Weight changes in type 2 diabetes and the impact of gender.

AIMS: Many studies suggest that weight gain occurs during treatment of type 2 diabetes, irrespective of the treatment type. The aim of this study was to address the questions (i) whether weight gain is inevitable in patients treated for type 2 diabetes, and (ii) whether treatment escalation is prompted by a rise in glycaemic control [haemoglobin A 1c (HbA 1c)] or weight gain. METHODS: A diabetes database was used to identify all patients with type 2 diabetes attending our clinic between 1 January 1990 and 31 December 2000. To facilitate further analysis, independent anonymized database resources were established. Data collected included height, weight, gender, HbA(1c), age and diabetes treatment at each visit. RESULTS: One thousand and eighty-four patients were included; after 6 months of treatment, patients' average weight had reduced by 1.0 kg (s.d. 4.6) (p < 0.001). Sixty per cent of the patients had either a decrease or no change in weight, while 40% demonstrated a weight gain. Women demonstrated more weight loss than men. After a mean follow-up of 50 months (s.d. 25.7), 439 patients (40%) who received treatment with diet alone, diet followed by metformin or metformin alone demonstrated a maintained weight reduction in addition to improved glycaemic control. A rise in HbA(1c) rather than weight gain prompted treatment change. CONCLUSIONS: This study provides evidence that weight gain is not a necessary consequence of the treatment of type 2 diabetes. Women were more successful than men in losing weight, and diet, with or without the addition of metformin, was the treatment type most usually associated with weight loss.

Dopamine inhibits angiotensin-stimulated aldosterone biosynthesis in bovine adrenal cells.

The possibility that dopamine may play a role in the in vivo control of aldosterone production in man was suggested to us by reports from others; (a) that bromocriptine, a dopaminergic agonist, inhibits the aldosterone response to diuresis and to the infusion of angiotensin or ACTH; and (b) that metaclopramide, a dopamine blocking agent, causes elevations in plasma aldosterone levels. To determine whether such effects were direct or indirect, we examined the action of dopamine on aldosterone biosynthesis in isolated, bovine adrenal cells. Dopamine significantly inhibits the aldosterone response to angiotensin (P < 0.001), but does not influence basal aldosterone biosynthesis. It has previously been reported that angiotensin stimulates both the early and late phases of aldosterone biosynthesis. The present experiments demonstrated that the enhancing effect of angiotensin on the conversion of deoxycorticosterone to aldosterone (late phase of aldosterone biosynthesis) was almost completely inhibited by dopamine (P < 0.001). A significant inhibitory effect of dopamine (10 nM) was seen even when aldosterone biosynthesis was stimulated by a grossly supraphysiological concentration of angiotensin II (10 muM). However, these studies did not demonstrate any direct effect of dopamine on the early phase of aldosterone biosynthesis (cholesterol to pregnenolone) basally or when stimulated, or on the late phase of aldosterone biosynthesis under basal conditions. These in vitro studies suggest a direct inhibitory role for dopamine on the late phase of aldosterone biosynthesis, which may account for the in vivo inhibition of the aldosterone response to angiotensin in subjects treated with a dopaminergic agent.

The cost of treating type 2 diabetes (CODEIRE).

