Phenobarbital in the acute management of febrile convulsions. Blood levels of phenobarbital were determined after a single oral or intramuscular (IM) dose in children in the hospital after febrile convulsions. At a dose of 15 mg/kg, both the oral and IM routes gave therapeutic blood levels within 90 minutes. Absorption from the IM route before 90 minutes was inconsistent and would be unlikely to arrest an established convulsion within a critical time period. For use as a drug to prevent convulsions, oral phenobarbital at 15 mg/kg deserves further study.


Paying for pediatric training and care.

Paying for pediatric training and care.


Outpatient pediatric surgery in a developing country. A total of 5,522 outpatient surgical procedures were performed at the Children's Hospital in Kingston, Jamaica, West Indies, between 1968 and 1973. This included 2,662 general surgical procedures. There were no deaths or major complications. Parents participated actively in the preoperative and postoperative care. Outpatient surgery can be a safe, inexpensive, and effective means of health care delivery. It is of special value in developing countries with limited facilities for inpatient care.


Ethical issues in pediatric surgery: a national survey of pediatricians and pediatric surgeons. The findings reported in this article are based on a nationwide survey of the attitudes and practices of pediatric surgeons and pediatricians with respect to some of the difficult ethical choices confronting them in medical practice. Four hundred fifty-seven physicians completed a questionnaire in the spring of 1975 in which they reacted to a wide range of issues that have been of increasing concern to the public, as well as to the medical profession. The survey attempts to identify some areas of physician consensus as well as some of the factors, personal and professional, influencing physicians' attitudes. The survey and its statistical analysis are intended to provide current sociological data and are not intended by the authors as an endorsement of any particular point of view or course of action.


Are we missing amblyopia? The answer: preschool screening.


Recurrent adolescent suicidal behavior.

Recurrent adolescent suicidal behavior.


Influence of life events and family routines on childhood respiratory tract illness.


Child psychiatry and pediatrics: the state of the relationship. A great deal of attention has been focused on the notion that child psychiatry and pediatrics should develop strong ties. Yet, a review of the literature suggests that, in spite of exhortations to the contrary, little true collaboration has developed between the two disciplines. This study surveys the major pediatric teaching and training centers throughout the country in an attempt to assess the current state of the relationship between child psychiatry and pediatrics. Of the 82 centers surveyed, 68% responded. Although enthusiasm and desire for closer collaboration were expressed repeatedly, actual successful efforts remain minimal. Psychiatric consultations on pediatric inpatient units continue to be the predominant child psychiatry service provided. A method for achieving closer relationships between the two disciplines is proposed.


Temperament as a factor in early school adjustment. Infant temperament profiles of "difficult," "intermediate," and "easy" in a randomly selected group of 51 children were shown to correlate with impulsivity and school adjustment at ages 5 1/2 to 7 years. However, the nonlinear relationship makes this a finding of uncertain significance. On the other hand, contemporaneous temperament determinations using the Behavioral Style Questionnaire completed by the children's mothers showed a significant correlation between the adaptability subscale and teacher judgments of school adjustment. This latter finding adds support to the view that temperament is a significant factor in school adjustment and that it can be measured by a clinical instrument appropriate for pediatric use.


Periosteal reaction due to foreign body-induced inflammation of soft tissue.


Multiple metatarsal fractures in child abuse.


Computerized growth record for clinic use.


Failure of pediatricians to provide automobile restraint information to parents.


Child psychiatry and pediatrics.

Child psychiatry and pediatrics.


The case for day-care surgery.

The case for day-care surgery.


"We won't leave you".

"We won't leave you".


Flame-resistant sleepwear: have the bird-watchers gone ape?


[125I]hGH metabolism in acromegaly: effects of chronic treatment with 2-Br-alpha-ergocryptine. To assess the effects of 2-Br-alpha-ergocryptine (CB-154 Sandoz) on hGH metabolism, six acromegalic women were studied before and after 2 months of treatment with 10 mg bromocriptine/day. GH kinetics were evaluated by noncompartmental analysis of the plasma disappearance curve of immunoprecipitable [125I]human GH after pulse administration of the labeled hormone. MCR was increased in all acromegalics after treatment; the difference between the means [153 +/- 11 vs. 200 +/- 16 ml/min . m2 (mean +/- SE)] was highly significant. Secretion rate (SR), measured as the product of MCR by integrated 12-h concentration, was decreased in four patients after treatment, while it was slightly increased in the other two. No change was found after treatment, either initial distribution volume [2.0 +/-0.1 before (B) vs. 2.1 +/- 0.1 liters/m2 after (A)] or total distribution volume [5.0 +/- 0.3 (B) vs. 5.4 +/- 0.4 liters/m2 (A)]. Diffusion of GH from the intravascular pool, measured as reentry rate, was unchanged with treatment [66 +/- 4 (B) vs. 76 +/- 11 ml/min . m2 (A)]. In conclusion, our study shows that in acromegaly, by increasing the MCR of the hormone, and 2) by reducing the SR. The mechanisms by which bromocriptine increased MCR of the GH are also suggested on the basis of kinetic results; like dopamine, bromocriptine could induce a redistribution of blood flows to different organs, thus resulting in a net increase of blood flow to the liver and kidneys which are the major catabolic sites of GH.


Environmental Carcinogens. Selected methods of analysis: Volume 1-Analysis of volatile nitrosamines in food.


Radioimmunoassay of human thyroglobulin: effect of antithyroglobulin autoantibodies. This study was designed to investigate quantitatively the interference of thyroglobulin autoantibodies in the RIA of human thyroglobulin (hTG). Anti-hTG autoantibodies were combined with purified hTG to produce samples with known antibody titers and hTG concentrations. These samples were analyzed in the RIA. By using anti-human globulin serum it was first shown that immune complexes formed between labeled hTG and human anti-hTG. It was then shown that the most important factor in determining the direction of the interference was the specificity of the precipitating (second) antiserum with respect to these immune complexes. When the precipitating antiserum was specific, i.e. did not recognize human antibodies, the immune complexes remained in the supernatant and the measured hTG concentration was falsely elevated. When the precipitating antiserum cross-reacted with human antibodies, the direction of the interference depended on the sample volume. At small volumes there was false depression while at large volumes there was false elevation of apparent hTG levels, depending on the capacity of the precipitating antiserum to combine with human antibodies. Anti-hTG titers far below those detected by the tanned-red cell hemagglutination test had very large effects, to the point where measurements of hTG could not be made, when a cross-reactive precipitating antiserum was used. Therefore, the procedure which investigators have used until now, to exclude samples with anti-hTG hemagglutination titers above an arbitrary limit, is not adequate. It is necessary, until methods are developed which avoid the problem of autoantibody interference, to characterize each assay to determine the limits of anti-hTG that can be tolerated. The factors which influence anti-hTG interference in the hTG RIA are 1) the specificity of the precipitating antiserum, 2) the sample volume, 3) the maximum tracer binding, and 4) the anti-hTG titer.


SC 25152: A potent mineralocorticoid antagonist with reduced affinity for the 5 alpha-dihydrotestosterone receptor of human and rat prostate. It has previously been shown that spironolactone possesses antiandrogenic activity in the rat and interacts with rat prostate 5 alpha-dihydrotestosterone cytoplasmic receptors to block the nuclear uptake of this hormone. Current evidence suggests that this androgen receptor interaction may be an important mechanism through which spironolactone causes endocrine side effects in rat and man. We have analyzed the interactions of several spirolactone analogs with the androgen receptor of human and rat prostate and the mineralocorticoid receptor of human and rat kidney. One analog, SC 25152, was found to have considerably reduced affinity for the prostate 5 alpha-dihydrotestosterone receptor [Ka = 24 +/- 1% and 19 +/- 6% (mean +/- SE) in the human and rat, respectively, of the Ka for spironolactone] while maintaining similar affinity for the mineralocorticoid receptors of human and rat kidney [Ka = 113 +/- 37% and 86 +/- 7% (mean +/- SE), respectively, of the Ka for spironolactone]. These findings would predict this analog to have reduced antiandrogenicity at equivalent therapeutic doses.


Calcitonin secretion in normal human subjects. A sensitive RIA for human calcitonin has been developed which can detect 1-2 pg hormone. This procedure permits the measurement of the low concentrations of calcitonin in the unextracted plasma of normal human subjects. In 55 normal adults, mean plasma calcitonin was 24 pg/ml with an SD of +/- 18 pg/ml, an SE of +/- 2 pg/ml, and a range of less than 10 - 75 pg/ml. There were no discernible age or sex differences in basal hormone concentration. Infusions of calcium, pentagastrin, and glucagon stimulated plasma calcitonin, whereas food and oral calcium did not. The stimulatory effect of pentagastrin was greater in males than in females. These data demonstrate that the low concentration of calcitonin in humans can be stimulated by several secretagogues and suggest that females may have decreased calcitonin reserve.


Serum 3,5,3'-triiodothyronine, thyroxine, and thyrotropin in hypothyroid infants with congenital goiter and the response to iodine. Iodine deficiency in adults caused preferred synthesis of T3; this observation has not been reported in iodine-deficient hypothyroid newborns. Serum total T4, total T3, and TSH have been determined in nine full term newborns with congenital hypothyroid goiter before and after cutaneous application of iodine. The mothers of these infants had untreated euthyroid goiter and lived during pregnancy in the area of Göttingen, West Germany, known as an iodine-deficient region. Mean total T4 in the newborns was 6.3 +/- 1.6 (mean +/- SD) micrograms/dl compared to 16.6 +/- 3.4 micrograms/dl in normal newborns at 3-4 days of age. Mean T3 in the goitrous newborns was 2.74 +/- 0.66 ng/ml compared to 1.58 +/-0.41 ng/ml in the control group of the same age. Serum TSH remained elevated during the first week of life, with a concentration of 40.9 +/- 28.7 microU/ml (control group, 4.16 +/- 1.43 microU/ml). The cutaneous application of iodine resulted in rapid disappearance of goiter and normalization of T4 and TSH within 5 days. After 30 days of iodine treatment, T3 decreased slowly but remained elevated (2.0 +/- 0.42 ng/ml vs. 1.67 +/- 0.36 ng/ml in the control group). The present findings confirm preferential T3 secretion in newborns with hypothyroid goiter. The goiter is thought to be caused by intrauterine iodine deficiency, because hypothyroid values of T4 and TSH normalized during iodine treatment. General iodine prophylaxis of the population is recommended.


Opiates, prolactin, and the dopamine receptor. The administration of a dopamine antagonist, chlorpromazine, and two opiates, morphine and methadone, resulted in a significant rise in serum PRL within 90-150 min. Prior administration of dopamine receptor agonists (apomorphine, levodopa, aand bromocriptine) blocked this effect. In contrast, cyproheptadine, a serotonin antagonist, did not. We suggest that the opiates induce hyperprolactinemia in man via dopamine receptor blockade.


Lack of arginine vasopressin response to central dopamine blockade in normal adults. Haloperidol, a central nervous system dopamine blocker, was given im to seven normal volunteers at a dose level (1.0 mg) known to have central nervous system effects. Plasma PRL levels rose sharply in response to haloperidol, but plasma arginine vasopressin levels did not change significantly. These data do not support the hypothesis of a prominent dopamine neurotransmitter regulation of arginine vasopressin secretion.


