THE INFLUENCE OF EXOGENOUS OESTRADIOL BENZOATE ON THE PITUITARY RESPONSIVENESS TO LHRH DURING THE PUERPERIUM IN WOMEN

The FSH and LH response to 25 μg LHRH was measured in lactating women and the results compared to a similar group in whom lactation was suppressed by administration of bromocriptine shortly after delivery. The response was also measured in both groups after “challenge” with oestradiol benzoate. In lactating women the FSH response to LHRH was diminished following the oestradiol challenge, as compared with that in unchallenged women. At the same time the LH responses were low in both circumstances, indicating a negative feedback effect of oestradiol. However, the oestradiol challenge resulted in a significantly increased response of FSH and LH to LHRH in bromocriptine-treated puerperal women, i.e. a positive feedback effect of oestradiol. We concluded that this and previous experiments favour the hypothesis that the lactational amenorrhoea during hyperprolactinaemia is caused by hypothalamic changes due to a predominance of the negative feedback system.     

MODULATION OF PITUITARY RESPONSIVENESS TO EXOGENOUS LHRH BY AN OESTROGENIC AND AN ANTI-OESTROGENIC COMPOUND IN THE NORMAL MALE

The effect of clomiphene (100 mg daily for 10 days) and ethinyl oestradiol (100 μg daily for 10 days) on the gonadotrophin response to synthetic LHRH has been investigated in two groups of five normal males. A third group of five men served as control group. LHRH, 25 μg, was injected intravenously on days 0, 4, 7 and 10 and the response of serum LH and FSH was monitored by radioimmunoassay. In contrast to the wide inter-individual variation of the response pattern, the intraindividual variation of the response to LHRH in the control group was small. Clomiphene induced a significant elevation of the baseline levels of LH and FSH after a few days of treatment; the pituitary responsiveness to LHRH, however, was significantly reduced. Oestrogen treatment resulted in a uniform suppression of both basal gonadotrophin levels and pituitary responsiveness. The decreased gonadotrophin response to LHRH during clomiphene treatment is thought to be caused by a relative and temporary pituitary depletion of the releasable gonadotrophin content. Although the suppression of LH and FSH response during oestrogen treatment may point to a direct inhibitory effect of oestrogen on pituitary gonadotrophin release, an indirect hypothalamic pathway, through suppression of endogenous LHRH, cannot be ruled out.     

STUDIES ON THE ROLE OF HISTAMINE IN HUMAN PITUITARY FUNCTION

To elucidate further the role of histamine in pituitary regulation, TRH and L-DOPA stimulation tests were performed with and without diphenhydramine, cimetidine, or betazole pre-treatment. Betazole blunted the GH response to L-DOPA and slightly enhanced the T3 response to TRH without altering the TSH or PRL increments. Neither diphenhydramine nor cimetidine had any acute effect on the hormonal responses examined. Histamine appears to play only a limited role in these aspects of human pituitary regulation.     

RAPID COMMUNICATION: A COMPARISON OF FREE T4 AND THE RATIO OF TOTAL T4 TO T4-BINDING GLOBULIN IN SERUM THROUGH PREGNANCY

Serum free T4 concentrations have been variously reported as either constant or falling in pregnancy. In this study, 122 serum samples from apparently normal pregnancies were used to derive euthyroid ranges throughout pregnancy for T4 and free T 4 (measured by the Amerlex kits) and for T4-binding globulin (TBG). The mean free T4 concentration fell with increasing gestational age, the range of values in the third trimester being narrower than the non-pregnant normal range. Evidence is reviewed which shows that the Amerlex free T4 assay is unaffected by the elevation of TBG in non-pregnant subjects. The decline in mean free T4 as pregnancy proceeds is in good agreement with the change in free T4 predicted by the falling T4/TBG ratio.     