Diabetes mellitus is the most common chronic metabolic disease and a major source of morbidity and mortality. Type 2 diabetes (T2D) is by far the most prevalent form of diabetes accounting for around 90% of cases worldwide. In recent years it has become apparent that a diabetes epidemic is unfolding as a result of increasing obesity, sedentary lifestyles and an ageing population. The enormity of the diabetes epidemic raises concern about the total cost to healthcare systems. This study was undertaken to investigate the direct healthcare costs of managing T2D in Ireland. Data was captured on 701 diabetes patients attending four diabetes centres. A bottom-up, prevalence-based design was used, which collected data on hospital resource use and clinical outcome measures over a 12-month period (1999/2000). The study was observational in nature, focusing on usual care of patients with T2D. Although the true prevalence of T2D in Ireland is unknown, conservative estimates are 3.9% for diagnosed diabetes and 6% for both diagnosed and undiagnosed diabetes. Using these figures the annual total direct cost was estimated at 377.2 million euro for diagnosed diabetes and 580.2 million euro for both diagnosed and undiagnosed diabetes. This corresponds to 4.1% and 6.4% of total healthcare expenditure respectively. Hospitalisations were the main driver of costs, accounting for almost half of overall costs, while ambulatory and drug costs accounted for 27% and 25% respectively. Hospitalisation costs were high because 60% of patients had developed complications. The most common microvascular and macrovascular complications were neuropathy and angina respectively. The annual cost of care for patients with microvascular and macrovascular complications were 1.8 and 2.9 times the cost of treating those without clinical evidence of complications respectively. The figure for patients with both types of complications was 3.8. This study shows that T2D is a very costly disease, largely due to the cost of and the management of complications. Many diabetes related complications are preventable, therefore it would appear a cost-effective approach for government to invest in the prevention of T2D and diabetes related complications.

The impact on clinical practice of routine screening for macroprolactin.

BACKGROUND: Macroprolactin has reduced bioactivity in vivo and accumulates in the sera of some subjects, resulting in pseudo-hyperprolactinemia and consequent misdiagnosis. METHODS: We have audited our experience of routine screening for macroprolactin using polyethylene glycol (PEG) precipitation over a 5-yr period in a single center. RESULTS: Application of a reference range for monomeric prolactin (the residual prolactin present in macroprolactin-depleted serum) for normal individuals revealed that 453 of 2089 hyperprolactinemic samples (22%) identified by Delfia immunoassay were explained entirely by macroprolactin. The percentage of hyperprolactinemic samples explained by macroprolactinemia was similar across all levels of total prolactin (18, 21, 19, and 17% of samples from 700-1000, 1000-2000, 2000-3000, and greater than 3000 mU/liter, respectively). Application of an absolute prolactin threshold after polyethylene glycol treatment of sera, rather than the traditional method, i.e. less than 40% recovery, minimizes the opportunity for misclassification of patients in whom macroprolactin accounted for more than 60% of prolactin and the residual bioactive prolactin was present in excess. Macroprolactinemic patients could not be differentiated from true hyperprolactinemic patients on the basis of clinical features alone. Although oligomenorrhea/amenorrhea and galactorrhea were more common in patients with true hyperprolactinemia (P < 0.05), they were also frequently present in macroprolactinemic patients. Plasma levels of estradiol and LH and the LH/FSH ratio were significantly greater in macroprolactinemic compared with true hyperprolactinemic subjects (P < 0.05). Reduced use of imaging and dopamine agonist treatment resulted in a net cost savings, offsetting the additional cost associated with the introduction of screening. CONCLUSION: Routine screening of all hyperprolactinemic sera for macroprolactin is recommended.

Normal cortisol response to corticotropin in patients with secondary adrenal failure.

A normal plasma cortisol response to exogenous corticotropin has been advanced as a reliable indication of adequate hypothalamic-pituitary-adrenal function in patients suspected of having secondary adrenal failure. We have examined the validity of this diagnostic strategy in five patients who had undergone hypophysectomy and 27 patients recently treated with glucocorticoids. Eleven of the patients had normal adrenal responses to cosyntropin but had subnormal responses when the entire hypothalamic-pituitary-adrenal axis was examined using metyrapone; no patient who responded normally to metyrapone failed to respond to cosyntropin. Inducing hypoglycemia with insulin yielded results concordant with the results induced by metyrapone in four patients tested. A normal cortisol response to corticotropin alone should not be relied on to exclude secondary adrenal insufficiency. To do this it is necessary to demonstrate normal activity of the entire hypothalamic-pituitary-adrenal axis, which can be conveniently examined using metyrapone.

Papilledema in two patients with acromegaly and intrasellar pituitary tumors.

