and in 1965 phenmetrazine (Preludin) and in 1968 methylphenidate (Ritalin) were removed from the market. Patients now requiring amphetamines are registered with the government. Sweden has about 10,000 drug addicts (almost all between 15 and 30 years of age) using central stimulants intravenously; this is about the same percentage of their population as the estimated percentage of heroin addicts in New York City.1 In contrast, the number of heroin and opiate addicts in Sweden is estimated to be less than 500. In 1970, the Food and Drug Administration (FDA) responded to the problem of amphetamine abuse in the United States by limiting the package insert labeling for amphetamines to three indications: narcolepsy, hyperkinesis in children, and the short-term treatment of obesity. Currently, the latter indication is being reviewed and may no longer be valid. Among the related agents there is some specificity in labeling, e.g., methylphenidate is approved for use in adults with mild depression, narcolepsy at any age, and children with minimal brain dysfunction but not obesity; phenmetrazine for use only in obesity, etc. However, in the broad view there is a similarity in the pharmacologic properties, side effects, and abuse liability of dextro-amphetamine, methamphetamine, methylphenidate, and phenmetrazine.

Extract: Six patients with the syndrome of congenital adrenocortical unresponsiveness to ACTH are reported. This syndrome is characterized by feeding problems early in life, hypoglycemic episodes and hyper-pigmentation of the skin (table I). Blood pressure and levels of electrolytes in serum were normal (table II). PPD and histoplasmin skin tests were negative, while antibodies to adrenal, thyroid, and gastric tissues were undetectable. Urinary excretion of 17-hydroxycorticosteroids and cortisol production rates were low and did not respond to administration of ACTH (table III). While receiving a low sodium diet, the patients were able to conserve sodium (figs. 2, 3 and 4) and to increase the rate of aldosterone secretion (tables IV and V). In one case, adrenal pathology showed a normal zona glomerulosa with atrophy of the zonae fasciculata and reticularis. This isolated deficiency in cortisol secretion is not due to a defect in pituitary function or a deficiency of one of the enzymes directly involved in steroid biosynthesis. The most probable pathogenesis is an abnormality at the site (or one of the sites) of ACTH action on cortisol biosynthesis. Speculation: It is probable that some young infants in whom a diagnosis of Addison's disease is made do, in fact, have the syndrome of congenital adrenocortical unresponsiveness to ACTH. Studies of cortisol secretion rates prior to and during ACTH administration and a determination of aldosterone secretion rates while receiving normal and low salt diets will permit differentiation of the two disorders.

I. Hon, E. H., and Khazin, A. F.: Biochemical studies of the fetus. Part I, Obstet. Gynec. 33: 219, 1969. 2. Hon, E. H., Khazin, A. F., and Paul, R. H.: Biochemical studies of the fetus. Part II, Obstet. Gynec. 33: 237, 1969. 3. Seeds, A. E., and Behrman, R. E.: Acid-base monitoring of the fetus during labor with blood obtained from the scalp, J. P~mAT. 74: 804, 1969. 4. Phillips, L., Lumley, J., Paterson, P., and Wood, C.: Fetal hypoglycemia, Amer. J. Obstet. Gynec. 102: 371, 1968. 5. Hobel, C. J.: The influence of anemia on the acid-base state of the fetus and newborn, Amer. J. Obstet. Gynec. 106: 303, 1970. 6. Saling, E.: Amnioscopy and fetal blood sampiing: Observaffons on foetal acidosis, Arch. Dis. Child. 41: 472, 1966. 7. Wintrobe, M. N.: Clinical hematology, ed. 6, Philadelphia, 1967, Lea & Febiger, Publishers, p. 429. 8. Liley, A. W.: Errors in the assessment of hemolytic disease from amniotic fluid, Amer. J. Obstet. Gynec. 86: 485, 1963. 9. Wu, P. Y. K., and Oh, W.: Evaluation of the newborn, in Charles, A. G., and Friedman, E. A., editors: Rh isoimmunization and erythroblastosis fetalis, New York, 1969, AppletonCentury-Crofts, Inc., p. 168.

Follicle-stimulating hormone (FSH) and luteinizing hormone (HL) assays of sera from girls with premature thelarche (26 4-month-old to 7-year-olds) sexual precocity (20 2-8 year olds) and premature adrenarche (5 5-8 year olds) were compared with those of normal girls. In the cases of sexual precocity there was a corresponding increase in FSH and LH which may have caused the precocity. There was a slight increase in hormonal levels in premature thelarche. In premature adrenarche there was a slight suppression of the hypothalmic pituitary-gonadotropin release mechanism.

