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Search for other papers by E. W. HILLHOUSE in
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Search for other papers by M. T. JONES in
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SUMMARY
The rat hypothalamus in vitro preparation was used to investigate the effect of bilateral adrenalectomy, with and without replacement therapy, on the release of corticotrophin-releasing factor (CRF). Corticotrophin-releasing factor was estimated using 48 h basal hypothalamic lesioned assay rats and corticosterone production of excised adrenals was used as the end point.
Bilateral adrenalectomy resulted in depletion of hypothalamic CRF content within the first 2 h after the operation but this effect was prevented by replacement therapy with corticosterone. Thereafter, the hypothalamic CRF content returned to values not significantly different from the intact control level. Bilateral adrenalectomy caused an increase in both basal and acetylcholine-induced release of CRF and it is suggested that corticosteroids exert a negative feedback effect on the hypothalamus.
Search for other papers by Daniel M Kelly in
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Department of Human Metabolism, Robert Hague Centre for Diabetes and Endocrinology, Medical School, The University of Sheffield, Sheffield S10 2RX, UK
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Coronary heart disease is a leading cause of premature death in men. Epidemiological studies have shown a high prevalence of low serum testosterone levels in men with cardiovascular disease (CVD). Furthermore, a low testosterone level is associated in some but not in all observational studies with an increase in cardiovascular events and mortality. Testosterone has beneficial effects on several cardiovascular risk factors, which include cholesterol, endothelial dysfunction and inflammation: key mediators of atherosclerosis. A bidirectional relationship between low endogenous testosterone levels and concurrent illness complicates attempts to validate causality in this association and potential mechanistic actions are complex. Testosterone is a vasoactive hormone that predominantly has vasodilatory actions on several vascular beds, although some studies have reported conflicting effects. In clinical studies, acute and chronic testosterone administration increases coronary artery diameter and flow, improves cardiac ischaemia and symptoms in men with chronic stable angina and reduces peripheral vascular resistance in chronic heart failure. Although the mechanism of the action of testosterone on vascular tone in vivo is not understood, laboratory research has found that testosterone is an L-calcium channel blocker and induces potassium channel activation in vascular smooth muscle cells. Animal studies have consistently demonstrated that testosterone is atheroprotective, whereas testosterone deficiency promotes the early stages of atherogenesis. The translational effects of testosterone between in vitro animal and human studies, some of which have conflicting effects, will be discussed in this review. We review the evidence for a role of testosterone in vascular health, its therapeutic potential and safety in hypogonadal men with CVD, and some of the possible underlying mechanisms.
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Department of Human Metabolism, Robert Hague Centre for Diabetes and Endocrinology, Medical School, The University of Sheffield, Sheffield S10 2RX, UK
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Testosterone is a hormone that plays a key role in carbohydrate, fat and protein metabolism. It has been known for some time that testosterone has a major influence on body fat composition and muscle mass in the male. Testosterone deficiency is associated with an increased fat mass (in particular central adiposity), reduced insulin sensitivity, impaired glucose tolerance, elevated triglycerides and cholesterol and low HDL-cholesterol. All these factors are found in the metabolic syndrome (MetS) and type 2 diabetes, contributing to cardiovascular risk. Clinical trials demonstrate that testosterone replacement therapy improves the insulin resistance found in these conditions as well as glycaemic control and also reduces body fat mass, in particular truncal adiposity, cholesterol and triglycerides. The mechanisms by which testosterone acts on pathways to control metabolism are not fully clear. There is, however, an increasing body of evidence from animal, cell and clinical studies that testosterone at the molecular level controls the expression of important regulatory proteins involved in glycolysis, glycogen synthesis and lipid and cholesterol metabolism. The effects of testosterone differ in the major tissues involved in insulin action, which include liver, muscle and fat, suggesting a complex regulatory influence on metabolism. The cumulative effects of testosterone on these biochemical pathways would account for the overall benefit on insulin sensitivity observed in clinical trials. This review discusses the current knowledge of the metabolic actions of testosterone and how testosterone deficiency contributes to the clinical disease states of obesity, MetS and type 2 diabetes and the role of testosterone replacement.