Two patients had bilateral papilledema complicating acromegaly. Both patients had enlarged blind spots, but otherwise visual fields were normal. Suprasellar extension of the pituitary tumors was diligently sought with the use of visual field examination, pneumoencephalography, internal carotid arteriography, and computed axial tomography, and tumor extension did not exist. Transphenoidal and transethmoidal routes were used to perform partial hypophysectomies in these patients. The procedure was completely successful in one patient and partially successful in the other patient. After hypophysectomy, papilledema resolved in both patients. This beneficial effect may be the result of anatomical changes, the reduction in growth hormone levels, or both. These observations suggest that the acromegaly may be different from papilledema that occurs secondary to suprasellar expansion of pituitary tumors.

Premixed insulin preparations in pen syringes maintain glycemic control and are preferred by patients.

OBJECTIVE: To examine the impact on glycemic control of substituting a range of premixed insulins for the standard treatment with patient-mixed insulin combinations. In addition, a pen-type syringe was substituted for the conventional insulin syringe, and the patients' preference was ascertained at the end of the study. RESEARCH DESIGN AND METHODS: Before the study, all patients had maintained a constant insulin dosage for 2 months. For the first month of the study, all patients were encouraged to make any adjustment in insulin dosage required to optimize control. Twenty-seven patients participated in the study. At the end of the first month, patients were randomized either to change to premixed insulins or to continue with self-mixed insulins for 2 months. At the end of the 2-month period, participants changed to the alternative regime for a further 2 months. Glycemic control was measured by assessment of glycosylated hemoglobin levels at the start of the study and after each 2-month period of the study. In addition, during the 1-month run-in period and during both 2-month study periods, a seven-point blood glucose profile was obtained extending from before breakfast to just before retiring for sleep. RESULTS: Glycosylated hemoglobin levels were unchanged throughout the duration of the study. Similarly, there were no systematic changes in individual seven-point blood glucose profiles. The frequency of hypoglycemic reactions was similar on patient-mixed and premixed insulin programs. However, 83% of patients expressed a preference for premixed insulins. A similar percentage regarded pen-type insulin syringes to be preferable to the conventional syringe. CONCLUSIONS: Glycemic control was similar on patient-mixed and premixed insulins, and patients had a marked preference for premixed insulins delivered in a pen-type syringe over conventional insulin therapy. Premixed insulin delivered by a pen-type syringe promises to ease the burden of daily injections for many diabetic patients.

Examination of the effects of epinephrine, norepinephrine, and dopamine on aldosterone production in bovine glomerulosa cells in vitro.

This study was undertaken to explore the possibility that the neurogenic amines epinephrine and norepinephrine may influence aldosterone production in vitro and to examine again the previously reported inhibitory effect of dopamine on aldosterone production. This was accomplished using bovine glomerulosa cell suspensions and a highly specific RIA for aldosterone. Epinephrine and norepinephrine (10(-6) - 10(-10) M) had no significant effect on aldosterone production. Both basal and angiotensin II-stimulated aldosterone production were significantly inhibited by dopamine, 10(-4) M, P less than 0.05. Basal aldosterone production was unaffected by lower concentrations of dopamine whereas angiotensin II-stimulated aldosterone production was inhibited in a dose-dependent manner that was significant to 10(-6) M dopamine (P less than 0.05). Pretreatment of glomerulosa cells with the dopamine antagonist metoclopramide impaired the inhibitory effect of dopamine on aldosterone production. This study supports the hypothesis that dopamine may be a significant inhibitor of aldosterone production in vivo. The other neurogenic amines studied, epinephrine and norepinephrine, had no significant effect on aldosterone production in vitro.

Chlorbutol, a new inhibitor of aldosterone biosynthesis identified during examination of heparin effect on aldosterone production.

