Physiology of the pituitary,thyroid, parathyroid and adrenal glands

The pituitary gland is made of clusters of cells producing specific hormones that control growth (growth hormone), thyroid function (triiodothyronine (T₃) and thyroxine (T₄)), adrenal function (adrenocorticotrophic hormone (ACTH)) and gonadal function (follicle-stimulating hormone and luteinizing hormone). In addition, the neurons that join the posterior pituitary (neurohypophysis) secrete vasopressin – the antidiuretic hormone involved in maintaining water balance.     

Hypothalamic and pituitary function

The endocrine system consists of groups of cells (glands) that secrete messengers (hormones), which affect distant groups of cells (target organs). It controls mainly basal processes. Hormonal action may be on receptors in the target cell membrane (e.g. leading to alterations in membrane channel properties), in which case it is rapid, or it may affect gene function and thus protein synthesis, in which case the onset of action is relatively slow. Endocrine function is controlled via single and multiple feedback mechanisms from products of the various target organs. It is largely under the control of the hypothalamus via the pituitary gland. Releasing factors and hormones from the hypothalamus act on the pituitary, which produces its own hormones (antidiuretic hormone, oxytocin, growth hormone and prolactin) as well as hormones and releasing factors that affect other endocrine glands (adrenocorticotrophic hormone, thyroid stimulating hormone, luteinizing hormone and follicle stimulating hormone). Growth hormone controls skeletal growth via the release of insulin-like growth factors from the liver; it promotes anabolism, but also antagonizes the hypoglycaemic effect of insulin. Antidiuretic hormone secretion is stimulated by changes in osmolality and is a sensitive mechanism for conserving fluid via its action on the kidney. Oxytocin stimulates uterine contraction, and prolactin stimulates milk production. Luteinizing and follicle stimulating hormones affect the growth of the gonads.     

Potentiated hormonal responses in a model of traumatic injury

Although major trauma often involves repeated insults, few studies have examined the endocrine response to repeated injury. In earlier work, we described potentiated responses of circulating adrenocorticotropin (ACTH) and adrenal secretion of cortisol, epinephrine, and norepinephrine to the second of two small hemorrhages separated by 24 hr. To investigate the response of other hormones to repeated hemorrhage and to examine possible hormonal interactions in a shorter, more clinically relevant time frame, we placed chronic adrenal vein cannulas in eight splenectomized, trained dogs. Each animal was bled 10% of measured blood volume with reinfusion of shed blood at 30 min. The hemorrhage was repeated 5 hr later. Initial hemorrhage led to a small but significant increase in adrenal cortisol secretion and circulating ACTH, vasopressin (AVP), angiotensin II (AII), and plasma renin activity (PRA). Although a 5-hr time interval between stimuli is commonly thought to lead to cortisol feedback, the circulating ACTH and adrenal cortisol secretory responses to the second hemorrhage were exaggerated in comparison to their initial responses. Similarly, the AVP response to the second hemorrhage was also increased. In contrast, the responses of PRA and AII to the second hemorrhage were not greater than their responses to the initial hemorrhage. No differences in measured blood volume before each hemorrhage or in the heart rate and arterial pressure responses to hemorrhage were observed that could explain the potentiated hormonal responses. Thus, potentiated responses of cortisol, ACTH, and AVP, but not of PRA and AII, were observed in a model of trauma that emphasizes repeated injury in a clinically relevant time frame.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute endocrine failure after brain death?

After brain death, 32 potential organ donors were studied to determine serum and plasma concentrations of hypothalamic-pituitary hormones, thyroid hormones, and cortisol over a period of up to 80 hr. Diagnosis of brain death was established either on the basis of clinical criteria (n = 16) or by angiography (n = 16). While 78% of the organ donors developed diabetes insipidus, none of the circulating hormones of the anterior pituitary gland showed a progressive decline in concentration according to their plasma half-lives. With the exception of arginine vasopressin (AVP), no hormone concentration was found to be subnormal due to the onset of brain death. The subnormal free triiodothyronine (FT3) values in 62% of cases (median FT3 of 2.2 pmol/L within the first 24 hr) and the cortisol concentration of 6.9 micrograms/dl correlate with the frequency of similar findings in patients with severe head injuries. While the adrenocorticotropic hormone (ACTH) concentrations of 10-53 pg/ml remained constant during the study period, thyroid-stimulating hormone (TSH) and human growth hormone (hGH) concentrations showed a 12- and 35-fold increase from baseline values after 30-40 hr. These results suggest that, despite the now generally accepted criteria of brain death, there is still some residual function, and thus also perfusion of the hypothalamic-pituitary neuroendocrine system. This residual function appears to be sufficient to maintain hormonal plasma levels at least in the low reference range in most donors. Hormonal depletion in organ donors subsequent to brain death, as suggested repeatedly in the literature, could not be confirmed. The analysis of serum or plasma concentration patterns of a number of hormonal parameters following brain death does not support the rationale for a routine replacement therapy of total triiodothyronine (TT3) or cortisol to maintain endocrine homeostasis prior to organ harvest. However, dexamethasone therapy may be followed by suppression of the adrenal cortex of the organ donor. In these cases, cortisol substitution may be indicated.     