Conjugated glucocorticoids in amniotic fluid and fetal lung maturation. While recent studies suggest that cortisol plays a role in lung maturation, conflicting reports have recently appeared relating cortisol in amniotic fluid to indices of lung maturation. the variation in the levels and differences in correlation appear to be due to differences in methodology, principally with respect to cross-reactivity in the radioimmunoassays with the conjugates of cortisol and corticosterone. We have found that the glucocorticoid conjugates correlate better with lung maturation (rs = 0.79) than does cortisol itself (rs = 0.58). This is probably because the conjugates are derived exclusively from the fetal compartment whereas cortisol is also produced by the chorionic membrane. In anencephaly, conjugate levels were very low while cortisol levels were relatively normal. Conjugate levels (mainly sulfates) appear promising as an adjunct to tests of fetal maturation.


Melatonin concentration in human blood and cerebrospinal fluid: relationship to stress. In 35 daytime paired blood and cerebrospinal fluid (CSF) samples from 15 patients, melatonin levels in CSF were undetectable or detectable but not higher than blood levels. During pneumoencephalography in 6 patients, no significant elevation of blood melatonin levels was observed, whereas cortisol concentration increased.


Damped oscillations in serum thyroid hormone levels of normal newborn infants. Exposure to the extrauterine environment is associated with marked stimulation of the hypothalamic-pituitary-thyroid system after which, pituitary-thyroid equilibrium must be reestablished. This marked endogenous perturbation offers the opportunity to study the manner in which the pituitary-thyroid axis is reequilibrated. T4, T3 and TSH concentrations have been measured by RIA in sera from 440 healthy newborn infants, whose ages ranged from birth to 236 h. Results were analyzed by nonlinear curve-fitting procedures to assess the changes in mean hormone concentrations with age (t). Equations have been derived by Danziger and Elmergreen to allow assessment of oscillatory behavior during hormone equilibration. Applying these equations to the present data, we observed the presence of an oscillatory cosine term in the equation for each hormone. This indicates significant oscillations in serum T4, T3, and TSH concentrations during the first 5 days of life. The period of the oscillations approximates 16 h. The oscillations in T4, lag 1/2 to 3/4 cycle behind TSH; T3 lags behind T4. Thus, disturbances in hypothalamic-pituitary-thyroid equilibrium seem to be followed by periodic oscillations in hormone concentrations; these oscillations decrease in amplitude as the negative feedback system establishes new equilibrium conditions.


Changes in NSILA-S in response to somatotropin administration and hypophysectomy. The effects on the serum levels of NSILA-S of the administration of human GH (hGH) or of hypophysectomy have been studied. hGH given im (5 mg daily for 3 days) raised the NSILA-S levels of three GH-deficient subjects into the normal range. Significant elevations of NSILA-S were also seen in three normal subjects given im GH. In the same groups of three normal and three GH-deficient subjects, 5 mg hGH administered iv induced an elevation of NSILA-S within 15-60 min. Hypophysectomy in three acromegalics and one subject with a chromophobe adenoma was followed by significant falls of serum NSILA-S. These studies provide further evidence of the dependence of NSILA-S levels on GH.


Assessment of acute and chronic changes in parathyroid hormone secretion by a radioimmunoassay with predominant specificity for the carboxy-terminal region of the molecule. A sensitive RIA for parathyroid hormone (PTH) with specificity for the carboxy-terminal region of the hormone was developed and applied to clinical studies. The assay was useful in identifying patients with chronic hyperparathyroid states, such as primary and secondary hyperparathyroidism. In addition, the assay could detect acute changes in PTH seen during calcium, pentagastrin, and EDTA infusions and after parathyroidectomy. These studies demonstrated that an immunoassay with predominant specificity for the carboxy-terminal fragment of PTH can be used to evaluate acute as well as chronic changes in hormone secretion.


Hydroxyproline peptides and bone mass in postmenopausal and osteoporotic women. Total and nondialyzable hydroxyproline excretion was measured in 59 postmenopausal women and 68 women with spinal osteoporosis. Hydroxyproline excretion was similar in both groups of women and the hypothesis that hydroxyproline excretion is normally distributed could not be rejected for either group. No relationship was found between hydroxyproline excretion (total and percentage of nondialyzable) and body weight, height, body surface area, or total body calcium or bone mineral content of the radius, or these latter values normalized for age, sex, and body size. There was no difference in hydroxyproline excretion in osteoporotic women who took supplemental calcium as compared to those that did not. These data fail to provide any evidence that bone turnover in osteoporotic women differs from that in younger postmenopausal women, or that osteoporosis arises from a subpopulation of women with rapid bone loss.


Adenylate cyclase of human parathyroid gland. Experiments were performed on a particulate fraction from human parathyroid glands. A high activity of adenylate cyclase was detected which was linear with time and protein concentration. The enzyme had an optimum pH in the range of 7-8 and a Km for ATP of 0.44 X 10(-3) M. Ca++ had a profound inhibitory effect; a concentration of 0.5 mM Ca++ reduced enzyme activity by 60%. Maximal enzyme activity was obtained with 5 mM Mg++; higher concentrations of this cation also inhibited enzyme activity. The effect of Mn++ was similar to that of Mg++. Enzyme activity was stimulated by NaF, catecholamines, glucagon, and calcitonin. The effect of catecholamines seems to be mediated through beta-adrenergic receptors.


Properties of human chorionic gonadotropin produced in vitro by ovarian carcinoma cells. The present study was designed to compare the immunological, physical, and biological properties of native hCG with an hCG molecule secreted ectopically in vitro by an ovarian adenocarcinoma cell line maintained in long term tissue culture. The hCG produced by the cell line was concentrated by ultrafiltration of the tissue culture medium. The inhibition curves generated by serial dilutions of the culture medium concentrates were parallel to those obtained with purified urinary hCG in the beta-hCG RIA and the rat Leydig cell radioreceptor assay (RRA). The ectopic hCG also reacted with an antibody generated against the carboxyl-terminal peptide (109-145) of beta-hCG. The immunoreactive material cochromatographed with urinary hCG on a Sephadex G-100 column, as determined by the beta-hCG RIA and RRA. Neither free alpha nor free beta subunits were found in the tissue culture medium. The tissue culture gonadotropin was adsorbed onto a Concanavalin A-Sepharose column and could be eluted with alpha-D-methylglucoside. The biological activity of the ectopic hCG was 9289 IU/mg, as determined by the ventral prostate weight (VPW) method in hypophysectomized immature male rats. The biological to immunological ratios by the ventral prostate weight method and RRA were 1.79 and 2.17, respectively. The in vivo disappearance rate of ectopic hCG after injection into immature female rats was significantly faster than that of placental or urinary hCG, but was considerably slower than the disappearance rate of human LH. These studies demonstrate that the immunoreactive and biologically active portions of the hCG produced by the ovarian adenocarcinoma cell line and native hCG are similar or identical. The faster disappearance rate of the ectopic hCG in the rat model may be due to incomplete sialylation of the oligosaccharide moiety of the hCG molecule.


Human endometrial cells in primary tissue culture: estrogen interactions and modulation of cell proliferation.


Metabolic clearance and production rates of 3,3',5-triiodothyronine in hyperthyroid, euthyroid, and hypothyroid subjects. To further elucidate the peripheral metabolism of rT3 and to determine if rT3 production rates vary directly with thyroid function, we measured the disappearance of [125I]rT3 in thyrotoxic and hypothyroid subjects as well as in athyreotic patients maintained eumetabolic on exogenous T4. Kinetic parameters were determined by noncompartmental analysis, and serum concentrations of rT3 and T4 were determined by specific RIAs. In six hyperthyroid, seven euthyroid, and six hypothyroid subjects, the MCRs were 190.7 +/- 15.7, 111.7 +/- 13.2, and 71.8 +/- 7.0 liters/day kg, respectively (mean +/- SE). Production rates (PR) for these same groups were 271.3 +/- 40.5, 51.7 +/- 9.1, and 4.3 +/- 0.6 micrograms/day/70 kg. The observed differences in MCR and PR among the three study groups were highly significant (P less than 0.002). These data indicate that in comparison to euthyroid subjects, rT3 PR and MCR are increased in thyrotoxic and decreased in hypothyroid individuals.


Measurement of the corticosteroid-binding globulin, progesterone, and progesterone "receptor" content in human endometrium. The corticosteroid-binding globulin (CBG) content has been determined in cytosols prepared from human endometrium taken at different phases of the menstrual cycle, at 8-10 weeks gestation, and during treatment with an oral contraceptive. The data were compared to the progesterone "receptor" and the progesterone concentration in the same tissue extracts. The plasma contamination was estimated by the serum albumin content. It was observed that CBG is a constant contaminant of the endometrial cytosols. All of the CBG content can be considered to be of plasma origin. The cytoplasmic progesterone "receptor" content is between 21-33% of the CBG concentration during the menstrual cycle and is only 1% during pregnancy. The cytosol progesterone concentration is much higher in endometrium than would be expected from the plasma contamination and the level of the progesterone "receptor".


Fetal hypothyroidism and maternal thyroid status in severe endemic goiter. The relationship between maternal thyroid function and newborn thyroid function was studied in a region of very severe endemic goiter (Ubangi, Republic of Zaïre). T4, T3, and TSH concentrations were measured in the sera of 56 mothers (at the time of delivery) and 60 newborns (in the cord). The results obtained in these groups (untreated) were compared with those obtained in two control groups, comprising 53 mothers whose iodine deficiency had been corrected by the injection of iodized oil and 68 neonates born to such mothers. The results show that the mean (+/- SEM) T4 serum concentration (micrograms per dl) was 11.5 +/- 0.7 in the untreated mothers compared with 15.7 +/- 0.7 in the treated mothers (P less than 0.001), and 9.4 +/- 0.8 in the untreated newborns compared with 12.4 +/- 0.5 in the newborns of treated mothers (P less than 0.01). The values observed for the mean T3 serum concentrations (nanograms per dl) in the same groups were 171 +/- 10 and 154 +/- 9 (mothers; P greater than 0.05) and 68 +/- 6 and 55 +/- 6 (newborns; P greater than 0.05); the mean TSH serum concentrations (microunits per ml) were 8.7 (7.6 - 9.9) and 5.4 (4.9 - 5.9; mothers; P less than 0.001) and 19.6 (16.6 - 23.2) and 6.4 (5.8 - 7.0; newborns; P less than 0.001). The proportion of untreated newborns, i.e. 40%, with individual TSH values deviating by more than 2 SDS above the mean of the treated newborns is much greater than the corresponding proportion, i.e. 15%, of untreated mothers in relation to the treated ones. In 6 out of 34 untreated newborns, definite biochemical signs of congenital hypothyroidism were observed. Correlation coefficients were calculated between the untreated subjects. A positive correlation coefficient of 0.80 (P less than 0.001) was observed between the serum T4 concentrations of the mothers and those of the newborns, and one of 0.61 (P less than 0.001) was observed between their respective serum TSH values. Significant inverse correlations were observed between maternal serum T4 and cord serum TSH (-0.79; P less than 0.001) and between cord T4 concentrations and maternal TSH concentrations (-0.57; P less than 0.01). No definite trend is observed between the variations of serum T3 on one hand, and those of serum T4 or serum TSH on the other hand. Out of 51 mothers in whom serum T4 was determined, 11 showed values below 8 micrograms /dl; the newborns of those mothers showed very low serum T4 values (5.5 +/- 1.6 micrograms/100 ml) and extremely high serum TSH levels [144 (98-210) microU/ml]. It is concluded that, contrary to the situation observed in physiological conditions, maternal thyroid function in regions of severe endemic goiter is a good indicator of newborn thyroid function. The reasons for this probably lie in the influence of environmental factors acting simultaneously on the mother and the fetus.