PITUITARY RESPONSIVENESS TO GONADOTROPHIN-RELEASING AND THYROTROPHIN-RELEASING HORMONES IN EPILEPTIC PATIENTS RECEIVING CARBAMAZEPINE OR PHENYTOIN

Pituitary responsiveness to gonadotrophin-releasing (LHRH) and thyrotrophin-releasing (TRH) hormones was studied in 19 epileptic patients receiving long-term carbamazepine or phenytoin therapy and 14 normal control subjects. Baseline prolactin levels were normal in the patients; 2h after LHRH-TRH the prolactin levels in women on carbamazepine were significantly higher than in the controls, but apart from this, no other differences were found. Baseline LH levels were raised in male patients and the response to LHRH-TRH was exaggerated in all patients on carbamazepine. FSH levels were normal throughout. The exaggerated LH response is consistent with primary hypogonadism caused by enhanced sex hormone metabolism, secondary to hepatic enzyme induction by the antiepileptic drugs.     

LOW SERUM l-T3 LEVELS IN THE ELDERLY SICK: PROTEIN BINDING, THYROID AND PITUITARY RESPONSIVENESS, AND REVERSE T3 CONCENTRATIONS

Thyroid function was studied in thirty-five euthyroid geriatric inpatients to define the relative importance of T4 to T3 conversion or pituitary-thyroid dysfunction as a cause of low serum T3 concentrations. A previously reported finding of low serum total T3 levels was confirmed, and was associated with a fall in mean unbound T3 to 5.23 pmol/l (6.70 in younger normal subjects) and a rise in unbound T4 to 52.7 pmol/l (36.4 in normals). However, the protein binding of T3 and T4 was weaker in the patients (e.g. per cent unbound T4 increased 1.4 times) despite a mean increase in serum immunoreactive TBG concentration of 30%. Mean serum reverse T3 concentration (rT3) was nearly doubled in the patients (0.42 nmol/l compared with 0.24 in normals) but the correlation between high rT3 and low T3 was not close, and in a fifth of patients low T3 was not associated with high rT3. The T3 response to TSH injection was greater in patients with low T3 levels, and the T4 response smaller. The overall effect of TSH injection was to restore the previously increased T4 to T3 ratio of the patients to normal. The TSH response to TRH was absent in about a third of patients, and delayed in about another quarter, especially, although not exclusively so, in patients with low serum T3. The data suggest that several factors are concerned in the pathogenesis of low serum T3 concentrations in the elderly in hospital. Among these may be a shift in T4 deiodination from T3 to rT3, and hypothalamo-pituitary TSH dysfunction. But it appears that other undefined factors may be responsible (such as nutrition or steroid levels); the pathogenesis is probably not the same in all patients.     

THE ROLE OF TRIIODOTHYRONINE (T3) IN THE MAINTENANCE OF EUTHYROIDISM IN ENDEMIC GOITRE

Serum concentrations of triiodothyronine (T3), thyroxine (T4) and thyroid stimulating hormone (TSH) have been measured in subjects from an endemic goitrous area of New Guinea. An increase in TSH concentration and a decrease in T4 concentration was found in both goitrous and non-goitrous subjects, both abnormalities being more frequent in the goitrous group. In the majority of subjects (93%) the T3 level fell within the normal range. Euthyroidism appears to be preserved in the iodine deficient state by the continued production of normal amounts of T3, the intrinsic metabolic activity of T4 being relatively unimportant.     

