D. Lynn Loriaux

Acute hypothalamic-pituitary-adrenal responses to the stress of treadmill exercise. Physiologic adaptations to physical training

To study the effects of physical conditioning on the hypothalamic-pituitary-adrenal axis, we examined the plasma ACTH, cortisol, and lactate responses in sedentary subjects, moderately trained runners, and highly trained runners to graded levels of treadmill exercise (50, 70, and 90 percent of maximal oxygen uptake) and to intravenous ovine corticotropin-releasing hormone (1 microgram per kilogram of body weight). Basal evening concentrations of ACTH and cortisol, but not of lactate, were elevated in highly trained runners as compared with sedentary subjects and moderately trained runners. Exercise-stimulated ACTH, cortisol, and lactate responses were similar in all groups and were proportional to the exercise intensity employed. These responses, however, were attenuated in the trained subjects when plotted against applied absolute workload. Only the highly trained group had diminished responses of ACTH and cortisol to ovine corticotropin-releasing hormone, consistent with sustained hypercortisolism. We conclude that physical conditioning is associated with a reduction in pituitary-adrenal activation in response to a given workload. Alterations of the hypothalamic-pituitary-adrenal axis consistent with mild hypercortisolism and similar to findings in depression and anorexia nervosa were found only in highly trained runners. Whether these alterations represent an adaptive change to the daily stress of strenuous exercise or a marker of a specific personality profile in highly trained athletes is unknown.

EFFECTS OF HUMAN PANCREATIC TUMOUR GROWTH HORMONE RELEASING FACTOR ON GROWTH HORMONE AND SOMATOMEDIN C LEVELS IN PATIENTS WITH IDIOPATHIC GROWTH HORMONE DEFICIENCY

Human pancreatic tumour growth hormone releasing factor (hpGRF-40) 10 micrograms/kg was administered intravenously to 6 normal young men and 12 adult patients who had presented in childhood with growth hormone (GH) deficiency (7 patients had isolated GH deficiency, 4 had multiple anterior pituitary hormone deficiencies, and 1 had Hand-Schüller-Christian [HSC] disease). hpGRF-40 administration increased serum GH concentrations in all normal subjects and in 3 of 7 patients with isolated GH deficiency and in the 1 with HSC disease; however, the mean serum GH concentration in the patients who responded was less than that of the normal subjects. Somatomedin C concentrations were increased 24 h after a single dose of hpGRF-40 in 8 of 10 patients with GH deficiency. All subjects experienced flushing in response to hpGRF-40. A patient with isolated GH deficiency received 0.33 micrograms/kg hpGRF-40 every 3 h for 5 days. Despite the modest increase in GH in response to a subsequent dose of 10 micrograms/kg hpGRF-40, serum somatomedin C levels increased within 12 h from 0.06 to 0.1 U/ml and peaked at 0.36 U/ml at 72 h; in addition the patient with HSC disease, treated with hpGRF-40 daily for 5 days, demonstrated an increase in somatomedin C from 0.4 to 0.58 U/ml. The increase after hpGRF-40 in serum GH levels in this patient and the similar or greater responses in 3 of 7 patients suggest that at least some of these patients may have hypothalamic GH-releasing-hormone deficiency. hpGRF-40 may be useful in distinguishing pituitary disease from hypothalamic disease. After hpGRF-40 administration serum somatomedin C levels may increase without a change in serum immunoreactive GH concentrations. Further studies are needed to determine whether hpGRF-40 is useful in promoting linear growth in children with GH deficiency.

A double-blind study of perioperative steroid requirements in secondary adrenal insufficiency

BACKGROUND Patients treated long-term with supraphysiologic doses of glucocorticoids experience secondary adrenal insufficiency and are routinely given large doses of steroids in the perioperative period to prevent hypotension. Because the dose of steroids required to prevent hypotension is not known, we conducted a randomized, double-blind study to determine whether patients treated long-term with glucocorticoids actually require increased steroids in the perioperative period. METHODS Patients who had been taking at least 7.5 mg prednisone daily for several months and had secondary adrenal insufficiency as defined by adrenocorticotropic hormone testing formed the study population. Patients were randomized to two groups. One group received perioperative injections of saline solution alone; the other received perioperative saline solution and cortisol. All patients received their usual daily prednisone dose throughout the study. RESULTS Six patients were in the steroid-treated group and 12 were in the saline-treated group. Most subjects underwent major operations such as joint replacements, abdominal operations, and miscellaneous other procedures. Two patients had hypotension, one in each group. Hypotension resolved with volume replacement in both patients. The average pulse rates and blood pressures were similar in both groups during the perioperative period. CONCLUSIONS Patients with secondary adrenal insufficiency do not experience hypotension or tachycardia caused by inadequate glucocorticoid levels when given only their daily dose of steroids for surgical procedures.