A direct microassay for aldosterone in plasma extracts. We previously described an RIA for aldosterone based on highly specific antibodies elicited with aldosterone-3,20 dioxime bovine gamma-globulin (Poulsen, K. J. Sancho, and E. Haber, Clin Immunol Immunopathol 2: 373, 1974). We now report the development of higher affinity antibodies of similar specificity that allow the direct measurement of normal aldosterone concentrations in extracts of 100 microliters plasma. The detection limit at +/- 2 SD of mean zero value was 0.2-0.3 pg. The assay was validated by 1) zero values in adrenalectomized plasma, 2) parallel displacement plots of aldosterone standards and plasma extracts, 3) 97.7 +/- 2.5% recovery of added tracer, 4) a correlation coefficient of 0.992 and a slope of 1.08 in a plot of added vs. recovered unlabeled aldosterone, 5) 10.2% interassay variation and 5.6% intraassay variation, and 6)failure of high concentrations of a variety of steroids added to plasma to perturb the measured aldosterone concentration. The simplicity of the assay results in a high degree of productivity, in that 195 plasma samples may be processed in duplicate, in addition to standard curves, in a single working day.


Approach to the mechanism of androgen overproduction in a case of Krukenbery tumor responsible for virilization during pregnancy. Virilization may occur during pregnancy as the result of an ovarian Krukenberg tumor. mechanism of the androgen overproduction in this exceptional condition is still poorly understood. A new case is reported in which only in the postpartum clinical, endocrine, and endoscopic studies led to the diagnosis of an ovarian Krukenberg tumor secondary to a gastric carcinoma. In the mother, basal hormonal studies were done 1 and 4 weeks after delivery, then after gastric and ovarian surgery. Three months after delivery, ovarian steroid response to hCG (priming dose, 5000 IU; then 1500 IU every other day for 12 days) and a study of progesterone (P) metabolism at a steady state after a constant infusion of [3H]P and cold P (92 micrograms/min leads to blood production rate (BPR) of 152 mg/day designed to reproduce the BPR of P usually seen in pregnancy) were successively performed. Hormones were measured by specific RIAs after chromatographical purification. Basal hormonal levels were normal in the child. In the mother, on the 5th day postpartum, mean hormone levels (in nanograms per dl) were: testosterone (T), 4181; androstenedione (delta 4), 8876; 17 alpha-hydroxyprogesterone (17-OHP), 9746; P 1075; estrone (E1), 195; and estradiol (E2), 151. One month later, levels were normal for the follicular phase; T, 40; delta 4, 146; P, 52; E2, 9; and E2, 4.5. At both times, dehydroepiandrosterone was normal (703-750). Hormone levels increased progressively during hCG stimulation but their time course was different between hormones. At the end of the test, T. 144; delta 4, 746;' 17-OHP, 789; P, 723; E1, 37; and E2, 20. The MCR of P was decreased, 1450 liters/day (normal, 2020). Conversion ratios between products and precursor during constant infusion were normal. From these data, obtained in four different conditions (postpartum period, hCG stimulation, progesterone infusion, and after oophorectomy), the following can be concluded: adrenal production of dehydroepiandrosterone was normal; the ovarian overproduction of androgens likely resulted from the excessive reductive metabolism of both placental and ovarian P along the delta 4 steroid biosynthetic pathway by an hypertrophic stromal compartment; and HCG stimulation seems to be the necessary stimulus for this condition. The enhancement by T on its own peripheral production is also discussed.


Prolactin stimulation of alpha-lactalbumin in normal primate mammary gland. An in vitro system has been developed to examine the effects of PRL on the normal primate mammary gland. alpha-Lactalbumin a milk protein, was found in breast tissue samples from 17 of 19 primates representing several Macaca and Papio species; concentrations ranged from 10-768 ng/mg protein. That none of the animals was pregnant or lactating and half were nulliparous indicates that milk protein production takes place under normal circumstances, even in breast tissue of nonlactating animals. Studies of the effect of PRL on alpha-lactalbumin production in these tissues in organ culture revealed that PRL maintained existing or stimulated new production of alpha-lactalbumin for periods of up to 9 days. Measurement of alpha-lactalbumin in medium bathing mammary tissue from three animals revealed that mean alpha-lactalbumin production during days 7-9 when PRL was added (100 and 1000 ng/ml) was 11 and 59 times greater, respectively, than control. Simultaneous measurement of tissue concentrations of alpha-lactalbumin revealed that those tissues maintained with PRL (1000 ng/ml) had a mean concentration of alpha-lactalbumin that was 61 times that of controls without PRL. PRL consistently maintained or increased alpha-lactalbumin production in tissues from all 22 primates tested. Even in those premenarchal animals in whose mammary tissue alpha-lactalbumin was undetectable initially, PRL stimulated alpha-lactalbumin production in a dose-related fashion. In contrast, when PRL was absent from medium, alpha-lactalbumin concentrations decreased at 9 days to less than 20% of the initial 3-day value in all cases. These studies provide evidence that mammary tissue from normal nonlactating, nonpregnant primates produces milk proteins and that when tissues are exposed to PRL in culture, production of alpha-lactalbumin is stimulated.


Growth failure with normal serum RIA-GH and low somatomedin activity: somatomedin restoration and growth acceleration after exogenous GH. Two three-year-old boys with dwarfism (height ages 1-4/2 and 1-11/12 years) and delayed bone ages (1-4/12 and 1-9/12 years) had normal growth hormone (GH) responses after stimulation and low levels of somatomedin. Unlike patients with Laron syndrome, the two patients generated normal levels of somatomedin after administration of exogenous hGH. Treatment with hGH (2 IU every other day) brought about a significant increase in the growth rate of both patients. The growth rate of the first patient increased from 2 cm/year before treatment to 12 cm/year on therapy. The growth rate of the second patient was 4.5 cm/year before treatment, and 8.3 cm/year while on treatment. The two cases represent a new syndrome of dwarfism which may be caused by secretion of a biologically inactive but immunoreactive GH.


3,3',5'-triiodothyronine, thyroxine, triiodothyronine, and thyrotropin levels in maternal and cord blood sera from endemic goiter regions of Brazil. T4, T3, rT3, and TSH were measured in cord blood of infants born in mild to severe endemic goiter areas and nonendemic urban areas in South and North America. A significantly high rT3 concentration was found in newborns living in the urban area of South America as compared to a Canadian newborn population. There were no differences among the various thyroid parameters in the groups of newborns studied. Blood from goitrous mothers showed significantly higher concentrations of T3 and TSH than nongoitrous mothers. However, these changes did not affect the concentrations of thyroid hormones, rT3, or TSH in the fetal circulation.


Hemoglobin A1c levels in a diabetes detection program. Hemoglobin A1c concentration (HbA1c) was compared to the plasma glucose responses at 1 and 2 h of an oral glucose tolerance test (OGTT) in 63 subjects preselected because of postprandial hyperglycemia. HbA1c concentrations were correlated with 1- and 2-hour plasma glucose responses during the OGTT (r = 0.776 and 0.8602, respectively). The OGTT responses were diabetic-like in 21, indeterminate in 15, and normal in 27 subjects. HbA1c values were within normal limits in all subjects who had a normal or indeterminate OGTT response and in 10 out of 21 with a diabetic OGTT. The 2-h OGTT response among the 10 diabetic responders with normal HbA1c was 200 +/- 31 mg/100 ml (mean +/- SD), while that of the 11 diabetic responders with elevated HbA1c was 352 +/- 122 mg/100 ml. All subjects with an elevated HbA1c had a 2-h plasma glucose above 228 mg/100 ml, whereas only 7% of subjects with a normal HbA1c had a 2-h glucose above this value. It is concluded that only about half of the patients currently diagnosed as having mild or chemical diabetes by OGTT have elevated HbA1c and that an elevated HbA1c is usually associated with 2-h OGTT levels above 228 mg/100 mg.


Conversion of androgen to estrogen by the human fetal ovary. The conversion of radiolabeled androgen to estrone and 17 beta-estradiol was assessed in tissues of human embryos that varied from phenotypically indifferent stages (1-3 cm crownrump length) to midgestation (15. 1-20 cm crownrump length). Significant rates of estrogen synthesis were demonstrated only in ovaries, liver, and brain. Estrogen synthesis was undetectable in gonads from 1-3 cm fetuses, but by the 3.1-5-cm stage it had reached an average rate of 1.9 pmol . h-1 . mg protein -1 in ovaries and remained at this level of activity through the latest stages examined. Estrogen formation was undetectable in testes at all stages examined, but the time of appearance of the capacity to form estrogens in the fetal ovary is similar to the onset of the capacity of the fetal testis to synthesize testosterone. The capacity of the fetal ovary to form estrogen develops before histological differentiation of the tissue.


Effect of propranolol on extrathyroidal metabolism of thyroxine and 3,3',5-triiodothyronine evaluated by noncompartmental kinetics. Kinetic studies of T4 and T3 using a noncompartmental approach were performed in seven patients with pretreatment severe hypothyroidism maintained on L-T4 replacement. Each subject received a combined tracer dose of labeled T4 and T3 as an iv bolus before and during peroral treatment with propranolol. Serum T4 was unchanged, while a significant decrease of 13% was found in serum T3. The disposal rates (DR) of T4 and T3 decreased significantly, and the ratio between the DR off T3 and the DR of T4, the conversion rate, was significantly reduced during propranolol treatment. The decrease in the DR of T4 suggests a reduction in the bioavailability of L-T4 during propranolol, possibly due to a decrease in intestinal absorption. The decrease in the conversion rate indicates a reduced extrathyroidal conversion of T4 to T3 during propranolol treatment.


Steroid production by definitive and fetal zones of the human fetal adrenal gland. This study was performed to assess the relative contributions of the fetal and definitive zones of the human fetal adrenal gland to "corticoid" (cortisol and perhaps other corticosteroids) and dehydroepiandrosterone sulfate (DHAS) production, and the possible regulatory role of ACTH and the fetal pituitary in the secretion of of these steroids. Corticoid and radioimmunoassayable DHAS or total aromatizable androgen secretion by the isolated definitive and fetal zones of the human fetal adrenal gland between 10-20 weeks gestation has been studied in a superfusion system. Different functional capacities of the two zones were seen; corticoids were found to be secreted primarily by the definitive zone, while DHAS was found to be the main secretory product of the fetal zone. Addition of ACTH (250 ng/ml) or fetal pituitary homogenate produced a 2- to 5-fold stimulation of corticoid production by the definitive zone at all gestational ages studied. DHAS secretion by the fetal zone was also stimulated by ACTH. These results indicate that the definitive and fetal zones of the human fetal adrenal gland at midgestation have the capacity to respond to ACTH with increased corticoid or DHAS secretion, respectively.


