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T. Clausen, J. Elbrink and B.R. Martin

Several years ago, it was suggested that Ca++ ions might be involved in the stimulation of sugar permeability seen during muscular contraction (Holloszy & Narabara 1967).

More recently, experiments with epididymal fat pads suggested that lipolytic hormones and metabolic poisons, which stimulate 3-0-methylglucose transport (Clausen 1969a), can induce a release of Ca into the cytoplasm (Clausen 1970). In the isolated rat soleus muscle, hyperosmolarity, metabolic poisons and caffeine, which stimulate 3-0-methylglucose transport (Clausen et al. 1970, Kohn & Clausen 1971) were found to augment the resting tension and the rate coefficient of 45Ca-release (Elbrink et al., in preparation). Furthermore, exposure to Na+free buffers or inhibition of the active Na+-K+-transport, which leads to stimulation of sugar transport in isolated fat cells (Ho et al. 1966, Letarte & Renold 1969), was found to increase the uptake of 45Ca in this preparation (Fig. 1).

These observations suggested that

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Roman B. Melnyk and J. M. Martin

Abstract. We have previously shown that [125I]insulin binding to medial hypothalamic receptors is attenuated following 14 days of food restriction. Such rats are characterized by considerably reduced circulating insulin levels with unchanged hypothalamic insulin concentration. The present data demonstrate that, in contrast to the effects of starvation, [125I]insulin binding to hypothalamic receptors from rats made hyperinsulinaemic by daily injections of protamine zinc insulin (4–6 U/rat/day for 14 days) is unaffected by this manipulation, even though hypothalamic insulin concentration in insulininjected animals was significantly higher than in salineinjected controls. Insulin binding to partially purified membranes from the medial hypothalamic region was significantly greater than that from the lateral area, confirming a finding in our earlier study. Insulin treatment was associated with slight reductions in maximal insulin-binding capacity of medial hypothalamic receptors, a tendency which appeared to be compensated by reciprocal changes in receptor affinity for this hormone. The data indicate that hypothalamic insulin receptors are not regulated by peripheral or even central insulin levels per se; it appears, rather, that some other, as yet unidentified, correlate(s) of significantly altered food intake and/or body weight can modify hypothalamic insulin receptor function. Perhaps such modifications could, in turn, participate in the activation of regulatory mechanisms involved in correcting energy imbalance.

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Roman B. Melnyk and J. M. Martin

Abstract. In order to determine whether insulin binding to receptors in the central nervous system can be modified by changes in energy balance, hypothalami from 48 h food deprived and 14 day food restricted (8 or 4 g chow/day) rats were removed and insulin binding to partially purified membranes from both medial and lateral hypothalamic regions was studied. Hypothalamic insulin concentration was measured in similarly treated animals. Although hypothalamic insulin concentration did not vary, insulin binding to lateral receptors was significantly lower than that obtained from the medial region. After prolonged food restriction, binding to medial receptors was significantly reduced in comparison to controls, whereas binding in the lateral region remained unchanged; differences were most pronounced at near-physiological insulin concentrations. Changes in per cent specific [125I]insulin binding were associated with corresponding changes in maximal insulin-binding capacity, the latter being inversely related to receptor affinity for this hormone. These results are consistent with the hypothesis that insulin, acting via hypothalamic receptors, may serve as a metabolic feedback signal linking the periphery with central body weight regulatory mechanisms.

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F. I. R. Martin and A. B. G. Carden

ABSTRACT

Two men with chorionepithelioma and gynaecomastia are described. In both, urinary oestrogens (Brown et al. 1957) were similar with very high total oestrogens and an excess of oestrone. Urinary gonadotrophins were also elevated. Autopsy examination in one case revealed a seminoma of the testis in association with widespread chorionepithelioma metastases and the presence of interstitial cell hyperplasia and tubular atrophy in the unaffected testis. It is concluded that the gynaecomastia was produced by excess oestrogens due to the action of chorionic gonadotrophin on the interstitial cells of the testis.