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Search for other papers by P. K. BRIDGES in
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In earlier studies (Bridges & Jones, 1967, 1968) we found a significant relationship between adrenocortical responses to the psychological stress of an oral university examination (2nd M.B. Anatomy examination) and body-build, assessed by means of phenotyping by the method of Parnell (1958). This assumes three basic components of physique: fatness (F), muscularity (M) and linearity (L). It was found that the mean plasma corticosteroid concentration at the time of the examination was significantly greater in the primarily linear group than in the mainly muscular students, and there was a significant negative correlation between the examination corticosteroid values and the muscularity scores (r = − 0·225; P < 0·05). One explanation for these findings would be that the muscular group was characterized by a lower sensitivity of adrenocortical response. It was decided to test this possibility using the methods of Landon, James, Wharton & Friedman (1967).
For the present study, 38 students
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Search for other papers by M. T. Jones in
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ABSTRACT
Female Wistar-derived rats with regular oestrous cycles were injected s.c. at 15.00 h on pro-oestrus with difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase. The drug (10–100 mg/rat) caused a dose-related reduction in the concentration of LH in plasma taken at 19.00 h (the time of the peak of the LH surge in this colony). There was also a dose-related reduction in the pituitary content of total polyamines. The reduction in the plasma concentration of LH was not due to the shifting of the time of the peak of the surge, as concentrations were significantly lower than control from 17.00 to 21.00 h, the overall reduction in total LH release being approximately 50%. The number of ova in the oviducts at 06.00 h next morning was significantly reduced by treatment with 50 mg DFMO/rat, by an average of 70%.
Injection of DFMO enhanced the fall in plasma oestradiol concentrations seen between 15.00 and 19.00 h, in a dose-related manner. It also prevented the rise in progesterone concentrations seen in control animals during this period. The ability of DFMO to prevent the rise in plasma concentrations of LH was not secondary to the effects of the drug on ovarian steroid production because DFMO also significantly reduced the LH surge in animals ovariectomized on dioestrus and given appropriate replacement injections of oestradiol and progesterone.
It seems possible that part of the action of DFMO is exercised at the hypothalamus, since when 50 mg DFMO/rat was given either 2 or 4 h before the expected peak of the LH surge, the LHRH content of the hypothalamus was significantly reduced at that time. These results suggest that activation of ornithine decarboxylase is a necessary prerequisite for a normal LH surge, and that this activation is steroid-dependent. This conclusion is borne out by results from direct observations on the activity of the enzyme in pituitary tissue incubated in vitro.
J. Endocr. (1988) 117, 447–453
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ABSTRACT
Uteri from mature baboons at various stages of the menstrual cycle were collected at autopsy. Transverse slices of the uteri were incubated with [3H]prostaglandins in Tyrode's buffer. Bound and free ligands were separated by filtration. Prostaglandin (PG) accumulation by the tissue slices was evaluated as a function of incubation time, PG type and concentration, temperature, wet weight of tissue and stage of the menstrual cycle. There was no significant difference in PG accumulation in response to PG type (PGE2 or PGF2α) or stage of the menstrual cycle. These results from baboon uteri were compared with those using baboon oviducts and also rabbit uteri and oviducts. Unlike the rabbit tissues, the baboon oviducts and uterine tissues did not exhibit specific net accumulation of prostaglandins.