Iodide organification defect in iodine deficiency endemic goiter. In 17 goitrous persons in an iodine-deficient area, in 23 nongoitrous inhabitants of the same village, in 10 goitrous persons in Athens, and 8 normal controls the perchlorate discharge test was performed, either in the simple standard form or after pretreatment with either 0.5 or 2.0 mg potassium iodide or 2.5 mg carbimazole. With the simple test or with 0.5 mg potassium iodide, there was no significant discharge in any group studied. With 2.5 mg carbimazole, there was a profound discharge of the trapped iodide in both groups in the iodine-deficient area. With 2.0 mg potassium iodide, however, there was a clear discharge in the two goitrous groups (i.e. the one in the endemic area and the second in Athens), a less pronounced discharge in the controls studied in Athens, and no discharge at all in the nongoitrous inhabitants of the iodine-deficient endemic area. These findings provide evidence for an abnormality present in the patients with endemic goiter, most probably faulty iodine utilization due to impaired organic binding. The nongoitrous persons in the endemic areas, on the other hand, seem to be even more efficient in handling the trapped iodide than the controls studied in Athens. These findings may provide an explanation for previous observations that in endemic areas only part of the population develop a goiter, whereas the others adapt successfully to iodine deficiency without significantly enlarging their glands.


Calcium-regulating hormones during the menstrual cycle. Calcium metabolism during the menstrual cycle was studied in seven women from whom fasting blood samples were drawn daily or every other day throughout ovulatory cycles. Total calcium (Ca), ionic calcium (Ca++), magnesium (Mg), phosphorus (P), and immunoreactive parathyroid hormone (PTH) and calcitonin (CT) were measured. LH levels were used to date each cycle and progesterone levels were used to confirm ovulation. Plasma estradiol was measured in two of the subjects. In six subjects with cycle lengths of 27-31 days, PTH levels rose progressively through the follicular phase to a peak at or slightly before the LH surge, then fell progressively through the luteal phase; peak PTH levels were 30-35% above early follicular and late luteal values. CT levels were also highest at midcycle, but the CT pattern was somewhat more variable than that of PTH. Ca++ tended to fall until 3-4 days before ovulation and then to increase, while Ca, Mg, and P exhibited no particular pattern. One subject experienced a prolonged (44 day) ovulatory cycle characterized by three distinct PTH peaks, each of which coincided with elevations in plasma estradiol level. These results represent the first report of menstrual cyclicity in calcium-regulating hormones. The timing suggest an estrogen effect and it is hypothesized that estrogen inhibits PTH-induced bone resorption, lowering serum Ca++, which in turn provokes a compensatory PTH output. With the decline of the preovulatory estrogen peak, Ca++ levels rise and PTH secretion falls. Alternatively, it is possible that the primary action may be an estrogen-induced rise in CT release, causing hypocalcemia and consequent PTH output. Cyclic changes in PRL release or vitamin D metabolism might also be involved.


Calcium and salmon calcitonin in treatment of osteoporosis. Calcitonin has been considered of therapeutic value in osteoporosis because of its effects in tissue culture. In the whole animal, however, the predominant result seems to be hypocalcemia, which might be expected to have the opposite effect of stimulating parathyroid hormone secretion and therefore resorption of bone. Indeed, in a short term study of 3- and 4-month duration in osteoporotic women, this was found to be so. A combination of calcium and calcitonin was therefore considered a more promising therapeutic alternative for this disease. Calcium was given to 26 patients, alone or with vitamin D, for a period of 15 months, and the effects on serum and urine calcium and phosphorus and on bone resorption and formation were evaluated. Calcium and vitamin D decreased serum parathyroid hormone levels, reduced bone resorption, and increased urinary calcium. The addition of calcitonin to the calcium and vitamin D did not seem to change these effects. Neither form of treatment resulted in change of bone mass. Calcium, with or without vitamin D supplements, may prevent the development of osteoporosis, but it seems unlikely that calcitonin has any additional desirable effect in the disease.


Carbidopa inhibits the growth hormone- and prolactin-suppressive effect of L-dopa in acromegalic patients. The plasma GH, PRL, TSH, and dopamine (DA) responses to an infusion of L-dopa were examined in six acromegalic patients before and after pretreatment with carbidopa, a drug which inhibits the peripheral conversion of L-dopa to DA. Carbidopa neither modified baseline DA nor induced changes in baseline GH, PRL, or TSH levels. The drug instead markedly reduced the L-dopa-induced DA rise, an effect which was concomitant to a striking reduction of the suppressive effect of L-dopa on plasma GH and a partial inhibition of the suppressive effect of L-dopa on plasma PRL. TSH levels did not change either after L-dopa alone or L-dopa plus carbidopa. These data demonstrate that in "responder" acromegalics, L-dopa inhibits GH secretion through its peripheral conversion to DA and not via activation of central DA neurotransmission. For the effect of L-dopa on PRL secretion, in addition to a peripheral dopaminergic component, a central component cannot be disregarded.


Clinical, endocrinological, and enzymatic characterization of two patients with 5 alpha-reductase deficiency: evidence that a single enzyme is responsible for the 5 alpha-reduction of cortisol and testosterone. Two siblings with 46,XY male pseudohermapthroditism were demonstrated to have the phenotype characteristic of 5 alpha-reductase deficiency, namely normal testes and male Wolffian duct derivatives (epididymis, vas deferens, and seminal vesicle) terminating in a blind-ending vagina. Clitoromegaly was present at birth and increased further at the time of expected puberty. The diagnosis of 5 alpha-reductase deficiency was confirmed by demonstration of male levels of testosterone and testosterone precursors before and after hCG administration, elevated plasma testosterone to dihydrotestosterone and urinary etiocholanolone to androsterone ratios, and by in vitro studies indicating 5 alpha-reductase enzyme deficiency in the epididymis of one patient. Studies of control and mutant epididymal microsomes indicated that a single enzyme is responsible in the normal person for the 5 alpha-reduction of testosterone and cortisol (and probably other delta 4-3-ketosteroids as well) and that 5 alpha-reductase activity is undetectable for all substrates examined in the mutant. This finding explains why the formation of 5 alpha-reduced glucocorticoids is also defective in the disorder.


Extraction of human chorionic thyrotropin (hCT) from term placentas: failure to recover thyrotropic activity. We extracted human placentas by three methods to obtain chorionic TSH (hCT). The extracts were assayed by a sensitive homologous RIA for bovine TSH with an antibody which had veen used previously for assay of hCT. Based on the RIA for hCT, the yield of hCT was only 0.68 +/- 0.15 (SE) mU/100 g placenta by the Bates method, 2.01 +/- 0.35 mU/100 g by the Reisfeld method, and 4 mU/100 g by a Concanavalin A-Sepharose technique. Thyrotropic activity was detected by bioassay only in one Reisfeld extract; this biological activity could be attributed to hCG in this fraction. In TSH bioassays of other extracts, the responses were less than the sensitivity of the assay; some extracts were lethal to the bioassay mice. The low yield of hCT, about one-tenth to one-hundredth of that reported previously, casts doubt on the validity of the previous observations.


Collaborative study of the effects of human growth hormone in growth hormone deficiency. V. Treatment with growth hormone administered once a week. Twenty-two GH-deficient patients received 6 IU GH weekly for 6 months. They increased their growth rate from 1.0 +/- 0.2 to 2.9 +/- 0.3 (SE) cm/6 months (P less than 0.01). However, their rate of growth was significantly less (P less than 0.05) than the rate [4.1 +/- 0.5 (SE) cm/6 months] observed earlier when they had received 2 IU GH three times a week. Seven patients received weekly GH for 18 months and they also grew significantly less (P less than 0.01) than when they had received GH divided over the week. These results suggest that once a week GH does not provide the most effective therapy for GH deficiency.


Effect of pyridoxine on pituitary release of growth hormone and prolactin in childhood and adolescence. The dopamine agonist, pyridoxine, was administered to 10 children being evaluated for short stature. Serum GH and PRL responses were contrasted to those after insulin-induced hypoglycemia (ITT) and L-dopa administration. Levels of GH did not change after pyridoxine, but PRL fell (P less than 0.05) to 42% of the zero time concentration. Significant increments of GH occurred during ITT and after L-dopa, while PRL was suppressed to a greater extent by L-dopa. We conclude that pyridoxine is not useful in assessment of hypothalamic-pituitary function.


Some properties of the specific androgen-binding activities in cultured human genital skin fibroblasts. Specific 5 alpha-dihydrotestosterone (DHT)-binding activity in the cytosol (C) and 0.4 M KCl-extractable nuclear fraction (N) of cultured human fibroblast cell strains developed from preputial (n = 12) and labium majus (n = 12) skin were analyzed by gel exclusion chromatography, sucrose gradient sedimentation, and thermostability. Both fractions had activities that were excluded from Sephacryl S-200 columns; another component (mol wt, 20,000) was present in the N fraction. The C was more thermostable than a homologous N activity, and addition to the former of KCl to 0.4 M had no effect. There was large, overlapping variation in thermostability of the C and N activities among strains from either site, sister strains developed from a single skin biopsy, and even among serial subcultures within a strain; likewise, the variable sedimentability of the C (4-7S) and N (3.2-5.9S) activities prevented their consistent discrimination. Each type of variation occurred despite excellent intraexperimental replication. The thermostability of a given N activity varied directly with its sedimentation coefficient. By cluster analysis, the data relating thermostability of a given N activity with the percentage of 0.4 M KCl-resistant nuclear activity segregated into two populations; within each population these two measurements were related inversely. We suggest that these coordinate behaviors of the N activity reflect intrinsic properties of the androgen-receptor system in normal genital skin fibroblasts which may be useful for defining qualitative aberrations of the system in receptor-positive forms of congenital androgen insensitivity.


Radioimmunoassay of reverse triiodothyronine. rT3 RIA standard curves were generated using rT3 standards from various sources. The rT3 antiserum and the method of free and bound hormone separation used were the same in all assays. The slopes of rT3 RIA curves differed considerably; standard curves generated with Henning (Berlin) rT3 standard had the steepest slope. Because of the differences in slopes of standard curves, bound to free estimates, when extrapolated from standard curves generated with various rT3 standards, resulted in 2- to 3-fold differences in rT3 assay values in the same sera. Circulating rT3 concentration in human sera was 20 ng/100 ml when Henning rT3 standard was used in the assay, whereas with Jorgensen's rT3 standard, a value of 42 ng/100 ml was noted. As the rT3 antiserum and assay conditions used were identical in all comparisons (except rT3 standards), the 2- to 3-fold differences in rT3 values noted in the same sera suggested variability in potency of rT3 standards. The differences in rT3 values in the same sera (resulting from extrapolation from standard curves using different rT3 standards) were of the same magnitude as that noted in normal human sera in various studies, suggesting that the reported rT3 variations in sera of euthyroid individuals may also be due to differences in rT3 standards employed in the assay.