This study was designed to examine the mechanism whereby routine heparin therapy inhibits adrenal aldosterone production. In bovine adrenal glomerulosa cell suspensions, pure heparin, in concentrations up to 500 U/ml, had no significant effect on basal or angiotensin II-stimulated aldosterone production. A therapeutic preparation of heparin for parenteral use containing the preservative chlorbutol (2.8 X 10(-2) M) inhibited aldosterone production [67 +/- 8.7% (+/- SE); P less than 0.005]. Chlorbutol alone, in a dose-dependent manner, inhibited basal aldosterone production from 1548 +/- 355 to 316 +/- 152 pg/ml (P less than 0.001) and inhibited angiotensin II-stimulated production from 4950 +/- 724 to 589 +/- 257 pg/ml (P less than 0.001). To elucidate the inhibitory mechanism of chlorbutol, we used trilostane, an inhibitor of the conversion of pregnenolone to progesterone, and aminoglutethimide, an inhibitor of the conversion of cholesterol to pregnenolone. Aldosterone production was completely suppressed by each inhibitor. Pregnenolone accumulation in trilostane-treated cells fell from 9.70 +/- 1.66 to 1.40 +/- 0.28 ng/ml (P less than 0.005) with the addition of chlorbutol. Aldosterone accumulation from corticosterone added to aminoglutethimide-treated cells fell from 715 +/- 96 to 348 +/- 59 pg/ml (P less than 0.02) in cells incubated with chlorbutol. Thus, chlorbutol is a potent inhibitor of aldosterone production, inhibiting both the early biosynthetic phase and, to a lesser extent, the late phase. Since chlorbutol is a widely used pharmaceutical preservative and has a slow metabolic clearance, these findings may be of toxicological significance and may account for the inhibition of aldosterone production previously attributed to heparin.

Routine heparin therapy inhibits adrenal aldosterone production.

While heparin-induced aldosterone deficiency has been sporadically reported, it is not known whether heparin always inhibits aldosterone production to a variable extent or if this is an idiosyncratic effect, nor is the mechanism underlying the phenomenon known. We have examined plasma aldosterone, PRA, and aldosterone to renin activity ratios in 20 patients before, during and after treatment with heparin. Aldosterone cell during heparin treatment from 73.5 +/- 20.5 to 36.8 +/- 11.2 pg/ml (P less than 0.05) and rose after its withdrawal to 94.8 +/- 37.1 p/ml (P less than 0.05). PRA rose with heparin treatment from 2.8 +/- 1.0 to 6.1 +/- 1.6 ng/ml . h (P less than 0.05) and fell to 2.4 +/- 0.5 ng/ml . h (P less than 0.05) when the drug was withdrawn. Aldosterone to renin activity ratios, which are indices of aldosterone responsiveness to angiotensin, fell from 59.5 +/- 1.7 to 25 +/- 14.9 (P less than 0.01) with heparin treatment and rose after withdrawal of the drug to 58.5 +/- 24.9 (P less than 0.01). There was a significant small fall in serum sodium levels with the introduction of heparin, but none of the patients developed clinical mineralocorticoid deficiency. Although heparin consistently perturbs aldosterone production in the glomerulosa cell, this effect is not clinically significant when normal adjustments can be made in the generation of angiotensin. However, where limitations in the renin-angiotensin-aldosterone axis exist, e.g. in diabetes mellitus, mineralocorticoid insufficiency may be precipitated by heparin.

Plasma pregnenolone and 17-OH-pregnenolone in patients with adrenal tumors, ACTH excess, or idiopathic hirsutism.

Plasma levels of the delta5-pregnenes, pregenolone and 17-OH-pregnenolone, were measured in patients with disordered steroidogenesis. While 17-OH-pregnenolone was within the normal range in patients with hypercortisolemia due to Cushing's disease, ectopic ACTH or adrenal adenrenal adenoma, 4 of 6 patients with an adrenal carcinoma had elevated levels of this precursor. Thus, elevated plasma 17-OH-pregnenolone levels in patients with Cushing's syndrome indicate adrenal carcinoma, although a normal value does not exclude this diagnosis. Abnormal resistance of delta5-pregnenes to suppression with dexamethasone proved useful in detecting the presence of residual tumor in the post-operative evaluation of adrenal carcinoma. Basal plasma pregnenolone was within the normal range in 19 of 20 patients with Cushing's disease and was invariably normal in patients with other varieties of hypercortisolism. Since acute administration of ACTH causes marked elevation of delta5-pregnene levels while patients with chronic ACTH excess (Cushing's disease and ectopic ACTH production) have normal levels, it is suggested that ACTH has a chronic influence on the intraadrenal utilization of delta5-pregnenes in addition to stimulating their formation. In pre-menopausal women with idiopathic hirsutism, basal levels of both delta5-pregnenes were elevated (P less than 0.001). Following dexamethasone administration the absolute decrease in delta5-pregnenes levels was greater than that seen in normal subjects. This observation indicates that the metabolism of delta5-pregnenes is abnormal in patients with idiopathic hirsutism.