Developmental processes in early adolescence: Relations among chronologic age, pubertal stage, height, weight, and serum levels of gonadotropins, sex steroids, and adrenal androgens

Cross-sectional data are presented on 108 young adolescents (56 boys, 52 girls), ages 9 to 14 years. The measures were: for all subjects, pubertal stage (Tanner criteria for genital/breast and pubic hair stage); height and weight; serum hormone concentrations for gonadotropins (luteinizing hormone and follicle-stimulating hormone), sex steroids (testosterone, estradiol, and the computed testosterone to estradiol ratio), adrenal androgens (dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione), and testosterone-estradiol binding globulin. In addition, testicular volume for boys and menarchial status for girls are reported. The study goal was to provide interrelations among these measures, based on the same sample, and examine their interchangeability. Results suggest that it would be reasonable to compare research across as well as within studies based on different markers. Multiple regression analysis showed that the strongest hormone correlates of pubertal development were androgen levels (primarily testosterone in boys and primarily dehydroepiandrosterone sulphate and androstenedione in girls). Estradiol level in girls was the strongest correlate only for menarchial status. Level of testosterone-estradiol binding globulin, which was lower at successive pubertal stages for boys and showed no consistent differences for girls, may be a useful measure for studying the developmental processes and gender differences during puberty.

The progesterone antagonist RU 486. A potential new contraceptive agent.

Abstract Since progesterone supports endometrial nidation of the fertilized ovum, a progesterone antagonist would theoretically block this process and thus have contraceptive potential. We have explored the ability of RU 486, a newly developed competitive progesterone antagonist, to function as a contraceptive agent. A single oral dose of 10 mg per kilogram of body weight given in the midluteal phase consistently induced menses within 72 hours in women with normal cycles and no risk of pregnancy. Bleeding was not prevented by administration of human chorionic gonadotropin in the midluteal phase. This suggested that giving a single dose of RU 486 late in the menstrual cycle might be an effective contraceptive strategy. This concept was tested in monkeys. When given to rhesus females on day 25 of the cycle, a single intramuscular dose of RU 486 (5 mg per kilogram) prevented pregnancy. The vehicle-treated control animals had a 28 percent pregnancy rate (P<0.05 by chi-square analysis). No side effects were no...

Efficacy of a gonadotropin-releasing hormone agonist in the treatment of uterine leiomyomata: long-term follow-up *

The authors employed a gonadotropin-releasing hormone agonist (GnRH-a) (D-His6-pro9-NET-GnRH) to treat 19 patients with symptomatic uterine leiomyomata, by daily subcutaneous injections (4 micrograms/kg) for 6 months. After therapy, patients were followed for 6 months without any therapy. Uterine volumes were measured by serial pelvic examinations and pelvic sonography. Measurements of serum estradiol, luteinizing hormone, and follicle-stimulating hormone were used to assess treatment response. Pituitary desensitization and hypoestrogenemia were achieved in all within 8 weeks, and in 18 of 19, hypoestrogenemia was maintained for the duration. Uterine volume at the conclusion of therapy (207.5 +/- 152.7 ml) was significantly reduced in all patients when compared with pretreatment sizes (420.8 +/- 276.4, P less than 0.05). Side effects included hot flashes (78%), vaginal dryness (32%), and transient frontal headaches (55%). All patients reported partial or complete relief from their symptomatic leiomyomata. Uterine volume at the conclusion of follow-up (345.4 +/- 195.7 ml) was greater than at the conclusion of therapy. Menses resumed in all patients within 4 to 8 weeks. In conclusion, GnRH-a therapy does not provide definitive therapy for symptomatic uterine leiomyomata but is effective in reducing the size of leiomyomata as a temporary measure. Gonadotropin-releasing hormone agonist therapy may be useful as an adjunct before myomectomy or hysterectomy and deserves further investigation.

Receptor-mediated effects of glucocorticoids on inflammation: enhancement of the inflammatory response with a glucocorticoid antagonist

Glucocorticoids suppress the inflammatory response by altering leukocyte traffic and function, cytokine secretion and action, and phospholipid metabolism. We employed the glucocorticoid receptor antagonist RU 486, to examine whether glucocorticoids suppress the inflammatory response through a receptor-mediated mechanism and whether basal glucocorticoid secretion exerts antiinflammatory effects in the resting (non-stress) state. To test these hypotheses we evaluated the effects of increasing doses of dexamethasone, RU 486, or dexamethasone plus RU 486 on the exudate volume and concentrations of leukocytes, prostaglandin E2, (PGE2) and leukotriene B4 (LTB4) in intact rats that received subcutaneous carrageenin. Exudate volume, leukocyte concentration and LTB4 and PGE2 levels were all suppressed by dexamethasone in a dose-dependent fashion (P less than 0.005). RU 486 was able to antagonize fully the suppressive effects of dexamethasone on the inflammatory response (P less than 0.001) and to cause increases of exudate volume and leukocyte, PGE2 and LTB4 concentrations when given alone (P less than 0.05). These increases ranged between 30 and 100% above the basal inflammatory response. We conclude that glucocorticoids most likely suppress the inflammatory response by a glucocorticoid receptor-mediated mechanism and under basal conditions exert tonic antiinflammatory effects.

