K. Noonan

The effect of growth hormone replacement on cortisol metabolism and glucocorticoid sensitivity in hypopituitary adults.

OBJECTIVE Growth hormone (GH) replacement therapy in hypopituitary adults is associated with sodium and water retention. The underlying mechanisms are incompletely understood and a possible contribution of altered cortisol metabolism or action has not been evaluated. We have investigated the effect of GH replacement therapy on cortisol metabolism, cortisol binding globulin and In‐vitro glucocorticold sensitivity in a group of adult hypopituitary patients.

The effect of growth hormone replacement therapy on cortisol–cortisone interconversion in hypopituitary adults: evidence for growth hormone modulation of extrarenal 11β‐hydroxysteroid dehydrogenase activity

Growth hormone (GH) replacement therapy in hypopituitary adults has been associated with a decreased urinary ratio of 11‐hydroxy/11‐oxo‐cortisol metabolites (CoM). This could result from GH regulation of the activity of hepatic or renal 11β‐hydroxysteroid dehydrogenase (11β‐HSD1 and 2), the enzymes responsible for cortisol–cortisone interconversion, or alternatively it might reflect decreased cortisol availability. To elucidate this, we examined the effect of GH on urinary cortisol, cortisone and cortisol metabolites in hypopituitary adults at increasing doses of hydrocortisone replacement.

Decreased sex hormone binding globulin (SHBG) and insulin-like growth factor binding protein (IGFBP-1) in extreme obesity

Obesity may be characterized by abnormal sex steroid secretion and reduced sex hormone binding globulin (SHBG) which in turn is related to fat distribution and insulin secretion. Recent in‐vitro and in‐vivo evidence suggests that insulin is the common mechanism regulating the secretion of SHBG and insulin‐like growth factor small binding protein (IGFBP‐1). IGFBP‐1 appears not only to be a carrier for insulin growth factors (IGFs) but also to play an active role in growth processes, independent of growth hormone secretion. We have examined the possible relationship between fasting insulin, SHBG, testosterone, IGF‐1, IGFBP‐1 and fat distribution in 25 extremely obese, menstruating women (mean weight 107 |Mp 3 kg) with normal glucose tolerance. Fat distribution was assessed from measurements of the waist to hip ratio (W/H). The obese women showed an elevated fasting insulin (mean |Mp SEM; 21 |Mp 2 μmo1/1), a normal IGF‐1, but reduced IGFBP‐1 (14.6 |Mp 2, μg/1); in 15 women IGFBP‐1 levels were undetectable by the present assay. In addition, SHBG levels were reduced in the obese women (24|Mp2 nmol/1) but total testosterone values (1.9 |Mp 0.1 nmo1/1) were normal. The elevated fasting insulin levels were positively correlated with increasing upper segment obesity as expressed by a rising W/I‐1 ratio (P < 0.01, r2=0.306) and inversely correlated with SHBG (P <0.01, r2= 0.483). Similarly, reduced SHBG values showed an inverse correlation with increasing W/H ratio (P < 0.001, r2= 0.383). No correlation was found between IGFBP‐1 and W/H ratio but a strong positive correlation was seen between IGFBP‐1 and SHBG (P < 0.001, r2=0.466). Furthermore, an equally significant inverse correlation was found between IGFBP‐1 and insulin levels (P <0.001, r2=0.474). Testosterone and fasting IGF‐1 did not show any correlation with the studied variables. Multivariate analysis suggested that insulin was the strongest factor involved in the regulation of IGFBP‐1 levels, whereas the level of SHBG was primarily determined by IGFBP‐1 concentration and W/H ratio. We conclude that reduced SHBG and IGFBP‐1 found in extreme obesity are inversely correlated to the prevailing hyperinsulinaemia and to increasing upper segment obesity. These findings provide further evidence to support the hypothesis for insulin being an important regulator of both binding proteins, SHBG and IGFBP‐1.

