Marie Culliton

The Relationship between Sex Steroids and Sex-Hormone-Binding Globulin in Plasma in Physiological and Pathological Conditions

Physiological and many pathological changes in plasma sex-hormone-binding globulin (SHBG) levels have been attributed to the opposing effects of androgens which lower, and oestrogens which elevate, levels. We examined four clinical situations in which changes in SHBG levels may not be explained by sex steroid alterations. (1) Dexamethasone caused an increase in SHBG levels in hyperandrogenaemic hirsute women whether or not androgens were suppressed. (2) In male patients with untreated isolated gonadotrophin deficiency there was a highly significant correlation between SHBG levels and age, but there was no relationship between the levels of SHBG and those of plasma testosterone, androstenedione or DHEAS. (3) Two 46-XY siblings, phenotypic female subjects with complete androgen insensitivity, demonstrated a marked decline in SHBG levels between the ages of 9–13 and 12–16 years. (4) SHBG was suppressed in obese oligomenorrhoeic women while plasma concentrations of testosterone, androstenedione and oestradiol were normal and that of oestrone was elevated; however, the testosterone: SHBG ratio, an index of free testosterone, was elevated. These observations indicate that the decline in SHBG levels which normally occurs in men during the second decade of life is independent of androgen activity and is under the influence of as yet unidentified factors. Glucocorticoids in small doses increase SHBG levels independently of sex steroid alterations while elevated free testosterone concentration may contribute to suppression of SHBG in obesity.

ADRENAL ABNORMALITIES IN IDIOPATHIC HIRSUTISM

The possibility that abnormal adrenal androgen production may be present in patients with idiopathic hirsutism was examined. Plasma testosterone, dihydrotestosterone and androstenedione levels were elevated in hirsute patients. In response to exogenous α1–24 ACTH the increments in plasma androstenedione, dehydroepiandrosterone (DHA) and cortisol were significantly greater in hirsute patients than in normal subjects. The testosterone response was exaggerated following endogenous stimulation induced by metyrapone. Treatment with dexamethasone, 0.5 mg each night for 3 months, corrected both the androgen excess and the exaggerated androgen responses but not the excessive cortisol response to stimulation. These observations indicate adrenal abnormalities in idiopathic hirsutism. The dissociation of cortisol and adrenal androgen responsiveness following dexamethasone suggests that the abnormalities observed may be due to excessive adrenal androgen production stimulated by a dexamethasone‐suppressible factor other than ACTH. Excess adrenal androgen production may be the primary disorder leading to the development of idiopathic hirsutism.

Altered androstenedione and estrone dynamics associated with abnormal hormonal profiles in amenorrheic subjects with weight loss or obesity

The present study was designed for exploration of hormonal disturbances underlying common forms of amenorrhea. Polycystic ovary syndrome (PCO) patients and obese amenorrheic subjects had significantly elevated estrone (E1) levels, elevated luteinizing hormone/follicle-stimulating hormone ratios, and an exaggerated luteinizing hormone response to luteinizing hormone-releasing hormone. However, androstenedione (delta 4A), the precursor of E1, was elevated only in PCO. Thus, the E1/delta 4A ratio, which provides an indirect index of aromatase activity in extraglandular sites, was raised in obese subjects as a group but not in PCO subjects. These findings suggest that elevated E1 levels, which give rise to abnormal gonadotropin secretion, arise from increased available androgens in PCO but from an increased effect of aromatase (present in adipose tissue) in obese subjects. Measurement of androgens and the E1/delta 4A ratio provides insights into the relative contributions of hyperandrogenemia and enhanced aromatase activity to the genesis of amenorrhea in these groups. In patients with suppressed estradiol levels associated with hyperprolactinemia or weight loss, follicle-stimulating hormone levels were suppressed, while luteinizing hormone was not elevated. Prolactin excess explains these findings in hyperprolactinemia. Plasma E1 levels and the E1/delta 4A ratio were suppressed in patients with weight loss, possibly as a consequence of reduced adiposity. This finding suggests that hypothesis that a minimum level of E1, dependent upon adequate adiposity, is critical for the normal mature function of the hypothalamic-pituitary-ovarian axis. Abnormal E1/delta 4A ratios, high in obesity-associated amenorrhea and suppressed in weight loss-associated amenorrhea, may provide specific markers for these groups of patients.

Evaluation of an Aldosterone Radioimmunoassay: The Renin—Angiotensin—Aldosterone Axis as a Function of Sex and Age

A highly specific radioimmunoassay for aldosterone in plasma has been developed utilising extraction from plasma into dichloromethane, an antiserum raised to aldosterone-3-carboxy-methyloxime-BSA and a radio-iodinated derivative of aldosterone. The plasma values obtained after only extraction correlated very well with the results following chromatography over celite. The within- and between-batch variations for plasma pools ranged between 5 and 15%. The range obtained, 100–1806 pmol/L for 96 random upright subjects, was comparable to others reported. Measurement of plasma aldosterone and plasma renin activity in these subjects showed that both these parameters are higher in subjects under 40 years of age than in those over 40. In addition, plasma aldosterone levels are higher in women than in men even though their plasma renin activity levels are similar. The plasma aldosterone/renin activity ratios which provide an index of adrenal sensitivity to stimulation, are lower in men than in women. The findings in this study suggest that higher aldosterone levels in younger subjects are associated with greater stimulation of the adrenals than in older subjects and that the adrenal is more sensitive in women than in men.

Irish endocrine society

LDL oxidation has been implicated as an important atherogenic factor. We have previously shown that the LDL estetified/free cholesterol ratio is different in diabetes. This study examines the effect ofLDL glycosylation on the susceptibility of LDL to in vitro oxidation. In particular it examines whether there is a relationship between LDL cholesterol esterification, LDL glycosylation and the susceptibility to oxidation. LDL was isolated by sequential ultracentrifugation from normoc holesternlaemic (n=l 0, serum cholesterol 5.30-+0.18mmol/ 1 ) and hypercholesterolaemic diabetic patients(n=7 serum cholesterol 7.18_+0.2mmol/1) and normocholesterolaemic control subjects (n=10, serum cholesterol 5.14_+0.28mmo1/1). LDL glycosylation was determined using aminophenylborate gel chromatography and LDL composition was determined. The susceptibility of LDL to oxidation in the presence of CuS04 was assessed by measuring thiobarbituric reactive substances (TBARS) LDL from the hypercholesterolaemic diabetic patients was more rapidly oxidised, TBARS at 1, 2, 3 and 4 hours being 12.6+3.7, 24.5+3.3, 38.4+2.3, and 40.0_+2.1 nmol/mg LDL protein compared with 4.8_+0.6,16.0+2.5, 24.5+9.5, and 32.4+2.1 for LDL from control subjects (p<0.05). Oxidation of LDL from the normocholeslerolaemic diabetic patients of 6.3_+0.7, 18.4=[_,0.3, 34.0+2.4 and 37.2+2.1, nmol/mg LDL protein, was also significantly greater than that from controls (p<0.05). The esterified/free cholesterol ratio correlated positively with the susceptibility of the LDL to oxidation (p<0.05) which was also related positively to the degree of LDL glycosylation (p<0.01). These results suggest a mechanism which would account for the increased accumulation of cholesterol in the atherosclerotic plaque of the normocholesterolaemic diabetic patient.