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G. Tolis, L. Kovacs, H. Friesen and J. B. Martin

ABSTRACT

Ten patients with active acromegaly were studied. In 9 plasma GH levels failed to suppress after glucose (OGTT), in 8 an increase in serum GH occurred after thyrotrophin releasing hormone (TRH). After L-Dopa, 4 patients showed no change in serum GH, 3 exhibited a decrease and in 3 an increase in serum hGH occurred. With a combined insulin (ITT) and arginine (ATT) test, 2 patients exhibited an increase in hGH, and in 6 no change occurred. Fasting serum GH concentration was less than 11 ng/ml in 5 patients. Basal prolactin (hPRL) levels were normal in all patients including two with galactorrhea. L-Dopa suppressed and TRH stimulated hPRL secretion in all, but the responses which were seen were subnormal. Hydrocortisone infusion in two acromegalics did not affect the prolactin induced increase after TRH but blunted the GH increase after TRH.

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M. T. Mano, B.J. Potter, G. B. Belling, D. M. Martin, B. G. Gragg, J. Chavadej and B. S. Hetzel

Abstract.

Studies have been carried out to investigate the role of maternal and fetal thyroid function in the effects of iodine deficiency on fetal brain development in sheep. Iodine deficiency was established with an especially prepared low-iodine diet of maize and pea pollard. The iodine-deficient sheep were mated and at the end of the second trimester of pregnancy (100 days gestation) were divided into groups which received either a sc injection of T4 or 3,5-dimethyl-3'-isopropyl-L-thyronine or an im injection of iodized oil. At 140 days gestation (10 days prior to parturition) comparison of the fetuses delivered by hysterotomy revealed that the retarded fetal brain development observed in iodine deficiency was greatly improved by T4 and by iodized oil. However, T4 and iodized oil failed to correct the reduction in the number and the increase in the length of synaptic appositions which were observed in the fetal cerebral cortex after iodine deficiency. In addition, the histological appearance of the fetal thyroid gland and the levels of plasma thyroid hormones were restored to normal. The administration of 3,5-dimethyl-3'-isopropyl-L-thyronine had no effect on the retarded fetal brain and body development of the iodine-deficient fetuses. The lack of response may be due to the inability of 3,5-dimethyl-3'-isopropyl-L-thyronine to cross the ovine placenta as no reduction in the abnormally elevated fetal plasma TSH was observed in spite of a fall in maternal plasma TSH and apparent restoration of maternal thyroid function. It is concluded that the retarded fetal brain development observed during iodine deficiency in sheep can be substantially improved by iodized oil or to a lesser extent by T4 administration at 100 days gestation and that this is dependent on the restoration of both maternal and fetal thyroid function which supports previous observations from this laboratory following fetal and maternal thyroidectomy. The persistence of some effects of iodine deficiency on the fetal brain suggests that irreversible damage may have occurred.

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D J Handelsman, B B Yeap, L Flicker, S Martin, G A Wittert and Lam P Ly

Aim

The age-specific population profiles in men of circulating testosterone and its two bioactive metabolites dihydrotestosterone (DHT) and estradiol (E2) across the adult lifespan and its determinants are not well described.

Objective

Our objective was to deduce smoothed age-specific centiles of circulating testosterone, DHT, and E2 in men using pooled data from population-based studies in three Australian cities from liquid chromatography–mass spectrometry steroid measurements in a single laboratory.

Design, setting, and participants

We pooled data of 10 904 serum samples (serum testosterone, DHT, E2, age, height, and weight) from observational population-based studies in three major cities across Australia.

Main outcome measures

Age-specific smoothed centiles for serum testosterone, DHT, and E2 in men aged 35–100 years were deduced by large sample data analysis methods.

Results

We found that serum testosterone, DHT, and E2 decline gradually from ages 35 onwards with a more marked decline after 80 years of age. Higher weight, BMI, and body surface area as well as shorter stature are associated with reduced serum testosterone, DHT, and E2.