GROWTH HORMONE RESPONSE TO GROWTH HORMONE RELEASING FACTOR IN DIABETIC MEN

Increased plasma concentrations of growth hormone (GH) are reported in diabetes and it is suggested that this may be important in the development of complications. We have investigated fasting GH levels and the response to 100 μg i.v. growth hormone releasing factor, GRF(1‐29)NH2, in age‐matched men: six normal weight controls, six obese controls, six insulin‐dependent diabetics, six normal weight non‐insulin dependent diabetics and six obese non‐insulin dependent diabetics. None of the diabetic men had clinical evidence of diabetic complications. Fasting GH values did not differ significantly between the five groups. The peak GH response to GRF was similar in the controls, insulin‐dependent diabetics (IDD) and non‐insulin dependent (NIDD) normal weight diabetics (mean peak±SEM: controls 25.5 ± 5 mU/1, IDD 26‐5 + 6 mU/1, NIDD 19.7 ± 5 mU/1) but was significantly reduced in the two obese groups (obese 6.4 ± 3mU/l, obese diabetics 4.5 ± 1 mU/1, P<001). This impairment of GH secretion was unrelated to either fasting plasma insulin or glucose concentration. We conclude that our results do not confirm the previous reports of abnormal GH secretion in diabetes but do demonstrate a markedly impaired GH response to GRF to be a feature of obesity.

An association between hypothalamic‐pituitary dysfunction and peripheral endocrine function in extreme obesity

Summary. objective The aim was to Investigate a possible relation‐ship between measures of Insulin secretion and glucose disposal and hypothalamic–pituitary function In extreme obesity.

IMPAIRED PROLACTIN SECRETION AND BODY FAT DISTRIBUTION IN OBESITY

Human obesity shows clustering within families. The hypothesis for the presence of a major gene or genes acting in human obesity is supported by recent evidence from studies of obesity in adoptees and their biological parents and siblings. The heterogeneity of obesity may be demonstrated by the shape of fat distribution and the prolactin response to insulin hypoglycaemia. Fat distribution has been shown to have a genetic background whereas a primary disorder of hypothalamic function is suspected in obese women who show an impaired prolactin response to insulin‐induced hypoglycaemia. We have investigated the possible association between fat distribution and hypothalamic function in 23 extremely obese, nondiabetic premenopausal women who have been characterized using their absolute body weight, body mass index (BMI), fat distribution (expressed as waist to hip ratio), fasting insulin, basal prolactin and prolactin response to hypoglycaemia. Fasting insulin values showed a significant correlation (P < 0‐05, R = 0.604) with increasing waist to hip ratio (upper body segment obesity), whereas the graded prolactin response to hypoglycaemia of the obese women showed a negative association with increasing upper body segment obesity (P < 0‐05; R=‐0.446). No relationship was observed between fasting insulin and the prolactin response to hypoglycaemia. We suggest that this previously unrecognized association of an impaired prolactin response to hypoglycaemia and upper body segment fatness may be useful for the investigation of the genetics of obesity.

Effects of ‘Non-Calcaemic’ Vitamin D Analogues on 24-Hydroxylase Expression in MG-63 Osteoblast-Like Cells

Background: New ‘non-calcaemic’ analogues of 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) are entering the clinical arena and some of them have been shown to have differential effects in bone. This may have a bearing on the evolution of bone lesions in uraemic patients receiving vitamin D therapies. A potential mechanism for differential effects of analogues lies in their target cell inactivation. Methods: Using a human osteoblastic cell line, MG-63, three analogues, 22-oxacalcitriol (OCT), 19-nor-1,25-dihydroxyvitamin D₂ (paricalcitol) and 1α,25-dihydroxydihydrotachysterol₂ (1,25(OH)₂DHT₂), were compared with 1,25(OH)₂D₃ for (1) their affinity for the vitamin D receptor (VDR) by competitive displacement of tritiated 1,25(OH)₂D₃ from calf thymus VDR; (2) effects on 24-hydroxylase mRNA expression using comparative RT-PCR, and (3) rates of metabolism, using high performance liquid chromatography, over a 24-hour time course. Results: Relative VDR-binding affinities (IC₅₀) were 1,25(OH)₂D₃ (100%), OCT (25%), paricalcitol (14%) and 1,25(OH)₂DHT₂ (0.3%). A ≧3-fold increase in 24-hydroxylase mRNA expression was observed for all compounds at 2 h peaking at 7- to 8-fold above control levels by 12 h, with no significant difference between the analogues and 1,25(OH)₂D₃. Differences in their rates of metabolism were observed [calculated t½ values = OCT (1.2 h) > paricalcitol (2.3 h) > 1,25(OH)₂D₃ (2.6 h) > 1,25(OH)₂DHT₂ (3.4 h)], with OCT having a significantly shorter half-life. Conclusion: In MG-63 cells these analogues up-regulate 24-hydroxylase mRNA expression with similar potency, in each case accelerating ligand inactivation, despite significant differences in VDR affinity. VDR affinity did not correspond to either 24-hydroxylase mRNA expression or the rates of ligand disappearance, suggesting cellular metabolism is one of several factors that determine the analogue specificity of these agents in bone.