FREE THYROID HORMONE LEVELS AND TSH RESPONSE TO TRH IN PATIENTS WITH AUTONOMOUS THYROID ADENOMATA AND NORMAL T3 AND T4

Free thyroid hormone levels together with basal and TRH stimulated TSH levels, have been determined in 50 patients with autonomous thyroid adenomata, who had normal serum total T3 and T4 values. Similar measurements were made in 33 healthy subjects. FT3 and FT4 plasma levels were significantly higher (P less than 0.01 and P less than 0.05 respectively), and basal and TRH stimulated TSH were significantly lower (P less than 0.05 and P less than 0.001 respectively) in the patients than in the controls. The TSH response to TRH was decreased in spite of normal free thyroid hormones in 25 patients and in a further ten both the delta TSH after TRH and the free fractions were normal. Eighteen patients were studied over periods from 4 37 months by repeating thyroid hormone levels and TRH tests. In six of them a change of these parameters toward toxicity was observed. The data obtained in the longitudinal study indicate that the values of free thyroid hormones and the result of the TRH test obtained by a single determination may represent different steps in the evolution of autonomous thyroid adenomata rather than a distinct pathophysiological condition.     

ROLE OF CHOLINERGIC MUSCARINIC PATHWAYS ON THE FREE FATTY ACID INHIBITION OF GH RESPONSES TO GHRH IN NORMAL MEN

In order to explore the mechanisms by which free fatty acids (FFA) inhibit GH secretion, we studied the effect of the acetylcholinesterase inhibitor pyridostigmine (120 mg p.o.) on the FFA blockade of GH responses to the administration of GHRH (100 micrograms i.v.) in seven normal subjects. GHRH-induced GH secretion was significantly reduced following elevation of circulating FFA levels by lipid-heparin infusion and significantly potentiated by previous pyridostigmine treatment. Peak GH levels following combined administration of pyridostigmine plus lipid-heparin plus GHRH were significantly higher (P less than 0.01) than after GHRH alone and significantly lower than after pyridostigmine plus GHRH (P less than 0.01). In conclusion, central cholinergic activation by pyridostigmine, with the presumed reduction in somatostatin discharge, reversed the blocking effect of FFA on GHRH-stimulated GH release. Conversely, FFA were able to reduce even a maximal GH stimulation by pyridostigmine plus GHRH.     

THE BIOACTIVITY OF IMMUNOREACTIVE ADRENOCORTICOTROPHIN IN HUMAN BLOOD IS DEPENDENT ON THE SECRETORY STATE OF THE PITUITARY GLAND

A highly sensitive bioassay, using preincubated purified isolated rat adrenal cells, has been developed for measuring plasma ACTH. This bioassay enables detection of ACTH in plasma of about 0.9 pmol/l. Bioactive ACTH (B-ACTH) plasma levels were determined during insulin-induced hypoglycaemia in 12 female subjects and the values were compared with immunoreactive ACTH (I-ACTH) levels. The mean (+/- SD) basal B-ACTH level amounted to 1.7 +/- 0.8 pmol/l, the mean I-ACTH to 2.9 +/- 1.4 pmol/l. The highest mean B-ACTH plasma value was found 30 min after insulin injection: 14.7 +/- 15.7 pmol/l (I-ACTH: 12.8 +/- 9.9 pmol/l). By 90 min the B-ACTH level had returned to baseline (1.6 +/- 0.8 pmol/l), whereas the I-ACTH level was still significantly higher (5.4 +/- 2.7 pmol/l) than at time zero. Remarkably, the B-ACTH to I-ACTH ratio (B/I ratio) showed a biphasic profile during the insulin tolerance test, the ratio increasing from 0.60 +/- 0.77 at time zero to 1.08 +/- 0.35 at the ACTH peak, and decreasing after that to a lower value of 0.33 +/- 0.11 at 90 min. From these results it is concluded: (1) in the morning hours a considerable amount of circulating I-ACTH has no steroidogenic activity; (2) the B/I ratio temporarily increases immediately after insulin injection but gradually decreases afterwards to values half the baseline level at 90 min. Whereas this decrease at 90 min can be explained by differences in disappearance rates, the increase of B-ACTH relative to I-ACTH at 30 min indicates that estimations of immunoreactive ACTH reflect the biological activity of newly released ACTH with greater precision than at steady state level. Thus, the B/I-ACTH ratio can be used as a tool for measuring the state of the pituitary releasing activity.     