Effect of adrenal steroids on testosterone and luteinizing hormone secretion in the ram

The effects of adrenal steroids on testosterone and LH secretion and changes in serum cortisol levels in response to treatments were studied in the ram. Acute administration of synthetic ACTH (10 micrograms/kg BW) elevated (P less than 0.01) serum cortisol and transiently suppressed (P less than 0.05) serum testosterone and LH. Acute dexamethasone treatment suppressed (P less than 0.01) serum cortisol, testosterone and LH. Administration of vehicle had no effect (P greater than 0.10) on serum hormone levels. These data support the contention that adrenal steroids inhibit testicular endocrine function indirectly by acting at the hypothalamic or pituitary level because both ACTH and dexamethasone treatments suppressed serum LH. To differentiate between hypothalamic and pituitary sites of action, the pituitary and testicular responses to an LHRH challenge (100 micrograms) were examined in rams chronically treated with dexamethasone (5 mg i.m., twice daily for 5 days). This treatment regimen suppressed (P less than 0.01) serum cortisol levels. Compared with controls, basal testosterone levels were suppressed (P less than 0.05) in dexamethasone-treated rams; however, no effect (P greater than 0.10) on the magnitude of the testosterone response to LHRH or on either basal or LHRH-stimulated LH secretion was observed. Thus, although a direct testicular effect cannot be eliminated, these data suggest that, in the ram, adrenal steroids inhibit testicular endocrine function by action at the level of the hypothalamus.     

Tumor necrosis factor: immune endocrine interaction

Tumor necrosis factor (TNF), a peptide produced by macrophages in response to endotoxin, has been implicated as a mediator of septic shock. This study examined the effects of injections of recombinant (r) human TNF on circulating levels of metabolic substrates and hormones in conscious, unrestrained rats and the effects of TNF on cortisol secretion from human adrenocortical cells in vitro. Sublethal doses of rTNF--doses that did not produce hemodynamic changes in previous work--produced rapid (1 hour), significant increases in blood levels of glucose, lactate, and triglycerides and decreases in plasma levels of branched chain amino acids. Plasma levels of glucagon, corticosterone, ACTH, norepinephrine, and dihydroxyphenylglycol were also increased significantly. Incubation of adrenocortical cells with either 0.15 or 1.5 micrograms of rTNF increased cortisol secretion to the same extent as did 10(-10) mol/L ACTH. Administration of TNF produces a variety of metabolic and neuroendocrine effects including stimulation of anterior pituitary, adrenal cortical, and pancreatic secretion, and sympathoneural activation. These changes, and the in vitro results, are consistent with the view that immune cells can interact with endocrine cells through release of TNF.     

Preclinical Cushing''s syndrome: Report of seven cases and a review of the literature

BACKGROUND: Adrenal adenomas showing autonomous cortisol secretion without specific endocrine symptoms are sometimes discovered in patients with adrenal incidentalomas. This entity has been described as subclinical or preclinical Cushing's syndrome (PCS), but the endocrine data of reported cases have varied and the diagnostic criteria of PCS have been uncertain. METHODS: We report seven Japanese cases of PCS due to a unilateral, solitary adrenal adenoma with examination of the endocrine data of these patients. The diagnostic parameters of subtle hypercortisolism and the risk of postoperative adrenal insufficiency and surgical indications are discussed and reviewed. RESULTS: In the present cases, the most frequently found biochemical parameters of autonomous cortisol secretion were a low adrenocorticotropic hormone (ACTH) level (100%) and insufficient suppression of cortisol by low-dose dexamethasone (85.7%). Unilateral accumulation of radiopharmaceuticals in tumors was also frequently observed (100%). A postoperative hydrocortisone supplement was given to six of the seven patients for 5-122 days. It was not given to case 4, because a moderate response of 11-deoxycortisol to metyrapone was identified. Plasma ACTH levels and the diurnal rhythm of plasma cortisol rapidly recovered within 3 weeks postoperatively in six of the seven cases. CONCLUSION: This entity is heterogeneous and various degrees of cortisol excess have been observed. It should be diagnosed in the wide spectrum and the risk of adrenal insufficiency after surgery should be evaluated by dynamic tests such as the corticotropin-releasing hormone (CRH) test. Based on the results of the present study and a review of the literature, PCS patients may not require hydrocortisone supplement therapy for a long period.     