Plasma sex hormone-binding globulin levels decrease during the second decade of life irrespective of pubertal status.

The plasma concentrations of sex hormone-binding globulin (SHBG) and sex steroids determine the nonprotein bound or free steroid fraction, which probably exerts the biological activity of sex steroids. Androgens lower and estrogens raise SHBG levels. The established pubertal fall in SHBG levels occurring in men has been attributed to rising androgen levels. In this study we examined the relationship between plasma SHBG and androgens in four men with untreated isolated gonadotropin deficiency and in two siblings with complete androgen insensitivity. In patients with untreated isolated gonadotropin deficiency there was a highly significant inverse correlation between SHBG levels and age (r = -0.9, P less than 0.001), although testosterone levels did not rise and there was no relationship between SHBG levels and testosterone, androstenedione, or dehydroepiandrosterone-sulfate. Two 46 XY siblings, who were phenotypic females, with complete androgen insensitivity had a marked decline in SHBG levels from 28.0 ng/ml at 9 yr to 17.1 ng/ml at 13 yr and from 15.2 ng/ml at 12 yr to 8.1 ng/ml at 16 yr, respectively. These observations indicate that the fall in SHBG levels during the second decade of life occurs irrespective of androgen activity and is under the control of other unidentified influences.

Amenorrhea with cryptic hyperandrogenemia.

It is current practice to assume that when menstrual disturbances are associated with androgen excess there will be additional clinical evidence of this. We have recently seen three women with secondary amenorrhea who did not have any other clinical features of androgen excess, i.e. hirsutism, acne, etc., but who had elevated plasma testosterone and androstenedione levels in addition to increased estrone values. Correction of hypertestosteronemia and elevated estrone levels was followed by ovulation, regular menstruation, and pregnancy. Variable tissue sensitivity to androgens probably accounts for these observations. If measurement of androgen levels is omitted in the evaluation of patients with amenorrhea without hirsutism, cryptic hyperandrogenemia will remain undetected. Plasma testosterone levels should be measured in all patients with amenorrhea of unknown etiology, and only if these are normal should a diagnosis of functional amenorrhea be assigned.

Diagnosis under random conditions of all disorders of the renin-angiotensin-aldosterone axis, including primary hyperaldosteronism.

Theoretically, the relationship between plasma aldosterone (PA) and PRA in normal subjects under random conditions should differ from that in patients with primary hyperaldosteronism or primary adrenal failure, but should be similar to that in patients with secondary hyperaldosteronism or hyporeninemic hypoaldosteronism. PA, expressed as a function of PRA, the PA/PRA ratio, provides an index of adrenal sensitivity in normal subjects under routine conditions. The random PA/PRA ratios in patients with primary adrenal disorders did not overlap with those in normal subjects, patients with secondary adrenal disorders, hypertensive subjects, or other patients. A single elevated PA/PRA ratio, i.e. more than 920, associated with elevated PA in 4 patients or normal PA in 6 patients indicated primary hyperaldosteronism in 10 patients. However, 5 of 17 patients with chronic renal failure had elevated PA/PRA ratios, but did not have primary hyperaldosteronism. All 14 patients with secondary hyperaldosteronism had elevated PA associated with normal PA/PRA ratios. A single PA/PRA ratio of less than 28 associated with low PA in 18 patients and a normal PA in 1 patient indicated primary adrenal insufficiency, while a low PA associated with a normal PA/PRA ratio indicated hyporeninemic hypoaldosteronism in 7 patients. Fifty-nine patients with nonadrenal disorders other than renal failure had normal PA and PA/PRA ratios. Therefore, with the exception of patients with advanced renal failure, only a single blood sample is required to establish all diagnoses of disorders of the renin-angiotensin-aldosterone axis under random conditions.