In the siblings reported, two affected boys have perineal hypospadias and bifid scrotum, and two affected girls have slight clitoral enlargement with otherwise normal genitalia. All are mild "salt losers" with spontaneous crises occurring late (3 months and 2 years) in the boys. The girls had negative sodium balance and hyponatremia only when stressed by salt deprivation at age 3 weeks and 4 years respectively. All had elevated 17-ketosteroid excretion when diagnosed, and in the two youngest, urinary dehydroisoandrosterone (DHA) exceeded androsterone. Cortisol production and/or 17-hydroxycorticosteroid excretions were normal. Steroid excretion patterns showed an increase of 3β-hydroxysteroid dehydrogenase (3-βHSD) activity with increased age, but with a persisting high excretion of pregrienetriol. At 2 months of age, one girl excreted per 24 hours: pregnanetriol–0.23 mg, pregnenetriol–1.2 mg, 17α- OH-pregnenolone–-2.6 mg, 16α-OH-pregnenolone– 8.2 mg, 16α-OH-DHA–5.4 mg, and DHA–0.5 mg. Her sister, at age 10 years, during withdrawal of cortisone therapy, excreted per 24 hours: pregnanetriol– 24 mg, pregnenetriol–14 mg, DHA–1.2 mg, and no 16αOH-pregnenolone or 16α-OH-DHA. We conclude that these patients have partial 3β-HSD deficiencies on the basis of inadequate fetal virilization and persistent postnatal excretion of large amounts of pregnenetriol. Possible explanations for the preponderance of urinary C-21 over C-19 steroids and for the large excretion of pregnanetriol are presented.

Utilizing an in vivo isotope dilution technique based on 48 hr urine pools, cortisol production rates (CPRs) and urinary 17-hydroxycorticosteroids (17-OHCS) were estimated in 16 infants and children with hypothyroidism, and in 9 children and young adults with hyperthyroidism. The results were compared statistically with those obtained in 20 normal infants, children and young adults previously reported. Hypothyroid patients between the ages of 5 and 17 yr had a decrease in both CPR and 17-OHCS. However, 3 athyreotic cretins, less than 3 months old, and a mildly hypothyroid older infant had normal CPRs. In the hypothyroid patients there appeared to be a correlation between the duration and degree of hypothyroidism and the degree of depression of the CPR. Hyperthyroidism in the age group 5–17 yr induced a marked increase in CPR in only a few patients, while increasing the urinary 17-OHCS to a greater extent and with greater regularity.

Natural and synthetic glucocorticoids, in use for 21 years, have outlived the phases of over-optimism regarding cura tive actions and over-pessimism over side effects. Some of the side effects can be evaded, as in alternate day therapy; others can be taken advantage of in the management of specific conditions as shown in the summary Table 3.

Cortisol production rates (CPR's) and urinary 17-hydroxycorticosteroids (17-OHCS) were estimated in 16 adolescent males, of whom 5 were selected from Stage 1 (early), 5 from Stage 3 (mid-) and 6 from Stage 5 (late) of sexual maturation. Both CPR and 17-OHCS were significantly increased in Stage 5 males when compared to the Stage 1 and Stage 3 subjects. In addition, significant positive correlations between CPR and 17-OHCS were observed when both estimations were compared with 3 indices of growth: 1) surface area, 2) weight and 3) urinary creatinine excretion, of the 16 subjects. No differences between the 3 groups were detected in the pattern of excretion of cortisol metabolites when comparison was made of radioactivity recovered in an unconjugated ethyl acetate extract, a β-glucuronidase liberated chloroform extract, and another ethyl acetate extract after the chloroform extraction.

of the 4 patients with SSPE (Table I I ) . Normal levels for individuals in the age group are < 8 to 64 with the complement fixation method and < 8 to 256 with the hemagglutination inhibition technique. None of the parents or siblings of these patients showed unusually elevated titers with either the CF or H I methods. Three pairs of siblings in 3 separate families had clinical measles during the same year as the affected patients. One sibling had live measles immunization at age 3 years.