Heterogeneous human prolactin from a giant pituitary tumor in a patient with panhypopituitarism. A patient with hypopituitarism and an unusually large chromophobe adenoma which secreted an enormous amount of human PRL (hPRL) provided us with a unique opportunity to study the heterogeneity of hPRL. Serum samples obtained before and after surgery as well as pituitary extract were studied. Each sample contained three distinct hPRL peaks on gel filtration designated as big medium, and small. The hPRL moiety of each peak fraction was stable in size, immunoreactivity, and bioreactivity, indicating that the polymorphic hPRL components, once formed, were not interconvertible. As the relative proportion of medium and small hPRL components in all blood samples obtained before surgery and in the pituitary tumor extracts were similar, it seems that these two forms of hPRL originate from the tumor. However, there was a lack of correlation between big, medium, and small hPRL in samples obtained before and 1 yr after surgery. Also, increasing amounts of radioactive substance similar to increasing amounts of radioactive substance similar to big PRL were formed by exposure of 125I-labeled small PRL to progressively larger concentrations of serum. Thus, only small and possibly medium PRL are secretory products.


Effect of flutamide on cortisol metabolism. The effect of flutamide on cortisol metabolism was studied in eight patients with prostate cancer. Flutamide markedly decreased the formation of 3 alpha, 17,21-trihydroxypregnane-11,20-dione (THF), and the 11-oxy-17-ketosteroid metabolites by 72%, 50%, and 46% respectively; however, 3 alpha, 11 beta, 17,21-tetrahydroxy-5 alpha- pregnan-20-one was increased by 46%. The 24-h mean plasma cortisol concentration was not altered. The cortisol production rate decreased by an average of 53% (from 32.7 to 15.5 mg/24 h). The effect of the drug on plasma cortisol kinetics was studied in three patients. This showed that flutamide increased the t1/2 (from 80 to 108 min) but decreased the distribution volume (from 17.8 to 13.8 liters) and the MCR (from 222 to 130 liters/24 h). The changes in THE and THF formation and in the t1/2 and MCR of [C]cortisol are similar to the effects observed in patients with intrahepatic cholestasis. It is suggested that in the case of flutamide these changes were also due to a cholestasis-producing effect of the drug on the liver. As the clinical response to the drug did not correlate with the cortisol metabolic changes, its therapeutic effect was probably not mediated by its effects on cortisol metabolism.


Parathyroid hormone secretion in magnesium deficiency. The effect of an acute elevation of the serum magnesium concentration on the concentrations of serum immunoreactive parathyroid hormone (IPTH) were studied in hypocalcemic hypomagnesemic patients, hyperparathyroid patients, and normal individuals. Basal serum IPTH concentrations in the hypomagnesemic patients ranged from undetectable to 3 times the upper limit of normal. All hypomagnesemic patients were observed to have an immediate rise in the serum IPTH concentration after magnesium administration regardless of the basal IPTH concentration. In contrast, normal individuals and patients with primary and secondary hyperparathyroidism responded to magnesium administration with either a decrease or little change in the serum IPTH concentration. These date indicate that an acute stimulation of PTH secretion induced by magnesium is characteristic of the magnesium-deficient state. The consistency of this response suggests that impaired PTH secretion is a significant factor contributing to the hypocalcemia of magnesium deficiency.


Metabolism of cortisol-21 glucosiduronate in man. The metabolism of cortisol-21-glucosiduronate has been studied in two subjects. Urinary excretion was about 65% in both subjects, with cortisol glucosiduronate as the principal metabolite accompanied by small amounts of 11 beta, 17,21-trihydroxypregnane-3,20-dione (THF) glucosiduronate. The absence of the other normal metabolites of cortisol [17,21-dihydroxypregnane-3,11-20-trione (THE), 3 alpha, 11 beta, 17, 20xi, 21-pentahydroxypregnane, and 3 alpha, 17, 20xi, 21-tetrahydroxypregnan-11-one] indicates that negligible hydrolysis at C-21 occurred and that an unoccupied C21 position is required for oxidation at C-11 and reduction at C-20. The limited conversion to THF suggests that a pathway through cortisol-21-glucosiduronate does not contribute significantly to the differences in specific activity of urinary THF and THE observed after administration of labeled cortisol.


Extraadrenal effects of metyrapone in man. [14C]Cortisol was injected iv into three subjects during a control period and while receiving metyrapone. The plasma kinetics of the tracer cortisol and the patterns of its urinary metabolites were measured. Metyrapone caused an increase in the volume of distribution of cortisol (34%) and in the MCR (75%); the half-life was decreased by 25%. There were marked changes in the urinary metabolite pattern: 3 alpha,11 beta,17,21-tetrahydroxy-5 alpha-pregnan-20-one, 3 alpha,17,21-trihydroxy-pregnane-11,20-dione(THE), pregnane-3 alpha,11 beta,17,20 alpha,21-pentol, plus pregnane-3 alpha,11 beta,17,20 beta-21-pentol (cortol), and 3 alpha,17,20 alpha,21-tetrahydroxypregnan-11-one (cortolone) all decreased by an average of 62%, 44%, 38%, 45%, and 25% respectively. In contrast, there was an increase of 296% in 3 alpha,17,20 beta,21-tetrahydroxypregnan-11-one (beta-cortolone). To account for these effects it is postulated that metyrapone has the following extraadrenal actions: 1) it inhibits the back reduction of cortisone to cortisol and 2) it stimulates the 20-ketosteroid reductase that converts THE to beta-cortolone.


Urinary 5 alpha-androstane-3 alpha,17 beta-diol radioimmunoassay: a new clinical evaluation. A rapid specific and reliable RIA for urinary 5 alpha-androstane-3 alpha,17 beta-diol (Adiol) is described using chromatographical purification and a specific antibody. Values are reported under some physiological and pathological conditions in 179 individuals. In 43 normal adult men, the mean (+/-SD) urinary Adiol excretion was 193 +/- 77 micrograms/24 h, and in 29 normal women it was 44 +/- 23 micrograms/24 h. These values are significantly different (P less than 0.01). In 49 hirsute women, urinary Adiol Excretion was elevated (137 +/- 51 micrograms/24 h) and significantly different from this value in normal women (P less than 0.01). The urinary Adiol excretion in 10 postmenopausal women was very low (less than 5 micrograms/24 h). In normal adult subjects, the theoretical contribution to urinary Adiol of the major secreted androgens was calculated. Whereas dehydroisoandrosterone and dehydroisoandrosterone sulfate yield the same amount of urinary Adiol in both sexes, testosterone is the main precursor of Adiol in men and androstenedione is the main precursor in normal premenopausal and hirsute women. However, the amount of Adiol recovered in the 24-h urine depends not only on the secretion rate of androstenedione and testosterone but is also related to the testosterone 5 alpha-reductase activity present in androgen target cells, especially in sexual skin.


Effect of starvation on the production and peripheral metabolism of 3,3',5'-triiodothyronine in euthyroid obese subjects. The effect of starvation on the peripheral metabolism of rT3 was evaluated in four obese euthyroid patients. During starvation, the serum rT3 concentration increased by 69% while the MCR of rT3 decreased in all four patients from control values of 96 +/- 23 (mean +/- SD) to 68 +/- 17 liters/70 kg . day, resulting in a slight increase in the mean production rate of rT3. These findings are in contrast to the marked decrease in T3 production rate associated with fasting, indicating that inner and outer ring deiodination of T4 can be varied independently.


Prolonged hyperprolactinemia in preterm infants. Serum PRL levels were followed serially in full term (FT; 39-41 weeks) and preterm (PT; 30-32 weeks) infants, from birth to 12 and 20 postnatal weeks, respectively. Values were higher in FT infants than in PT infants on day 1 after birth (267 +/- 20 vs. 156 +/- 8 ng/ml) but were similar in both by the age of 2-4 weeks (69 +/- 8 vs. 69 +/- 6 ng/ml). Between the ages of 4-12 weeks, the serum PRL in FT infants fell to near adult levels (24 +/- 2 ng/ml), but this fall was seen much later in PT infants, between 12-20 weeks postnatally (23 +/- 2 ng/ml). When values in FT and PT infants were compared at parallel postmenstrual ages in contradistinction to postnatal ages, a similar course of PRL was discernable in both groups. These data may provide indirect evidence for the establishment and maturation of inhibition of PRL secretion (i.e. PRL-inhibitory factor production) postnatally, between 44-52 weeks postmenstrually.


ESPAS: The Endocrine Society Presidential Address Syndrome.


A new method of paired thyrotropin assay as a screening test for neonatal hypothyroidism. A simple and reliable method of paired TSH assay was developed and used in screening for neonatal primary hypothyroidism. In this method, a paired assay is first done. Equal parts of the extracts of dried blood spots on filter paper (9 mm diameter) from two infants 4-7 days old are combined and assayed for TSH by double antibody RIA. If the value obtained is over the cut-off point, the extracts are assayed separately for TSH in a second assay to identify the abnormal sample. Two systems, A and B, with different cut-off points were tested. On the basis of reference blood samples (serum levels of TSH, 80 microU/ml in system A and 40 microU/ml in system B), the cut-off point was selected as follows: upper 5 (A) or 4 (B) percentile in the paired assay and values of reference blood samples in the second individual assay. Four cases (2 in A and 2 in B) of neonatal primary hypothyroidism were found among 25 infants (23 in A and 2 in B) who were recalled from a general population 41,400 infants (24,200 in A and 17,200 in B) by 22,700 assays. This paired TSH neonatal hypothyroidism.


Effect of intraamniotic fluid thyroxine injection on fetal serum and amniotic fluid iodothyronine concentrations. Seven hundred micrograms of T4 were injected into the amniotic cavity 24 h before delivery of five pregnant women scheduled for elective cesarean section at term. T4, T3, and rT3 concentrations were measured by RIA in amniotic fluid obtained at the time of the injection and in amniotic fluid and cord serum samples collected at delivery. Iodothyronine concentrations also were determined on cord samples from 24 full term control infants. The geometric mean serum T4 concentration in the experimental infants was 27.2 micrograms/dl, almost 3 times that of the control population (10.3 micrograms/dl); serum rT3 concentrations were markedly elevated to a mean of 657 ng/dl, compared to 254 ng/dl in control infants. The mean serum T3 concentration was slightly but significantly increased to 61.3 ng/dl (control, 48.3 ng/dl; P less than 0.02). Amniotic fluid T4, T3, and rT3 concentrations all increased significantly. T4 injection into the amniotic fluid is an effective method of increasing fetal serum T4 concentrations. The preferential pathway of monodeiodination of the injected T4 in the human fetus is to rT3 rather than T3.