EFFECT OF STILBOESTEROL THERAPY ON THYROTROPHIN-RELEASING HORMONE (TRH) RESPONSIVENESS IN MALES

TRH responsiveness was investigated in twenty-four males (aged 66-83 years) undergoing stilboesterol therapy for carcinoma of the prostrate. Twelve were taking 2-6 mg daily by mouth for periods of 5 days to 12 months (mean 5 months) (Group A) and the remainder were on daily i.v. doses of 250-500 mg for periods of 3-10 days (mean 8 days) (Group B). In the former group TRH responsiveness was enhanced compared to age matched controls. A contrary effect was observed in the latter group in that the group mean TRH response was significantly lower than that of Group A or of the control group. Basal serum TSH values were unchanged in Group A compared to controls, but a significant elevation in the basal mean value was observed in Group B. The mechanism of action of stilboesterol in the subjects studied remains to be elucidated. Our data are in keeping with either a hypothalamic or pituitary locus for such actions.     

CHANGES IN THE RESPONSIVENESS OF LUTEINIZING HORMONE SECRETION TO INFUSION OF THE OPIOID ANTAGONIST NALOXONE THROUGHOUT MALE SEXUAL MATURATION

The present study investigated the time of male sexual maturation during which hypothalamic inhibitory opioid activity can be detected. Normal prepubertal (Tanner stage G 1 (Ts-G1) (n = 4], early pubertal (Ts-G2 (n = 5], pubertal (Ts-G3 (n = 4), and Ts-G4 (n = 2] and adult subjects (Ts-G5 (n = 4] receives a rapid infusion of the selective opiate antagonist nalocone (NAL) (20 mg over 10 min). LH secretion was assessed by frequent (every 10 min for 2 h) venous sampling before and after administration of the opiate blocker, as well as by the LH response to exogenous GnRH. All but one (a Ts-G2 subject) pubertal boys showed aprompt and sustained increase in serum LH concentrations after NAL administration, as disclosed by the areas under the LH curve (aLHc) calculated from samples obtained before and after NAL infusion (aLHc in four Ts-G2 responders, 162 +/- 20 (mean +/- SEM) vs 314 +/- 56 mIU/ml/min before and after NAL respectively, P less than 0.025; Ts-G3, 227 +/- 35 vs 362 +/- 56 mIU/ml/min, P less than 0.025; Ts-G4 and Ts-G5, 432 +/- 77 vs 687 +/- 91 mIU/ml/min, P less than 0.05). In contrast, none of the prepubertal children had significant changes in LH secretion after the NAL challenge (154 +/- 17 vs 154 +/- 9 mIU/ml/min). Although all NAL responders exhibited serum testosterone (T) levels above 5 nmol/l, a positive correlation between individual T values and magnitude of LH responses to NAL was not found. All subjects had significant serum LH increments after GnRH administration. In a second series of studies, additional groups of Ts-G1 subjects were primed during 5 days either with GnRH alone or with GnRH plus sex steroids (ethinyl oestradiol 12.5 micrograms/12 h or testosterone enanthate 1.8 mg/kg body weight (single dose], before NAL administration, to investigate whether hypothalamic opioid activity might be unmasked by additional sex steroids. None of the priming schemes significantly modified the pituitary LH responses to NAL infusion (GnRH-primed group, 145 +/- 48 vs 139 +/- 43 mIU/ml/min before and after NAL, respectively; GnRH plus ethinyl oestradiol-primed group, 124 +/- 42 vs 107 +/- 34 mIU/ml/min; GnRH plus testosterone enanthate-primed group, 64 +/- 10 vs 57 +/- 24 mIU/ml/min). This study suggests that the development and/or maturation of the opioid control of LH secretion is temporally related with the onset of puberty.(ABSTRACT TRUNCATED AT 400 WORDS)     