Cortisol production rates (CPRs) and urinary 17-hydroxycorticosteroid (17-OHCS) excretion were studied in 13 subjects in mid- and late pregnancy and compared with those of nonpregnant women. CPRs and 17-OHCS were significantly lower (p

Adrenal function in six obese adolescents was evaluated by estimation of cortisol secretion rate (CSR) and urinary 17-hydroxycorticosteroid excretion (17-OHCS). CSR and 17-OHCS were elevated in comparison to nonobese adolescents (p p

Antihistamines were introduced in France by Halpern in 1942 and in the United States at the end of World War II; they had been investigated extensively during the war for therapy of motion sickness. By the late 1940s, a mass of information on the structure activity relationship had accumulated and most major drug manufacturens had introduced antihistamines into the market for oral, parenteral, and topical administration. Topical use was efficacious in acute dermatitis because the local anesthetic activity of the drugs diminished pruritus. The first reports of sensitization to the topical antihistamines, which began to appear in 1947, incriminated tnipelennamine (Pyribenzamine), diphenhydramine (Benadryl), antazoline (Antistine), and pheniramine (Trimeton).1-4 In the ensuing 25 years, though thousands of instances of antihistamine contact dermatitis have occurred, many topical antihistamines remain on the market. The Committee is concerned about the use of topical antihistamines which are sold over the counter for use in such conditions as chickenpox and poison ivy. Table I lists most of the preparations currently available for topical use. CLASSES OF ANTIHISTAMINES The antihistamines are classified according to their chemical structure into five primary groups as shown in Table II. Each drug carries its own index of sensitization and other adverse effects when employed topically. The ethylenediamine derivatives include the following: antazoline phosphate (Antistine), promethazine hydrochloride (Phenergan*), and tripelennamine (Pyribenzamine). They are particularly active in inducing contact dermatitis and were responsible for the cases first reported.5,6 Ethylenediamine, because of its dibasic structure, is widely used in various organic syntheses for the preparation of dyes, inhibitors, rubber accelerators, fungicides, synthetic waxes, resins, insecticides, and asphalt-wetting agents.

The frequent use of marijuana by American youth has compelled the Committee on Drugs to explore the present methods of and recommendations for controlling marijuana. On October 15, 1970, the Executive Board of the American Academy of Pediatrics endorsed in principle a statement on marijuana which was prepared by the Massachusetts Chapter of the Academy and published in the Academy's Newsletter.1 This statement called for considering possession of marijuana as a misdemeanor rather than a felony, but it was against legalizing use of marijuana at the present time. On October 27, 1970, President Nixon signed into law the Comprehensive Drug Abuse, Prevention and Control Act of 1970 (P.L. 91-513). This law became effective May 1, 1971; it is the Federal Government's attempt to control drug abuse by scientific and medical measures (under control of the Department of Health, Education, and Welfare) and by law enforcement activities (Department of Justice). The new Federal law has stopped short of legalizing marijuana, but it does allow a judge the discrelion to withhold criminal charges for the first offense of possession. The Massachusetts Chapter notes2 that marijuana is not a narcotic and does not produce addiction. Short-term physical effects are innocuous. However, impaired performance on simple intellectual and psychomotor tests is seen after individuals have smoked marijuana for the first time; but, such effects are not seen in regular users. There is no evidence to substantiate the common misconceptions that use of marijuana leads to crime or addiction to opiates. But, so little scientific information is available on the long-term use of marijuana that it should be considered a potentially harmful drug.

Since their introduction into clinical use, corticosteroids have been employed as therapeutic agents in virtually every known disease state, ranging from minor dermatologic disorders to major and serious diseases. These agents have undoubtedly altered the clinical picture and prognosis of certain diseases. However, the use of corticosteroids is always potentially associated with a variety of untoward effects, some of which may be life threatening, i.e., decreased resistance to infection, growth retardation, neurological reactions, hypertension, peptic ulcerations, and many others.1 The time honored principle—first do no harm—should always be the guideline of therapy, especially when a definite indication for a particular therapeutic agent has not been established. In recent years corticosteroids have been employed in the treatment of bronchiolitis on the hypothesis that their anti-inflammatory action would decrease swelling, inflammation, and the consequent respiratory obstruction. The opinions of different investigators on the efficacy of corticosteroids in this disorder have varied greatly; some have regarded their use as ineffective and others as lifesaving. It is the purpose of this report to review the findings from various studies and to outline the current status the use of corticosteroids in this common disorder of infants and children. Bronchiolitis is a common, acute respiratory syndrome characterized by infection of the bronchioles and respiratory distress of varying degrees due to obstructive emphysema. It is common in the first year of life and is rare in the child over 2 years of age. It frequently occurs in outbreaks. The great majority of cases are due to viruses, especially the respiratory syncitial, influenza B, and parainfluenza viruses, but it may be due to bacteria and other respiratory pathogens.