A radioimmunoassay for 3',5'-diiodothyronine. The present report describes a RIA for 3',5'-diiodothyronine (T2) that can be performed on unextracted serum and which has a lower limit of detectability of 2 ng/dl. Cross-reactivity with other iodothyronines was negligible, except for rT3 which began to demonstrate cross-reactivity when rT3 levels were elevated to 180 ng/dl. Employing this RIA for T2, we have determined that 83 healthy individuals had a mean  (+/-SE) serum T2 concentration of 5.0 +/- 0.3 ng/dl, thyrotoxic subjects (n = 12) had a mean T2 level that was elevated to 10.8 +/- 0.8 ng/dl, and each of 6 hypothyroid subjects had undetectable (less than 2 ng/dl) concentrations. Athyreotic patients (n = 8), receiving 0.4 mg T4 daily, had serum T2 concentrations of 15.0 +/- 3.0 ng/dl. Fasting in obese subjects was associated with an increase in serum T2 to 6.9 +/- 0.6 ng/dl from a basal level of 4.4 +/- 0.4 ng/dl in the fed state (P less than 0.01). Despite the fact that rT3 levels may be elevated in amniotic fluid and that rT3 is expected to represent the major source from which extrathyroidal T2 arises, T2 levels were low in amniotic fluid, being undetectable (less than 2 ng/dl) in 9 of 19 samples; the mean (+/-SE) T2 concentration in the 10 detectable samples was 5.4 +/- 1 ng/dl. These data indicate T2 is a normal component of serum and that the majority of serum T2 is probably derived from peripheral conversion. Furthermore, these observations suggest that situations associated with elevated rT3 levels (e.g. thyrotoxicosis and fasting) may also have increased T2 values.


Serum Neurophysins in familial central diabetes insipidus. Antibovine neurophysin antibodies (anti-bNpI and/or anti-bNpII) are present in certain patients with familial central diabetes insipidus; these are exogenous origin, as they are not present in patients who have not received treatment with crude posterior pituitary extracts over the years preceding the analysis. Immunoreactive neurophysins were detectable in the blood of five patients with familial central diabetes insipidus, and in two of them, the levels increased after a short period of water restriction. There is marked polymorphism of these neurophysins from one serum to another: neurophysin I was consistently absent, while neurophysin II, accessory neurophysins, and other immunoreactive substances not present in normal sera were sometimes present in variable amounts. Immunoreactive AVP was undetectable in the urine of all patients, while immunoreactive OT was found in three of them; the latter substance could, however, be arginine vasotocin. Data are presented suggesting that the association between the biosynthesis of neurophysin I and AVP on the one hand, and neurophysin II and OT on the other hand is maintained in patients with isolated AVP deficiency on the basis of a congenital defect.


The use of specific radioimmunoassays to determine the renal clearance rates of estrone and 17 beta-estradiol during the menstrual cycle. Specific RIAs requiring ether extraction only were established for estrone and 17 beta-estradiol both in plasma and in urine from the nonpregnant female. These assays were used to measure the renal clearance rates of estrone and of 17 beta-estradiol in eight ambulatory women in the follicular and in the luteal phases of the menstrual cycle. The mean (+/-SE) for the renal clearance rate of estrone was 0.71 +/- 0.058 ml/min in the follicular phase and 1.26 +/- 0.35 ml/min in the luteal phase. The mean (+/-SE) renal clearance rate of 17 beta-estradiol was 0.44 +/- 0.055 ml/min in the follicular phase and 0.29 +/- 0.043 ml/min in the luteal phase. There was no significant difference in the renal clearance rates of either estrone or of 17 beta-estradiol between the follicular and luteal phases of the cycle. The renal clearances of estrone and 17 beta-estradiol were highly correlated (r = 0.84; P less than 0.01). The renal clearance rate of estrone was significantly greater than that of 17 beta-estradiol in both phases of the cycle (P less than 0.01).


A specific radioimmunoassay for estrone sulfate in plasma and urine without hydrolysis. Estrone sulfate, quantitatively the most important estrogen in plasma, has previously been determined only after hydrolysis and chromatography. An antiserum raised against estrone glucosiduronate-bovine thyroglobulin was found to be suitable for the specific RIA of estrone sulfate both in plasma and urine. Plasma levels were measured after solvent extraction without hydrolysis or chromatography. The mean (+/-SE) was 972 +/- 79 pg/ml (range, 537-1581) in 15 women in the follicular phase, 1806 +/- 160 pg/ml (range, 814-3358) in 15 women in the luteal phase, and 922 +/- 62 pg/ml (range, 461-1238) in 13 men. The urinary excretion of estrone sulfate, measured after simple chromatographic separation, ranged from 0.8-7.9 micrograms/24 h in men and 5.1-18.7 micrograms/24h in nonpregnant women. This was generally one-seventh to one-half the simultaneous estrone glucosiduronate excretion rate. An approximate mean renal clearance of estrone sulfate calculated from the above values was 2.7 ml/min. The low clearance rate is taken to reflect extensive binding of estrone sulfate by plasma proteins. The splanchnic extraction of estrone sulfate measured in 6 patients undergoing hepatic vein catheterization for diagnostic purposes was 29.8 +/- 11.1%, indicating net uptake of this compound by the splanchnic area.


Plasma immunoreactive relaxin levels in pregnant and nonpregnant women. Immunoreactive relaxin was measured in plasma samples obtained from human volunteers utilizing the RIA procedure of Sherwood et al., as modified by O'Byrne and Steinetz for heterologous plasma samples. Immunoreactive hormone was not detected in samples obtained from men, and only rarely in plasma of nonpregnant women. Immunoreactive relaxin was present as early as the fourth week of pregnancy and was detectable throughout the course of gestation. Immunoreactive relaxin tended to be higher early in pregnancy, and there was no peak just before parturition as occurs in many other species. Our results are at variance with those of Bryant and coworkers, who reported high levels of immunoreactive relaxin in men and nonpregnant as well as pregnant women. The possible reasons for this discrepancy are presented.


Regulation by plasma lipoproteins of progesterone biosynthesis and 3-hydroxy-3-methyl glutaryl coenzyme a reductase activity in cultured human choriocarcinoma cells. The regulation of both the activity of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG CoA) reductase [mevalonate-NADP+ oxidoreductase (CoA-acylating) EC 1.1.1.34] and the secretion of progesterone by human plasma lipoproteins has been investigated in human choriocarcinoma cells in culture. HMG CoA reductase activity was computed from the rate of formation of [14C]mevalonolactone from [14C]HMG CoA. The activity of HMG CoA reductase was expressed as nanomoles of mevalonolactone formed/min . mg solubilized cell protein. An inverse relationship was found between the presence of lipoprotein in the culture medium and the activity of HMG CoA reductase in these cells. In cells maintained in the presence of lipoprotein-enriched culture medium containing 840 micrograms cholesterol/ml, the average activity of HMG CoA reductase was 0.25 nmol/min . mg protein. After removal of lipoprotein, the activity of HMG CoA reductase increased to 1.3 nmol/min . mg protein. The average activity of HMG CoA reductase in cells maintained in lipoprotein-deficient culture medium was 1.5 nmol/min . mg protein but fell to 0.3 nmol/min . mg protein after addition of lipoprotein to the medium. When cells were maintained in the presence of lipoprotein, the rates of section of progesterone and pregnenolone into the culture medium were 2-8 times greater than the rates of secretion of these steroids by cells maintained in the absence of lipoprotein. On the basis of these results, it is concluded that lipoproteins control the rate of cholesterol biosynthesis in cultured choriocarcinoma cells by regulating the activity of HMG CoA reductase, and control the rate of synthesis of progesterone by providing the precursor, cholesterol. We suggest that progesterone synthesis by the trophoblast of the human placenta may also be regulated by the uptake of lipoprotein from maternal blood.


Low serum triiodothyronine and high serum reverse triiodothyronine in old age: an effect of disease not age. Serum concentrations of T4, T3, T3, free T4, free T3, and TSH were determined in four groups of adult subjects: group A, 27 healthy young volunteers (aged 18-29 yr); group B, 24 carefully selected healthy elderly subjects (aged 70-90 yr); group C, 41 subjects living at a municipal nursing home for the elderly (aged 70-90 yr); and group D, 35 hospitalized patients (aged 70-90 yr). Identical levels of iodothyronines in serum were found in the young and in the elderly healthy subjects. Moderate and severe disease induced alterations in iodothyronine concentrations in serum comparable to those reported earlier. Serum T3 and free T3 levels were low and serum rT3 levels were high in groups C and D subjects; serum free T4 was elevated in group D, while serum T4 was low. Serum TSH was lower in the healthy elderly subjects than in the young subjects. Serum TSH was higher in the elderly sick subjects (groups C and D) than in the healthy subjects (group B). We conclude that advanced age per se is not accompanied by alterations in free or total serum iodothyronine levels.


Twenty-four-hour plasma prolactin patterns in prepubertal and adolescent boys. The concentration of PRL was measured every 20 min for 24 h in six prepubertal and three adolescent boys. In both groups, PRL secretory episodes occurred throughout the 24-h period. In all subjects, the mean concentration of PRL was significantly higher during sleep than during wakefulness; the mean concentration during the entire 24-h period, during sleep or during wakefulness, was not different between the prepubertal subjects and the adolescents. These data suggest the absence of an ontogenetic change for PRL secretion in boys. During acute sleep-wake reversal, two of three pubertal boys showed significantly higher PRL during daytime sleep than during nocturnal wakefulness. This suggest that PRL release in adolescent boys is linked with sleep, rather than with clock time.


Brain growth-promoting activity in human serum: relationship to growth hormone and somatomedin. Brain growth-promoting activity and somatomedin activity were assessed in serum collected from patients with pituitary disorders of GH secretion. Brain growth-promoting activity correlated with somatomedin activity in serum, and both rose in response to GH administration.


Basal and human chorionic gonadotropin-stimulated 17 alpha-hydroxyprogesterone and testosterone levels in Klinefelter's syndrome. In nine patients with Klinefelter's syndrome, mean basal plasma levels of testosterone (302 +/- 145 ng/100 ml) and its major precursor, 17 alpha-hydroxyprogesterone (17-OHP; 86 +/- 46 ng/100 ml), were significantly lower (P less than 0.01 to less 0.05) than in eight eugonadal men (605 +/- 180 and 136 +/- 39 ng/100 ml, respectively). The ratio of 17-OHP to testosterone, however, was comparable in both groups (0.29 +/- 0.09 vs. 0.24 +/- 0.08; P less than 0.10). In the Klinefelter patients, basal plasma testosterone and 17-OHP levels were positively correlated (rs = 0.87). Administration of hCG for 3 days raised plasma testosterone and 17-OHP levels in both groups. In the Klinefelter patients, the plasma 17-OHP rise exceeded the testosterone increment, leading to a statistically significant increase (0.48 +/- 0.19) of the 17-OHP to testosterone ratio, whereas this ratio remained virtually unchanged in the control subjects (0.20 +/- 0.06). Together, these findings indicate that in the basal state testicular steroidogenesis is globally attenuated, whereas short term hCG stimulation shows that the later steps in the biosynthesis of testosterone may be rate limiting in Klinefelter's syndrome.