Adrenal abnormalities in polycystic ovary syndrome.

This study was undertaken to examine the role of adrenal androgen excess in the pathogenesis of polycystic ovary syndrome (PCOS) and, if such was present, to assess its reversibility using dexamethasone given in physiological dosage at night. Mean plasma testosterone (T), T/sex-hormone binding globulin (T/SHBG) ratio, androstenedione, and 17-OH-progesterone levels were elevated in the 19 patients studied. Plasma estrone values were elevated, whereas estradiol levels were normal. Plasma FSH was decreased and LH responsiveness to LHRH was exaggerated. Metyrapone, an 11-hydroxylase inhibitor, was administered at 2400 h to induce hypocortisolemia and compensatory ACTH secretion so that adrenal androgen and glucocorticoid responsiveness to endogenous stimulation could be examined. Plasma T, androstenedione, and 11-deoxycortisol responses to metyrapone were excessive in PCOS patients, thus indicating a specific adrenal abnormality. After 3 months treatment with dexamethasone, 0.5 mg at night, mean plasma T/SHBG and androstenedione declined to normal, and mean plasma dehydroepiandrosterone and dehydroepiandrosterone sulfate declined to below normal. The mean estrone value was slightly lower during dexamethasone. Plasma LH responsiveness to LHRH was no longer significantly different from normal, but FSH was suppressed. During treatment androgen responsiveness to metyrapone stimulation was normal, whereas 11-deoxycortisol responsiveness was suppressed. Fifteen patients completed 3 months of treatment with dexamethasone. Of these, 10 resumed regular menstruation. The latter group had suppression of plasma T, T/SHBG, androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate. Only plasma androstenedione fell significantly in the remainder. These observations support the hypothesis that, in at least some patients, PCOS develops in response to abnormal gonadotropin secretion induced by hyperestronemia occurring as a consequence of excessive adrenal androgen secretion.

Decline in insulin-like growth factor I levels after clomiphene citrate does not correct hyperandrogenemia in polycystic ovary syndrome.

It is widely accepted that the action of clomiphene citrate (CC) is mediated through its antiestrogenic properties on the hypothalamic-pituitary axis. Although insulin-like growth factor I (IGF-I) enhances the thecal cell response to LH, and estrogen treatment is associated with a reduction in IGF-I levels, CC is known to decrease circulatory IGF-I levels in polycystic ovary syndrome (PCOS) patients. The impact of lowering IGF-I levels on androgen levels in PCOS is unknown. This study was designed to examine the impact of CC treatment on the interrelationships of IGF-I, androgens, and estrogens in normal subjects and patients with PCOS. IGF-I, gonadotropin, androgen, estrogen, and sex hormone-binding globulin levels were measured in 8 PCOS patients and 10 normal subjects before and after treatment with the antiestrogen CC. Studies were performed in the early follicular phase, days 4-6 of the menstrual cycle in normal subjects. In normal subjects, CC treatment led to a significant increase in estradiol (84 +/- 10 to 234 +/- 62 pmol/L, untreated and CC treated; P < 0.05) and estrone (125 +/- 14 to 257 +/- 29 pmol/L; P < 0.05) levels with a significant lowering of IGF-I levels (297 +/- 25 to 230 +/- 17 micrograms/L; P < 0.05). Similarly, in PCOS patients a significant increase in estradiol (110 +/- 11 to 245 +/- 58 pmol/L; P < 0.05) and estrone (301 +/- 32 to 401 +/- 90 pmol/L; P < 0.05) levels and a significant lowering of IGF-I levels (330 +/- 43 to 214 +/- 27 micrograms/L; P < 0.05) were observed after CC treatment. However, no significant correlation was observed between changes in IGF-I and changes in estradiol in either group. Compared to pretreatment levels, no significant changes in the following parameters were observed after 5 days of CC treatment in either study group: testosterone, testosterone/sex hormone-binding globulin ratio, and androstenedione. The relationship among CC treatment, gonadotropin, estrogen, and IGF-I levels is complex. Changes in blood IGF-I levels are not associated with changes in androgen levels, although paracrine and or autocrine effects cannot be excluded.