When broad-spectrum antibiotics were first introduced two decades ago for the treatment of acne, justification for such therapy seemed reasonably straightforward, e.g., the suppression of the suppurative inflammatory lesions commonly encountered in acne. As time went on, however, certain observations raised questions concerning the rationale for this form of treatment. First, it became apparent with cumulative clinical experience that the disease could ordinarily be controlled by doses of antibiotics lower than those required to treat bacterial infections. Second, bacteriologic studies disclosed that the only bacteria regularly recoverable from acne lesions were the anaerobic diphtheroid Corynebacterium acnes and aerobic coagulase-negative cocci, predominantly staphylococcus type II; both of these bacteria are known to be normal resident skin organisms.1 Thus, as no reports of controlled studies were then available for assessing the true efficacy of antibiotics used in the treatment of acne, the uneasy suspicion arose that such therapy might be inducing a primarily placebo response. In 1965, Freinkel and her collaborators2 demonstrated that the oral administration of tetracycline, even in doses as small as 250 mg daily, resulted in a significant reduction of the free fatty acid concentration of the lipid (sebum) secreted to the skin surface by the sebaceous glands. This effect could be observed in normal subjects as well as in patients with acne and was entirely reversible on discontinuance of drug. The inflammatory lesions of acne are known to result from disorganization of the follicular epithelium, with consequent liberation of the intrafollicular contents, containing sebum, into the dermis.3

One of the most important concepts in pediatric pharmacology is that exposure to drugs or chemicals may have latent, unforeseen effects on the child later in life. Some of the most dramatic occurrences, other than teratogenesis, are those in which hormonal exposure during the fetal or newborn period alters adult sexual development. However, none of these episodes is more impressive and ominous than that reported by Herbst et al.1 Herbst, an obstetrician at the Massachusetts General Hospital, was intrigued by the presentation of seven patients with adenocarcinoma of the vagina, an extremely rare tumor not previously seen at the hospital. The patients ranged in age from 14 to 22 years and sought medical advice because of vaginal bleeding. Several had benign adenosis, suggesting that the malignant change seen in all was based on a fundamental alteration in the biology of the vaginal epithelium. Six of the patients were treated with radical surgery, and one was treated with wide, local excision. One of the patients died after surgery. In what could serve as a model of a scientifically conducted, epidemiologic study, each of the seven patients, plus an additional patient from another hospital, was matched with four controls born in the same hospital within four days. Thus, the "control" group was chosen in a manner to eliminate many biases of artificially contrived control populations. A wide variety of possible influences in both mothers and offspring were considered, e.g., maternal age, smoking habits, exposure to X-rays, breast-feeding, birth weight, age at menarche, medications during pregnancy, and so forth.

Serum concentrations of unconjugated estrone, estradiol, and free estradiol, were determined in normal neonates, prepubertal children, adolescents, and adults. The values were compared with those obtained in children with premature thelarche and female sexual precocity. Unconjugated E1 and E2 fell rapidly, and the percentage of FE2 more gradually during the neonatal period and remained low prepubertally. During adolescence girls had greater increases in E1 and E2 while the percentage of FE2 was higher in boys. In premature thelarche only the FE2 was significantly increased. In sexual precocity E1, E2, and FE2 were elevated. Reference standards are provided in Tables I and II for use in the diagnosis of conditions with under- or overproduction of estrogens during growth and development.

In a 14-year-old girl with untreated virilizing congenital adrenal hyperplasia, growth hormone and adrenocortical steroid levels were synchronous during a 24 hour period. Therapy with intramuscular or oral cortisone failed to suppress the spontaneous release, or alter appreciably the diurnal secretory pattern of growth hormone. The similarity of the growth hormone curves on three different days several weeks apart suggests persistence of the diurnal pattern of hormonal secretions in this particular patient.

Four patients had insufficiency of hGH, TSH, ACTH, and ADH following surgery for craniopharyngiomas. Despite hypopituitarism, and without hGH therapy, all showed “catch-up” growth during post-operative follow up. Prolactin, determined by RAI was normal in every patient, and therefore cannot be responsible for the increase in post-operative growth rate. Their prolactin values were similar to those of a large series of children with idiopathic hypopituitarism. In determined by bioassay and was normal. An additional patient who showed a normal growth rate (without “catch-up”) postoperatively also had normal somatomedin in the absence of growth hormone response to provocative tests. While the mechanism for catch-up growth in the patients remains enigmatic, the possibility cannot be excluded that hyperinsulinism could play a role, inasmuch as these patients are generally obese secondary to voracious appetites.