Intracerebroventricular corticotropin-releasing factor increases limbic glucose metabolism and has social context-dependent behavioral effects in nonhuman primates

Corticotropin-releasing factor (CRF) is a neuropeptide involved in integrating the behavioral, autonomic, and hormonal responses to stress within the central nervous system. Patients suffering from depression have abnormal activity in stress responsive brain regions and elevated cerebrospinal fluid CRF. The DSM-IV criteria for major depressive disorder include behavioral changes such as depressed mood, anhedonia, and psychomotor agitation/retardation. We studied the effects of 434 μg of CRF given intracerebroventricularly over 40 min in group and individually housed monkeys to examine the role of elevated levels of central CRF on behavior. CRF elicited a wide range of behaviors, which fell into three broad categories: anxiety-like, depressive-like, and externally oriented. Externally oriented behaviors decreased, and anxiety-like behaviors increased regardless of how the animals were housed. Interestingly, increased depressive-like behaviors were only observed when the animals were socially housed. In a separate experiment, we examined the effects of the same dose of CRF on the regional cerebral glucose metabolism of lightly anesthetized monkeys by using positron emission tomography and [18F]fluorodeoxyglucose. CRF infusion increased glucose metabolism in the pituitary/infundibulum, the amygdala, and hippocampus. These results indicate that increased central CRF tone affects primate behavior in a context-dependent manner, and that it activates limbic and stress-responsive regions. The fact that intracerebroventricular CRF increases depressive-like behavior in socially housed animals and increases activity in limbic brain regions may help explain the behavioral and metabolic alterations in humans with affective disorders, and this model could therefore have significant value in the development of novel antidepressant treatments.

Catecholamine-glucocorticoid interactions during surgical stress

The stress response involves activation of the hypothalamic-pituitary adrenal axis and the sympathetic nervous system. To study the relative contributions of glucocorticoids, epinephrine, norepinephrine, and dopamine to homeostasis, we examined the effects of cortisol and epinephrine deficiency on the norepinephrine and dopamine responses to surgical stress in nonhuman primates. Adult male cynomolgus monkeys (n = 7-8/group) underwent bilateral or sham adrenalectomy and were maintained for 4 months on physiologic glucocorticoid (hydrocortisone phosphate, 32 mg/M2/day) and mineralocorticoid (DOCA pivalate, 1 mg/day) replacement, or placebo injections, respectively. The adrenalectomized monkeys were then stratified into three groups receiving subphysiologic (X1/10), physiologic (X1), or supraphysiologic (X10) glucocorticoid replacement. A cholecystectomy was performed 4 days later and the pre-, intra-, and postoperative plasma catecholamine levels were measured. Adrenalectomized animals had markedly decreased plasma epinephrine concentrations and accentuated plasma norepinephrine and dopamine responses to cholecystectomy, when compared to sham-adrenalectomized controls. The magnitude of the norepinephrine accentuation was inversely related to the dose of cortisol administered preceding surgery. Norepinephrine and dopamine failed to completely normalize even at the high dose of glucocorticoid replacement which had been calculated to be similar to the cortisol production rate during maximal stress. Thus, surgical stress in the setting of inadequate glucocorticoid (cortisol) replacement and epinephrine deficiency, stimulates additional sympathetic activity, probably as an adaptive mechanism to maintain homeostasis. Both norepinephrine and dopamine are recruited to compensate for the glucocorticoid and epinephrine deficiency. Glucocorticoid administration decreases but does not normalize this compensatory sympathetic activity.

Anorexia nervosa: Behavioural and hypothalamic aspects

Anorexia nervosa (AN) has been the subject of medical investigation for centuries, yet no clear understanding of the aetiology and pathogenesis of this disorder has emerged. Though most physicians would agree that the diagnosis must be made on a psychiatric basis, the somatic manifestations of AN have stimulated exploration of possible organic aetiologies. In particular, the prevalence of secondary amenorrhoea has led endocrinologists to investigate and find a number of hypothalamic--pituitary abnormalities (Mecklenburg et al, 1974; Frankel and Jenkins, 1975). Since appetite and satiety are hypothalamic functions, it has been suggested by Mecklenburg et al (1974), based on the observation of a spectrum of disordered hypothalamic functions in five patients with AN, that anorexia nervosa may be a primary hypothalamic disease. We have expanded Mecklenburgs original series of five AN patients to include 32 patients. All patients presented have fulfilled the psychiatric criteria for the diagnosis of AN (vide infra). Twenty-three patients had extensive hypothalamic--pituitary evaluation. We will first present the diagnostic criteria for patient selection associated with observations about certain behavioural characteristics of these patients. This will be followed by the collected data assessing hypothalamic, pituitary and end-organ function in patients with AN.