Studies of the human testis. XI. Leydig cell clusters and levels of intratesticular testosterone and 20 alpha-dihydroprogesterone. Testosterone concentration in testes of 23 men, ages 51 to 90, was determined as 490 +/- 172 ng/g tissue (M +/- S.D.) and 20 alpha-dihydroprogesterone concentration as 10.0 +/- 2.3 ng/g tissue (M +/- S.D.) in 18 men of the same patient group. Leydig cells were estimated by the number of Leydig cell clusters per tubule. There was a high correlation (r = 0.88, p less than .001) of the Leydig cell index with intratesticular testosterone. It is proposed that the Leydig cell cluster index provides a direct index of steroid biosynthetic activity in the human testis as reflected in intratesticular testosterone levels. Although there was no significant correlation of 20 alpha-dihydroprogesterone levels in the testis with either the Leydig cell index or intratesticular testosterone, the high level of 20 alpha-dihydroprogesterone compared to peripheral levels suggests its production by the testis.


The evolving clinical course of patients with insulin receptor autoantibodies: spontaneous remission or receptor proliferation with hypoglycemia. Three patients with insulin resistance caused by autoantibodies to the insulin receptor were investigated serially over a 3-yr period. Major changes in carbohydrate metabolism, insulin receptor status, and titer of antireceptor antibodies were observed in each case. In one patient, normalization of glucose tolerance, insulin sensitivity, and receptor binding were associated with a spontaneous fall in the titer of antireceptor antibody. A second, more severely affected patient had two entirely distinct phase to her illness. The first, or hyperglycemic phase, was characterized by insulin resistance, negligible insulin binding to receptors on circulating monocytes, and high titers of circulating antireceptor antibodies. The second phase was characterized by refractory hypoglycemia, in association with proliferation of membrance insulin receptors; these occurred despite persistence of high titers of antireceptor antibody. An unusual heptic lesion, diffuse adenomatosis, was observed during this phase. A third patient showed features of both of the other patients, with spontaneous fall in antibody titer as well as a later phase of receptor proliferation. These studies demonstrate that patients with antibodies to insulin receptors may have a fluctuating clinical course. There may be spontaneous changes in antibody titers as well as independent changes in receptor concentration. Hypoglycemia and hepatic proliferation are newly recognized clinical sequelae in patients with this syndrome.


Effects of dexamethasone on fetal and maternal thyroxine, triiodothyronine, reverse triiodothyronine, and thyrotropin levels. The concentrations of T4, T3, rT3, and TSH were measured at term pregnancy in maternal and umbilical plasma and in amniotic fluid of 11 normal patients who received 8-16 mg dexamethasone 3-48 h before elective cesarean section and of 10 control patients who received no dexamethasone. The mean (+/- SE) concentrations of T4 (micrograms per dl) in maternal and umbilical plasma of dexamethasone-treated patients (12.5 +/- 0.9 and 13.0 +/- 0.9) were not significantly different (P less than 0.05) from those of the control patients (13.9 +/- 1.5 and 10.4 +/- 0.6, respectively). The mean (+/- SE) maternal plasma concentrations of T3 and rT3 (nanograms per dl) of dexamethasone-treated patients (204 +/- 6 and 82 +/- 11) were not significantly different (P less than 0.05) from those of the control patients (201 +/- 26 and 72 +/- 6, respectively). However, the mean (+/- SE) concentrations of T3 and rT3 (nanograms per dl) in umbilical plasma of dexamethasone-treated patients (106 +/- 13 and 360 +/- 35) were 3- and 2-fold and significantly higher (P less than 0.05) than those of the control group (39 +/- 6 and 195 +/- 19, respectively). No significant differences (P less than 0.05) were observed between the mean concentrations of TSH (microunits per ml) in maternal and umbilical plasma of dexamethasone-treated patients (2.5 +/- 0.5 and 3.0 +/- 1.0) and those of the control group (2.8 +/- 0.5 and 6.9 +/- 2.7, respectively). Under the conditions studied, no differences in the mean concentrations of amniotic fluid T4, T3, rT3, or TSH were observed between the two groups of patients (P less than 0.05). The increase of T3 and rT3 levels in umbilical plasma after dexamethasone administration indicates alteration in fetal thyroid economy.


Aminoglutethimide inhibits extraglandular estrogen production in postmenopausal women with breast carcinoma.


Heterogeneity of pituitary and plasma prolactin in man: decreased affinity of "Big" prolactin in a radioreceptor assay and evidence for its secretion.


Direct conversion of testosterone to dihydrotestosterone glucuronide in man. Tritiated testosterone and [14C]dihydrotestosterone (DHT) were administered by constant iv infusion into five young and five elderly men undergoing diagnostic cardiac catheterization. The radioactivity concentrations of free and conjugated DHT in arterial and hepatic vein blood samples were then determined. The analysis of the 3H:14C ratio of free DHT in arterial and hepatic vein blood showed that in both groups, the 3H:14C ratio of free DHT was the same in arterial and hepatic vein blood, indicating that splanchnic tissue is not the source of blood DHT from testosterone. This is in agreement with data that the transfer constant across the liver ([rho]T-DHT SD) was undetectable. In both young and elderly men, a significant increase of the 3H concentration of DHT glucuronide in hepatic vein blood was observed, indicating that the splanchnic compartment could be the site of production of DHT glucuronide. The 3H:14C ratio of DHT glucuronide was much higher than that of free DHT in both groups, suggesting that DHT glucuronide is derived from the blood testosterone pool, and most of the DHT from testosterone seems to be conjugated before mixing with blood DHT. This study indicates that a large fraction of DHT produced in the liver from testosterone is efficiently conjugated or further metabolized, and this results in the lack of splanchnic production of free DHT in men.


The production and metabolism of 3,5,3'-triiodothyronine and 3,3',5-triiodothyronine in normal and fasting subjects.


The effect of therapy on mature height in congenital adrenal hyperplasia.


Inhibitory effect of human follicular fluid upon the maturation of porcine oocytes in culture. Human follicular fluid (hFFl) was harvested from follicles (5-15 mm) of human ovaries obtained at laparotomy. Addition of native hFFl, or a low molecular weight fraction of it, to the culture medium was found to inhibit the spontaneous maturation of cumulus-enclosed porcine oocytes. It was also found that hFFl inhibited progesterone secretion by the cumulus cells. The results extend earlier observations in other mammalian species, indicating that in the human, also, a specific oocyte maturation inhibitor is responsible for keeping the oocyte in meiotic arrest.


Gamma-amino-beta-hydroxy butyric acid stimulates prolactin and growth hormone release in normal women. The influence of gamma-amino-beta-hydroxy butyric acid (GABOB) treatment on pituitary function has been investigated in this study. Different doses (50 x 100 mg) of GABOB were iv injected into three and six normal women, respectively. PRL and GH plasma levels were measured before and after the injection. The treatment with 150 mg GABOB, performed in another two normal women, was interrupted because of side-effects (loss of consciousness etc.) due to the treatment. The treatment with 50 mg GABOB did not induce significant variations of the two hormones; however, significant increases of PRL (P less than 0.05) and GH (P less than 0.01) plasma levels were observed after injection with 100 mg GABOB. The present data suggest that gamma-amino butyric acid (GABA) itself of GABAergic drugs might play an important role in the control of hypothalamic-pituitary function.


L-dopa absorption and the pituitary-hypothalamic axis. Administration of oral L-dopa is often used as a neuropharmacological probe to evaluate the pituitary hypothalamic axis. The effect of gastrointestinal absorption of L-dopa on the changes in plasma GH, PRL, and body temperature which occur after ingestion of this amino acid is unknown. Plasma L-dopa, GH, PRL, and rectal and skin temperatures were measured in 14 male volunteers after oral administration of 1.0 g measured in 24 men after random administration of L-dopa and a placebo. L-Dopa levels rose to 1.85 +/- 1.33 microgram/ml (mean +/- SD), but maximum plasma levels occurred at variable times from 30-230 min after drug administration. Plasma GH levels increased to 23.7 +/- 14.7 ng/ml, while PRL levels fell to 46.7 +/- 12.3% of the mean basal values. Rectal temperature decreased significantly in 3 of the men after L-dopa ingestion. Plasma GH levels after L-dopa correlated with the absorption of the drug (P less than 0.05) and inversely with the basal level of GH before L-dopa administration. There was no correlation between the basal PRL level or basal body temperature and the magnitude of the fall in PRL or body temperature after L-dopa administration. The variability of responses in GH, PRL, and body temperature after oral L-dopa ingestion is not the result of differences in  absorption in the amino acid alone, and indicate either that there is a different sensitivity in the mechanisms that stimulate GH secretion and lower plasma PRL and body temperature, or that L-dopa acts at different sites to bring about each of these changes.


Nomifensine: diagnostic test in hyperprolactinemic states. Nomifensine, an antidepressant agent which activates dopamine (D) neurotransmission mainly by inhibiting DA reuptake in the central nervous system, was administered either to puerperal lactating women or to subjects with nonpuerperal hyperprolactinemia. In 10 postpartum women and in 7 women with no evidence of PRL-secreting tumor, oral administration of nomifensine (100 or 200 mg, respectively) induced in the following 5 h a clear-cut inhibition of plasma PRL levels; in 10 patients with PRL-secreting tumors, the drug did not lower plasma PRL levels. In 2 of these patients nonsupressibility of plasma PRL levels to nomifensine was the only indication of the existence of a pituitary microadenoma. It is proposed that acute nomifensine testing may be a valid neuropharmacological tool for discriminating between individuals with and without pituitary adenoma.


Specific 5 alpha-dihydrotestosterone receptors in human gingiva. The cytoplasm of normal human male and female gingiva contains a receptor capable of specifically binding 5 alpha-dihydrotestosterone (DHT). This binding has a high affinity for DHT (Kd, approximately 2.2 x 10-9 M) and a low capacity (approximately 190 fmol/mg protein). The binding is extremely heat sensitive and exhibits a pattern of competition similar to that obtained with DHT receptors from other target tissues. The demonstration of a specific DHT receptor in human gingiva provides the first direct biochemical evidence that this tissue may function as a target organ for androgens. There was no correlation between the Kd in normal tissue and gingival hyperplasia or between the Kd or number of binding sites and the age or sex of the patient. However, there sites and the age or sex of the patient. However, there was a significant difference (P less than 0.0005) between the amount of DHT-binding sites per mg protein in normal tissue as compared to gingival hyperplasia (drugs or pregnancy).


LH and melatonin secretion patterns in pubertal boys. Four normal pubertal boys had plasma LH and melatonin measured at 20-minute intervals for 24-hours. All four subjects showed a significant augmentation of LH and melatonin during nocturnal sleep. There was also a significant correlation between the LH and melatonin levels (P less than 0.001). These data indicate that the peripheral concentrations of melatonin which occur during sleep are insufficient to prevent spontaneous LH secretion during puberty.


The diseased eye in Zambia.

The diseased eye in Zambia.


Some spurious parasitic infestations of man.


Prescribing habits in general practice.

Prescribing habits in general practice.


Small bowel rupture due to blunt abdominal trauma. Fourteen men with traumatic rupture of the small gut are analysed. Seven had alcohol intoxication. The diagnosis was made pre-operatively in eight. Ileal ruptures were the commonest, (11 of 14). Two patients died.