Gynecomastia was bilateral in five of seven prepubertal boys. Onset was between 2½ and 7½ years of age in five patients and was present from birth in another. Urinary estrogen excretion was increased in two patients. In six patients the condition was selflimited; one boy required mastectomy and the histopathological picture was that of dense fibrocollagenous and adipose stromacontaining ducts. In two instances, there was a family history of the condition in males.

Whereas aldosterone secretion changes little during growth and adrenal androgen excretion rises sharply at adolescence, cortisol production rate (CPR) increases gradually during growth and declines in old age. Previously published data on CPR obtained in our laboratory by an in vivo isotope dilution technique, in 96 subjects from birth to age 20 years, were recorrected for body surface area (/m2), body weight (/Kg.) and creatinine excretion (/Gm. cnne), i.e., muscle mass. The highest CPRs on the basis of /m2, /Kg., and /Gm. cnne were in babies under age 5 days, and the second highest values in the period 5–20 days. There-after in the age groups 20 days-5 years; 5–10 years; 10–15 years; and 15–20 years body surface area was the best predictor of CPR which decreased relative to muscle mass. In contrast to CPR, urinary 17-hydroxycorticosteroid (17-OHCS) excretion, (i.e., β-glucuronidase released Porter-Silber chromogens) was lowest in the age group less than age 5 days, and was still lowest when adjusted /m2. The recovery of 4-14C-cortisol metabolites in a “nonpolar”, conjugated (β-glucuronidase released chloroform extractable) fraction was also lowest in that age group. Nonconjugated “polar” metabolites were significant in the neonatal period. The data fail to elucidate the primary stimulus(i) for the changing rate of CPR from birth to age 20 years. However, they provide guidelines for the interpretation of adrenal function studies based on CPR or 17-OHCS determinations, and therefore are useful from the standpoints of diagnosis and therapy.

Cortisol production rates were estimated in patients with transient neonatal hypoglycemia, postneonatal hypoglycemia, and hypoglycemia with dwarfism. In the first group, four low-birth-weight males had abnormally low rates. In the second group, cortisol production rates were in the normal range. Low to low-normal rates were found in the group of dwarfs. Three of five older dwarfs had a history of low birth weight for gestational age. Of these, two were the smaller members of two sets of twins; one had documented neonatal hypoglycemia. These three patients may have had hypopituitarism in utero. Of the entire group of 23 patients, only one was above the fiftieth percentile in height, and 19 were below the twenty-fifth percentile. Growth failure in most of these patients with hypoglycemia is unexplained.

Four adolescent subjects without evidence of pituitary or adrenal disorder released GH during 24 hours in three to ten bursts, mainly during sleep. Cortisol was released periodically, but without any relationship to GH secretory episodes. These data were compared with data obtained in four clinical conditions known or presumed to affect F and/or GH secretion. In Cushing's disease cortisol was released episodically, yet the lowest concentrations were well above the normal nadir. Alternate-day administration of prednisone did not suppress the ultradian release of F on the day “of” therapy in one patient. Peak GH concentrations were lower in patients with Cushing's disease and during steroid therapy than in the four hospitalized adolescent control subjects. High mean concentrations of GH were observed during prolonged fasting in one patient and in another patient with poorly controlled diabetes mellitus, conditions which did not alter cortisol release.

Thirty-eight patients aged 2 to 18 years with hyperthyroidism were followed with hematologic studies while receiving propylthiouracil. Ten (26 per cent) had one or more episodes of leukopenia (white blood cell count

Two unrelated girls with clinical and radiologic features of peripheral dysostosis havebeen studied. Though each girl had an advanced bone age, their heights were appropriate for their ages. Investigation of the pituitary-adrenal-gonadal mechanisms, of insulin and growth hormone responsiveness, and of thyroid and parathyroid functions did not show any significant abnormality.

THE association of superficial moniliasis, idiopathic hypoparathyroidism, Addison's disease and Hashimoto's thyroiditis in a single patient is previously undocumented. One purpose of this paper is ...