THE ROLE OF INTRARENAL NITRIC OXIDE IN THE NATRIURETIC RESPONSE TO DOPAMINE-RECEPTOR ACTIVATION

Dopamine and dopamine-1 receptor agonists produce diuresis and natriuresis by causing changes in renal hemodynamics and by the activation of dopamine-1 receptors located within the various regions of the nephron. Nitric oxide plays an important role in the maintenance of systemic and regional hemodynamics. The present study was undertaken to investigate the effect of locally generated nitric oxide on renal function and its potential influence on the renal responses to dopamine-1 receptor agonists. The intrarenal infusion of a nitric oxide synthase inhibitor, L-NAME, (50 μg/kg min for 90 min) in anesthetized rats produced significant decreases in urine volume, urinary sodium excretion, glomerular filtration rate and fractional sodium excretion. These changes in renal function were associated with a concomitant decrease in urinary nitrate excretion, an indicator of nitric oxide release. However, L-NAME at this dose did not produce any significant changes in mean arterial pressure or heart rate. Intravenous infusion of fenoldopam (1 μg/kg min for 30 min), a selective dopamine-1 receptor agonist, produced diuresis and natriuresis without causing any changes in mean arterial pressure and heart rate. These renal effects of fenoldopam were significantly attenuated in animals that received the simultaneous infusion of L-NAME (intrarenal). Similar results were obtained with dopamine in that the natriuretic and diuretic response to dopamine was also attenuated during simultaneous infusion of dopamine with L-NAME. In addition, the diuresis and natriuresis produced by fenoldopam and dopamine was associated with increases in urinary nitrate excretion. Interestingly, these increases in the nitrate levels seen with fenoldopam and dopamine were also significantly reduced in the presence of L-NAME. These results indicate that intrarenal nitric oxide plays an important role in regulating renal sodium excretion and that an intact renal nitric oxide system is required for the full expression of diuretic and natriuretic response seen during dopamine-1 receptor activation.     

CD8~ T细胞在CD4~ T细胞耗竭小鼠卡氏肺孢子虫肺炎的致病作用(英文)

[目的 ]验证参与卡氏肺孢子虫致病过程中 ,宿主炎性反应及其对肺功能的影响。 [方法 ]:将小鼠CD4 T细胞耗竭或将小鼠CD4 和CD8 T细胞都耗竭后 ,经气管接种卡氏肺孢子虫。观察在CD8 T细胞缺如或存在的情况下 ,小鼠呼吸机能的改变和肺炎的程度。 [结果 ]耗竭CD4 和CD8 T细胞后 ,小鼠虽发生PCP ,但呼吸频率无明显加快 ,肺组织损伤程度也较轻。相反 ,仅耗竭CD4 T细胞保留CD8 T细胞的小鼠的呼吸频率明显加快 ,肺内炎性细胞反应和肺组织损伤程度均较重。支气管肺泡灌洗液 (BALF)中的CD8 T细胞和嗜中性白细胞的数量明显增多。 [结论 ]PCP的致病过程中 ,宿主的炎性细胞反应对肺功能有直接损伤作用 ,其中CD8 T细胞似起主要作用。     

DELAYED ADJUSTMENT OF THE PITUITARY RESPONSE TO VARIATIONS IN CIRCULATING THYROID HORMONES IN A CASE OF SUBACUTE THYROIDITIS

In a case of subacute de Quervain thyroiditis characterized by a period of pronouced hypermetabolism followed by hypometabolism, levels of T4, T3 and the TSH response to TRH were repeatedly measured. As expected, the response to TRH was absent or low during the hypermetabolic phase, high during the hypometabolic phase and returned to normal with recovery. However, at the beginning and at the end of the hypometabolic phase, while circulating levels of T3 and T4 both lay in the subnormal range, two periods of inadequate response to TRH could be demonstrated. During the first period, the response to TRH was zero or very small; during the second period, stimulation by TRH was exaggerated. The response to TRH thus depends not only on the level of circulating thyroid hormones but on other factors such as the previous state of pituitary stimulation or inhibition.