Conclusions

Among Australian men, there is a gradual progressive population-wide decline in androgen status during male aging until the age of 80 years after which there is a more marked decline. Obesity and short stature are associated with reduced androgen status. Research into the age-related decline in androgen status should focus on the progressive accumulation of age-related comorbidities to better inform optimal clinical trial design.

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Luis G. Martin, Milton S. Grossman, Thomas B. Connor, Lynn L. Levitsky, John W. Clark and Francine D. Camitta

ABSTRACT

The response of plasma growth hormone (GH) to insulin-induced hypoglycaemia (IIH) and arginine infusion (AI) was studied in 22 young males (ages 8 to 17 years) with short stature and absent or delayed sexual maturation, before and after androgen administration. During initial evaluation, 5 patients had blunted GH response to IIH, 12 responded subnormally to AI and 4 failed to respond normally to either stimulus. These same studies were repeated in each patient following androgen administration. The source of androgen was as follows: a) 5 days of testosterone propionate (25 mg intramuscularly daily) in 20 patients. b) Methyltestosterone, 10 mg t. i. d. orally for four days in the other 2 subjects. In almost every case, androgen administration resulted in raising the levels of fasting GH and enhancement of the GH responses to IIH and AI was observed. Patients manifesting subnormal GH responses to these stimuli before androgen consistently demonstrated a normal response when challenged with identical stimuli during androgen administration. Growth velocities during the year following these studies were significantly increased in most instances and the growth spurts correlated well with the progression of sexual maturation. Sustained improvement in the GH responses to IIH and AI were uniformly observed in 3 patients when repetitive studies were performed 8 to 12 months later during spontaneous advancing sexual development. The results indicate that brief androgen administration can be helpful in delineating the cause of growth retardation in boys with short stature and delayed sexual maturation, particularly when the diagnosis of isolated growth hormone deficiency is suspected. They also offer prognostic value in determining growth potential in this same group of young males.

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M S B Huda, T M Dovey, S P Wong, P J English, J C G Halford, P McCulloch, J Cleator, B Martin, J Cashen, K Hayden, M A Ghatei, S R Bloom, J P H Wilding and J H Pinkney

Objective

Short-term fasting is associated with increased GH pulsatility and mobilisation of fats, but underlying mechanisms are unclear. We studied ghrelin's role during fasting and the effects of exogenous ghrelin on lipid mobilisation.

Design

Randomised placebo-controlled study.

Methods

In this study, ten controls (body mass index (BMI) 23.3±3.2), ten morbidly obese subjects (BMI 50.1±10.6) and six post-gastrectomy subjects (BMI 25.2±1.0) were fasted for 36 h undergoing regular blood sampling. On a separate occasion, subjects were infused with either i.v. ghrelin (5 pmol/kg per min) or saline over 270 min.

Results

Obese and post-gastrectomy subjects had lower ghrelin compared with controls (ANOVA, P=0.02) during the fast. Controls and gastrectomy subjects showed a similar increase in GH pulsatility, circulating non-esterified fatty acids (NEFA) and 3β-hydroxybutyrate (3 HB). Obese subjects had an impaired GH response (P<0.001), reduced excursions of 3 HB (P=0.01) but no change in NEFA excursions (P=0.09) compared with controls. Ghrelin infusion increased GH, NEFA and ketone bodies (ANOVA, P<0.0001) in all the three groups, but GH response was impaired in the obese subjects (P=0.001). Ghrelin also induced a significant (ANOVA, P=0.004) biphasic NEFA response to meals in all the subjects.

Conclusions

Despite low circulating ghrelin, gastrectomy subjects maintain a normal metabolic response to fasting, implying that ghrelin plays a minimal role. In contrast, infused ghrelin has significant effects on lipid mobilisation and induces a marked biphasic NEFA response to meals. Hence, ghrelin may play a significant role in meal-related substrate utilisation and metabolic flexibility.