FUNCTIONING neoplasms of the adrenal cortex are clinically manifested by virilization, Cushing's syndrome, feminization, or hyperaldosteronism. In the present report, seven patients with virilizing adrenal tumors are described. In one case, virilization was present from birth. This is a unique instance of in utero virilization attributable to a tumor. Other unusual clinical, pathological, and laboratory findings are being reported. Methods The method used for 17-ketosteroid (17-KS) measurements was a modification of that of Callow et al. 1 The procedure of Allen et al 2 was used for dehydroisoandrosterone (DHA). Pregnanetriol was measured at the BioScience Laboratories, Los Angeles, by Cox's method. 3 The 17-hydroxycorticosteroids (17-OHCS) were measured by a modification 4 of the method of Glenn and Nelson. 5 Aldosterone was estimated in patient 1 by a modification of the procedure of Neher and Wettstein. 6 Cathecholamines were measured by the method of Jacobs et al, 7 and vanillyl mandelic acid as described

Nine consecutive children with craniopharyngiomas were studied who had relatively normal pituitary function prior to operation. Surgical attempts to remove the craniopharyngiomas were frequently followed by a loss of thyroid stimulating hormone, evaluated indirectly by the butanol extractable iodine, and by failure of adrenocorticotrophic hormone as reflected by a fall in urinary 17-hydroxycorticosteroids and a loss of previously normal SU-4885 responsiveness. In addition, diabetes insipidus, which had not been present preoperatively, invariably followed stalk section which was often necessary during surgery. Despite the postoperative appearance of diabetes insipidus and of thyroid-stimulating hormone and adrenocorticotropic hormone failure, three of ten patients showed “catch-up growth” postoperatively. One of the three had a growth spurt which carried him from below the third up to the fiftieth percentile in 1 1/2 years after operation. He showed no increase in serum growth hormone during arginine or insulin provocative tests. The growth spurts in these three patients are difficult to explain in view of the loss of integrity of their hypothalamic-pituitary pathways.

This paper describes the ultrastructure of the adrenal cortex in two children with Cushing's disease. The main ultrastructural changes were observed in the zonae fasciculata and reticularis. The hyperplastic cells seen by light microscopy in diffuse hyperplasia of the adrenal cortex of Cushing's disease appeared as electron light cells at the ultrastructural level. Their appearance resulted from dilatation and hyperplasia of the smooth-surfaced endoplasmic reticulum and a decrease in the size of lipid globules. Mitochondrial changes included two types of mitochondria, increased electron density of the matrix, outpouching of the outer membrane, intramitochondrial dense bodies, and tubular cristae. Our observations tend to agree with the findings of others in experimental animals and to differ with a previous report on Cushing's disease.

Rubella encephalopathy occurred in six children. This complication was estimated to have occurred in a ratio of 1:5,000 cases of rubella infection. Three children survived without sequelae; the other three died. Rubella virus was isolated from the throat of a survivor and from the lung of a child who subsequently died. Specimens had been collected on the sixth and seventh day after onset of rash, respectively. Other clinical and autopsy specimens, including brain, failed to yield virus. Antibodies against the rubella virus were demonstrated in the four cases from which serum was available. Cortisol-production rate was increased in the three patients, who subsequently died, who were treated with hypothermia, and was normal in a surviving patient with a milder case of rubella encephalopathy. Observations at autopsy revealed severe, nonspecific degeneration of the central nervous system but no changes specific for viral infection. The incidence and the clinical, virologic, and autopsy findings of this complication are contrasted with those of measles encephalitis.

Exophthalmometric measurements were made in normal children, using a small,inexpensive, plastic Luedde ruler. The data are useful to pediatricians who wish to determine the degree of exophthalmos or enophthalmos and to follow progressive changes in eye measurements in their patients.

CUSHING'S SYNDROME is uncommon in childhood and rare in infancy. In these age groups it is usually due to adrenal cortical tumors, although cases of adrenal hyperplasia are recorded. Approximately 60 adults have been reported, in whom Cushing's syndrome developed in association with nonendocrine tumors, ie, tumors not of pituitary, adrenocortical, or gonadal origin. Our patient had an adrenal neuroblastoma and was similar to the majority of these adults, in that sudden onset of symptoms, marked weakness associated with hypokalemia, and a rapidly fatal outcome characterized his course. This is the second report of Cushing's syndrome in an infant in association with a neuroblastoma. It is possible that awareness of the salient features of these cases might permit earlier diagnosis, and possibly complete tumor removal. Methods A modification of the method of Callow et al was used to measure 17-ketosteroids, 1 and 17-hydroxycorticosteroids were measured by a modification of the