Effects of nifedipine treatment on the renin-angiotensin-aldosterone axis.

Nifedipine is a commonly used agent in treating hypertension and angina because of its vasodilator properties. An inhibitory role of nifedipine on aldosterone (Aldo) biosynthesis has been documented in in vitro studies. This study was designed to examine the impact of a sustained release nifedipine formulation on Aldo biosynthesis and its clinical consequences. Early and late effects of nifedipine on Aldo, PRA, and Aldo/PRA ratio levels were studied in a single blind, placebo-controlled, 10-day pilot study. Ten normotensive subjects and 10 patients with hypertension were studied. Blood samples for the measurement of Aldo and PRA were obtained at 2-h intervals for 10 h on a control day and on days 1 and 8 of nifedipine treatment for the determination of baseline, early, and late values. Placebo was administered at 0800 h on the first and second days of the study, whereas nifedipine (60 mg/day) was given for the following 8 days. The Aldo/ PRA ratio was used as a sensitive indirect index of the responsiveness of Aldo secretion to adrenal stimulation with angiotensin. Compared to those on the control day, a significant rise in the integrated PRA levels occurred on the first day of nifedipine treatment, with a further rise observed on the eighth day of the treatment in the normotensive subjects (1.1 +/- 0.6, 1.7 +/- 1.2, and 2.5 +/- 1.8 ng/mL.h on the control day and the first and eighth days of treatment, respectively; P < 0.05) and by the eighth day in the hypertensive subjects (2.2 +/- 2.8 and 4.0 +/- 4.1 ng/mL.h; P < 0.05). A significant rise in integrated Aldo levels occurred in the normotensive subjects on the eighth day of nifedipine treatment (control day, 319 +/- 187; eighth day of nifedipine, 363 +/- 167 pmol/L; P < 0.05) and in the hypertensive subjects (426 +/- 219 and 535 +/- 284 pmol/L; P < 0.05). This was associated with a significant lowering of the Aldo/PRA ratio on the first day of the treatment, with further lowering on the eighth day in the normotensive (435 +/- 454, 269 +/- 209, and 182 +/- 107; P < 0.05) and by the eighth day in the hypertensive subjects (716 +/- 833 and 305 +/- 315; P < 0.05). When individual time points were examined in the normotensive subjects, Aldo/PRA levels were significantly lower on day 8 of nifedipine treatment at 1000, 1200, and 1400 h than corresponding values on the control day. The fall in the Aldo/PRA ratio during nifedipine treatment indicates that the previously reported in vitro inhibition of Aldo biosynthesis in adrenal cells is reproduced in vivo. In the absence of nifedipine, it is likely that Aldo levels would be higher for any given level of PRA. It is probable that the Aldo inhibition and the vasodilatatory effect of nifedipine combine to bring about the lowering of blood pressure. Drugs that inhibit renin-angiotensin axis activity are likely to be particularly effective when additional lowering of blood pressure is required.

Seventy-two hour infusions of LHRH in normal men: gonadotropin and testicular steroid responses.

Four normal male subjects received LHRH by continuous infusion for 72 hrs at 1.4 microgram/min. Mean basal LH was 7.7 +/- 1.0 mIU/ml, increased to a maximum of 120 +/- 22.7 mIU/ml, and then declined to levels between 28--34 mIU/ml for the last 30 hrs of infusion; FSH rose from 3.7 to 11.4 mIU/ml (p less than 0.05) at 16 hrs and then returned to baseline. Testosterone levels rose by 50% at 12 hrs, and remained elevated throughout with maximum values between 6.6 and 12 ng/ml. Estradiol-17beta levels were 26.2 +/- 4.7 pg/ml basally, rose to 104 +/- 8 pg/ml and while levels declined therafter, they were significantly above baseline throughout the 72 hrs. Plasma androstenedione and dehydroepiandrosterone levels also showed significant increases. By contrast, transient elevations in pregnenolone and 17-hydroxypregnenolone levels probably corresponded to the nomral morning rise in plasma levels of these steroids; 17-hydroxyprogesterone rose from 1.3 +/- 0.15 to 3.9 +/- 0.26 ng/ml at 12 hrs and remained elevated through the infusion. An increase in 17-hydroxyprogesterone:testosterone ratio was observed in all subjects. Thus, chronic LHRH infusion effected a persistent increase in endogenous LH with, in turn, prolonged stimulation of gonadal steroid secretion.