The prevalence and pattern of eye diseases in the Western Province, Zambia.


Anaemia in pregnancy--a report of two trials. In two separate trials, 140 cases of Pregnancy Anaemia were investigated in the University Teaching Hospital, Lusaka. The distribution of anaemia was as follows: Iron deficiency 118 (84.2%); dual deficiency 15 (19.7%); haemolytic five (35%); and megaloblastic 2 (1.4%). Anaemia with megaloblastic change was more common in the second study.


Isolation of Acinetobacter species in Lusaka.


Road accidents in greater Lusaka--a three-year survey.


A clinical study of haematemesis and malaena.


A review of autopsies at the University Teaching Hospital, Lusaka, 1975. Findings in all clinical autopsies performed in 1975 are presented. The autopsy rate for all deaths was 17%, it was only 10% in childhood deaths, but rose to nearly 34% if stillbirths and neonatal deaths are excluded. The main causes of death are classified in major fields. In adults neoplasms were the commonest cause of death with acute infections and cardiac diseases following in order of importance. The value of the clinical autopsy is briefly discussed.


The treatment of sepsis in superficial burns: effect of 1% Silver Sulphadiazine. One hundred patients with superficial burns were treated by the exposure method under ordinary ward conditions. Topical 1% Silver Sulphidiazine ("Flamazine") was used under controlled conditions. The exposure technique, with judicious local cleaning, resulted in spontaneous healing in 42% of cases. Topical "Flamazine" was used in 58% of cases. It was found to be soothing, giving patients instant relief of pain. It arrested crack and fissure formation with bleeding, especially in burnt areas in the neck and about major joints. It expedited healing; an astringent effect was also observed. It was concluded that the exposure technique, with topical "Flamazine", was beneficial in the treatment of superficial burns, obviating the routine daily bathing of the burnt.


Blood supply and position of the vermiform appendix in Zambians. The arterial blood supply, position, and length of the appendix were studied 103 Zambian cadavers. In 39.8%, more than one appendicular artery was found. In position, 43.6% were pelvic, and 20.3% retro-cecal. The average length of the appendix was 12.0 cm in males, and 11.4 cm in females. The prevalence of the dual blood supply and pelvic position, may partly explain the recorded rarity of appendicitis among Africans.


Air pollution in the region of Kafue industrial estate--a preliminary report.


Pulmonary tuberculosis in adults.

Pulmonary tuberculosis in adults.


Initial management of pulmonary tuberculosis in Lusaka, 1976. The records of 395 patients diagnosed in the Lusaka UTH as having pulmonary tuberculosis (TB) in 1976 were examined. A total of 4,308 patient days were spent by 319 TB patients on treatment at UTH: average 12 beds a day. Thirty (8%) absconded from the UTH: 80% were later transferred to Kabwe or Kafue Gorge. Initial diagnosis was made by smear only in 71% of cases; the known resistance rate in Zambia is about 25%. Treatment was variable: 86% were started on streptomycin and thiazine, about 50% of sputum-negative cases on triple regimes, and old cases were also sometimes restarted on streptomycin and thiazine. Ways of advancing TB control in Lusaka were suggested.


A clinical study of Osteomyelitis and septic arthritis. Sixty-nine cases of Osteomyelitis, and 27 of septic arthritis have been presented. 69/96 (71%) were children below 12. The sites frequently involved were tibia, femur and humerus. Septic arthritis commonly involved the knee. The commonest organism was Penicillin - resistant Staphylococcus aureus. Though we sought but failed to establish that overt clinical malnutrition was aetiologically important, since 54% were well-fed children, the virulence of the sepsis in which an entire bone shaft may die is disturbing but unexplained. Whereas arthrotomy plus antibiotics gave uniformly good results for septic arthritis, in osteomyelitis, no single treatment regime was outstanding. We would recommend the tetracyclines, (eg. "Reverin"), in addition to appropriate surgery, as a routine.


Thyrotoxicosis in the Zambian.

Thyrotoxicosis in the Zambian.


Hepatitis B surface antigenaemia: incidence and significance in Zambian blood donors. Forty-eight (5.0%) of 966 healthy Zambian blood donors were positive for hepatitis B surface antigen (HBsAg) when tested by the turkey erythrocyte passive haemagglutination (TEPHA) method. Twenty-six were investigated in detail, but only one blood donor was found to have liver disease, and this was thought unlikely to be causally related to HBsAg (alcohol-induced fatty infiltration). It is recommended however, that blood donors should be screened for HBsAg. Positive individuals should be rejected but their serum tested for aspartate transaminase (AST), and, if elevated, a liver biopsy performed. This ideal policy is not practicable in all tropical hospitals.


Paraplegic Centre of Zambia.

Paraplegic Centre of Zambia.


A study of 100 consecutive cases of measles.


Coronary heart disease--the doctor's dilemma.


Urophytobezoar in the stomach.

Urophytobezoar in the stomach.


Adverse reactions to methyldopa with particular reference to hypotension. Of 26,294 consecutive patients monitored in a comprehensive drug surveillance program, 1067 (4 per cent) received methyldopa for treatment of hypertension. Adverse reactions attributed to methyldopa were reported in 149 patients (14 per cent), the most frequent being hypotension. Life-threatening adverse effects were reported in nine patients (6 per cent of reactors)--the major problems being hypotension associated in several patients with signs of cardiac or cerebral ischemia. Hypotension attributed to methyldopa was more frequent in younger patients, in those with uremia, in lighter subjects, and in those receiving a high daily dose. Marked interaction between these factors was demonstrated and eightfold differences in the frequency of hypotension were observed in different sub-groups of methyldopa recipients. Adverse effects other than hypotension were reported infrequently and did not correlate well with the previously mentioned factors. The findings suggest that methyldopa therapy should be commenced cautiously in younger patients, in the non-obese, and in those with impairment of renal function as manifest by elevated blood urea nitrogen levels.


Animal bites and injuries--indications for metronidazole.


Common pulmonary vein atresia.

Common pulmonary vein atresia.


The surgical treatment of pressure sores.


Tibio-fibular synostosis for the treatment of tibial defects.


The preparation and use of a formulary in a provincial hospital.


An evaluation of the results of left ventricular aneurysmectomy: use of a simplified method for analysis of the left ventriculogram. Twenty-three patients underwent left ventricular aneurysmectomy without coronary artery bypass or other surgical procedure. Fourteen patients (Group 1) benefitted from surgery, and nine fared poorly (Group 2), including the four postoperative deaths. Among the 19 survivors, 17 had postoperative catheterizations. Pre- and postoperative left ventriculograms in the right anterior oblique projection were analyzed by planimetry of the aneurysmal and non-aneurysmal areas. This method provided data favorably altered by surgery in the improved patients and unchanged in the others. None of the preoperative ventriculographic measurements effectively separated the postoperative patient groups. The poor results in the Group 2 patients were of heterogeneous origin arising from pre-, peri- and postoperative factors. The more important factors were the largest and smallest aneurysms, surgically induced mitral insufficiency, and progressive coronary artery disease. Thus, the improvement in surgical results from better angiographic preoperative case selection is possible, but limited.


Coronary artery to pulmonary artery fistulas. Twelve patients with a total of 14 coronary artery to pulmonary artery fistulas were discovered at the time of diagnostic coronary angiography. Six patients had severe coronary artery disease, five patients had normal coronary arteriography, one patient had insignificant coronary artery disease, and one patient had rheumatic heart disease. Only two patients had characteristic continuous murmurs; one patient had a normal coronary angiogram, and the second patient had severe coronary artery disease. Ten fistulas originated from the left anterior descending artery, three from the right coronary artery, and one from the left circumflex artery. The fistulas were either composed of one large (five fistulas) or one or more small channels (seven fistulas) or poorly defined plexiform channels (two fistulas). Hydrogen studies performed in two patients were negative and dye dilution curves performed in all patients were normal. In only four out of the six patients with severe coronary artery disease, the fistulas originated from a diseased vessel and in each case the origin was proximal to the narrowing. The pathogenesis and functional role of these fistulas is largely unknown.


Permanent urinary diversion in Africa.

Permanent urinary diversion in Africa.


Migraine and the mitral valve prolapse syndrome. We believe there is a significant association between migraine and the prolapse mitral valve syndrome. Propranolol is the drug of choice in these patients for the treatment and prevention of migraine. Increased platelet aggregability may be the common pathophysiologic mechanism as relates to emboli from the valve and possibly in strokes related to migraine. Recognition of the association of the two syndromes will result in appropriate subacute bacterial endocarditis prophylaxis for patients at risk as well as prevention of improper medication to those patients with migraine who are at risk for stroke.


Mass casualties: a seminar.

Mass casualties: a seminar.


Oesophageal atresia.

Oesophageal atresia.


Leukocyte function after aortic valve replacement. Leukocyte function was studied in patients with prosthetic heart valves by oxygen consumption measurements during phagocytosis of polystyrene latex particles. The consumption reflects the phagocytotic capacity of the cells. In 38 patients with Starr-Edwards aortic ball valves the mean oxygen consumption was 3.95 nanoatoms per minute per 10(6) leukocytes, as compared to 4.15 in 50 healthy subjects, the difference not being statistically significant. The number of leukocytes per ml. of blood and the distribution of cell types was quite similar in the two groups, although slightly more younger cells were found in the patients. It is concluded that the capacity for phagocytosis is not significantly reduced after aortic ball valve implantation.


Investigation of the infertile couple.

Investigation of the infertile couple.


Quinidine pharmacokinetics in patients with cirrhosis or receiving propranolol. Quinidine pharmacokinetics (half-life, volume of distribution, and clearance) as well as protein binding were evaluated following a single 200 mg. oral dose of quinidine sulfate in eight control patients, in eight patients with moderate to severe cirrhosis, and in seven patients receiving 40 to 400 mg./day of propranolol. Patients with cirrhosis had a significantly longer quinidine half-life (9 +/- 1 hr; p less than .01) when compared to control patients (6 +/- 0.5h). This was not related to a reduced quinidine clearance rate but rather to an increase in quinidine volume of distribution (4.1 +/- .4 L./Kg. in cirrhotic patients vs 2.6 +/- 1 L./Kg. in control patients; p less than .01). Abnormal quinidine binding (greater than 25 per cent unbound fraction) was noted in seven of the eight cirrhotic patients. In contrast, patients receiving propranolol had a normal quinidine half-life of 6 +/- 0.5 hr. However, these patients had a significantly reduced quinidine clearance (3.3 +/- .7 ml./min./Kg. vs. 5.3 +/- .5 ml./min./Kg. in controls; p less than .05) and higher peak concentrations (1.25 +/- .20 micrograms/ml. vs. .80 +/- .5 micrograms/ml. in controls; p less than .05). Therefore in patients receiving propranolol, quinidine levels may be higher than expected shortly after dosage, and therefore a potential for transient toxicity exists in these patients. Maintenance quinidine dosage may have to be reduced in patients with moderate to severe hepatic cirrhosis, but not in patients receiving propranolol. Total quinidine concentration measurement underestimate free quinidine concentrations in most cirrhotic patients.


Conflicts in coronary care.

Conflicts in coronary care.