J. Endocr. (1985) 106, 49–53
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The effect of various steroids on the functional activity of the rat hypothalamus in vitro was investigated. The addition of corticosterone (10−7 mol/l) for 30 min to the incubation medium inhibited immediately the release of bioactive corticotrophin releasing factor (CRF) by tissue induced by serotonin (2·6×10−8 mol/l). This was followed by a period lasting from 30 min (coincident with removal of the steroid from the medium) to 60 min when no inhibition was seen. Finally a second period of suppression of hypothalamic CRF activity in vitro was shown to be fully established 120 min after addition of the steroid. In more detailed investigations the latter inhibition was shown to occur when the tissue was exposed to the steroid (3×10−7 mol/l) for 5 or 30 min, but not for 1 min, and it was dose-related. Of other steroids investigated, progesterone in high concentrations (3 × 10−6 mol/l) suppressed to a small extent the functional activity of the hypothalamus in vitro but 17α-hydroxyprogesterone, 11α-hydroxyprogesterone, 11α,17α-dihydroxyprogesterone and 11-epicortisol had no effect on the delayed inhibition. Progesterone (10−7 mol/l) potentiated the ability of corticosterone (10−8 mol/l) to induce the delayed suppression of hypothalamic CRF activity in vitro. In contrast, 17α-hydroxyprogesterone, 11α-hydroxyprogesterone, 1 1α,17α-dihydroxyprogesterone and 11-epicortisol competitively antagonized this inhibitory action of corticosterone (3 × 10−7 mol/l) in a dose-related manner (1·5 × 10−8–3 × 10−8 mol/l). The action of the antagonist 11-epicortisol was similar whether it was added to the tissue in vitro before corticosterone or antagonist and agonist were added together. The functional characterization of steroid action on the hypothalamus may lead to a clearer understanding of the mechanism by which the compounds influence hormone release.
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Introduction
Intercellular communication is effected through the release and action of substances known as paracrine agents. Recent studies are providing increasing evidence that pituitary hormone secretion is under the control of paracrine as well as hypothalamic factors. The individual cell types within the rat anterior pituitary gland appear to be arranged in specific groups and juxtapositions, and this precise organization of cells provides an anatomical basis for an intercellular control system in the pituitary gland. There is good circumstantial evidence for a variety of paracrine interactions within the anterior pituitary gland, although the exact physiological functions of different proposed paracrine agents have yet to be fully elucidated. Many substances have been shown to affect the release of each of the pituitary hormones directly, and there is evidence that some of these are synthesized and released within the anterior pituitary and may therefore act as paracrine agents. Established and
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ABSTRACT
Gonadotrophin-releasing hormone (GnRH) stimulated the accumulation of inositol phosphates and prolactin secretion in anterior pituitary cells from young male rats. Saralasin ([Sar1,Ala8]-angiotensin II; a competitive antagonist of angiotensin II) inhibited the increase in both inositol phosphates and prolactin in a dose-dependent manner. Since angiotensin II has been shown to be a potent stimulus for inositol phosphate accumulation and prolactin secretion in the lactotroph, these findings suggest that angiotensin II acts as a paracrine agent, being released from the gonadotroph in response to GnRH and causing the lactotroph to release prolactin through an effect on phosphoinositide metabolism. The ability of GnRH to promote prolactin release was lost in pituitaries from older rats, and the increase in total inositol phosphate accumulation was less. These findings provide evidence of a physiological role for the presence of the renin–angiotensin system within the pituitary gland.
J. Endocr. (1988) 116, 367–371
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ABSTRACT
To study the potential role of GH-releasing hormone (GHRH) in maintaining circulating levels of GH during pregnancy, 302 maternal plasma samples were collected from non-fasted subjects at various stages of pregnancy and assayed for GHRH using a 'two-site' immunoradiometric assay. The GH and placental lactogen levels were also determined. In addition, maternal plasma samples taken during labour, amniotic fluid and cord blood were also assayed for these hormones.
Maternal plasma GHRH levels were similar to non-pregnant levels throughout gestation despite fluctuations in GH values which were always higher than non-pregnant levels. There was no significant difference between GHRH levels in maternal plasma and cord blood although high GH levels were observed in the latter. These findings suggest that peripheral GHRH levels do not play an important role in maintaining circulating GH levels during pregnancy.
Journal of Endocrinology (1990) 125, 161–167