Circulating big human prolactin: conversion to small human prolactin by reduction of disulfide bonds.

The heterogeneity of circulating human PRL (hPRL) in sera of patients with hyperprolactinemia was studied by exclusion chromatography on Sephadex G-100. Big hPRL, which elutes between the void volume and the elution position of monomeric small hPRL, is stable upon rechromatography but is almost entirely converted into small hPRL after reduction with 0.5% mercaptoethanol. These results suggest that the existence of circulating big hPRL is dependent upon the formation of interpolypeptide disulfide bonds and does not represent a classical biosynthetic precursor of hPRL.

Plasma 16 beta-hydroxydehydroepiandrosterone in normal and pathological conditions in man.

Plasma 16beta-hydroxydehydroepiandrosterone (16 beta-OH-DHEA) levels in normal subjects and patients with certain pathological conditions have been evaluated using radioimmunoassay of the steroid. Plasma 16 beta-OH-DHEA levels in normal subjects rose sharply during adolescence and then declined slowly throughout adult life: 192 +/- 54 (SE) pg/ml between 7 and 11 yrs., 395 +/- 22 pg/ml between 15 and 19 yrs, 330 +/- 29 pg/ml between 20 and 39 yrs., 291 +/- 35 pg/ml between 40 and 59 yrs., and 124 +/- 20 over 60 yrs. No significant difference was found between male and female subjects. Plasma 16 beta-OH-DHEA rose significantly (P less than 0.001) during ACTH stimulation, declined significantly (P less than 0.005) during dexamethasone suppression, declined significantly (P less than 0.05) during gonadal suppression, rose significantly (P less than 0.05) during gonadal stimulation and rose significantly (P less than 0.005) after the administration of WIN 24,540, an inhibitor of 3 beta-ol-dehydrogenase. The concentration of 16 beta-OH-DHEA in adrenal venous blood was higher than in inferior vena cava blood, but 16 beta-OH-DHEA in hepatic venous blood was not higher than 16 beta-OH-DHEA in arterial blood. It is inferred that 16 beta-OH-DHEA is secreted directly by the adrenal cortex and probably the gonads. Plasma 16 beta-OH-DHEA was elevated in normal pregnant women, pregnant women with toxemia, and in patients with Cushing's disease, ectopic ACTH-producing tumor, and congenital adrenal hyperplasia, but it was not elevated in patients with low-renin essential hypertension.

PIP: Plasma 16 beta-hydroxydehydroepiandrosterone (16 beta-OH-DHEA) levels were measured by radioimmunoassay in normal and pathological conditions in man. 16 beta-OH-DHEA levels in normal subjects rose sharply during adolescence and then declined slowly throughout adult life: 192 pg/ml age 7-11, 395 pg/ml age 15-19, 330 pg/ml age 20-39, 261 pg/ml age 40-59, and 124 pg/ml over 60-years-old. No marked difference was seen between male and female subjects. 16 beta OH-DHEA rose significantly (p less than .01) during adrenocorticotropin (ACTH) stimulation, declined (p less than .005) during dexamethasome suppression and during gonadal suppression, rose (p less than .05) during gonadal stimulation and following administration of WIN 24540, an inhibitor of 3 beta-o1-dehydrogenase (p less than .005). 16 beta-OH-DHEA levels in adrenal venous blood were higher than in inferior vena cava blood but the levels in hepatic venous blood were not higher than in arterial blood. These results indicate that 16 beta-OH-DHEA is secreted directly by the adrenal cortex and probably the gonads. 16 beta-OH-DHEA levels were elevated in normal pregnant women, pregnant women with toxemia and in patients with Cushing's disease, ectopic ACTH-producing tumor and congenital adrenal hyperplasia but not in patients with low-renin essential hypertension.