Contemporary evaluation and management of Cushing's syndrome

Cushing's syndrome, characterized by unregulated cortisol secretion, may be caused by a variety of adrenal, pituitary, or other tumors. The best biochemical test for establishing the diagnosis is determination of 24-h urinary free cortisol. The specific causes for Cushing's syndrome may be further differentiated by plasma adrenocorticotrophic hormone (ACTH). Primary adrenal cortical diseases are associated with low levels of ACTH and are considered ACTH-independent. Pituitary disease and the ectopic ACTH syndrome are associated with normal or elevated ACTH levels and are considered ACTH-dependent. Adrenal forms of Cushing's syndrome may result from either adenoma or carcinoma. The diagnostic approach to Cushing's syndrome and the clinical, biochemical, and radiographic features that distiguish adrenal adenoma and carcinoma are the subjects of this paper.     

In Vitro and In Vivo Temporal Aspects of ACTH Secretion: Stimulatory Actions of Corticotropin‐Releasing Hormone and Vasopressin in Cattle

The objective of the present study was to evaluate the temporal aspects associated with corticotropin‐releasing hormone (CRH) and vasopressin (VP) stimulated bovine adrenocorticotropic hormone (ACTH) secretion in vitro and in vivo. For the in vitro studies, bovine anterior pituitary glands were enzymatically dispersed to establish primary cultures. On day 5 of culture, cells were challenged for 3 h with medium alone (Control) or various combinations and concentrations of bovine CRH (bCRH) and VP. Both CRH and VP each increased (P < 0.05) ACTH secretion. Maximal increases in ACTH secretion occurred in response to 0.1 μm CRH (5.5‐fold) and 1 μm VP (3.7‐fold), relative to Control cells. The in vivo portion of the study examined possible temporal differences in the activation of the pituitary‐adrenal axis by CRH and VP. Jersey cows were randomly assigned to one of four groups (n = 8 cows/group): (i) Control (saline); (ii) bCRH (0.3 μg/kg BW); (iii) VP (1 μg/kg BW) and (iv) bCRH (0.3 μg/kg BW) + VP (1 μg/kg BW). Jugular blood samples were collected at 15‐min intervals for 4 h pre‐ and for 6 h post‐treatment; samples were also taken at 1, 5 and 10 min post‐treatment. Plasma concentration of ACTH did not differ among treatment groups for the 4‐h pre‐treatment period. At 1 min post‐treatment, bCRH + VP, VP and bCRH increased ACTH secretion by 22.4‐, 9.6‐ and 2.2‐fold, respectively, relative to Control (32.7 ± 7.2 pg/ml). Maximal plasma concentration of ACTH occurred at 5, 10 and 15 min post‐treatment for the VP (1017.7 ± 219.9 pg/ml), bCRH + VP (1399.8 ± 260.1 pg/ml) and bCRH (324.8 ± 126.2 pg/ml) treatment groups respectively. Both the in vitro and in vivo data demonstrated that while VP acutely activates the bovine pituitary‐adrenal axis, CRH‐induced ACTH secretion is slower in onset but of longer duration. The present study also provides insight into the dynamics of ACTH and cortisol (CS) responsiveness to CRH and VP in cattle.     

Normal and pathologic endocrinology of the adrenal glands

The adrenal glands produce glucocorticoids (approximately 25 mg cortisol/day), mineralocorticoids (approximately 100 micrograms aldosterone/day) and androgens (e.g. dehydroepiandrosterone = DHEA approximately 10 mg/day) in their cortex and catecholamines in their medulla. Excessive cortisol production leads to Cushing's syndrome. In approximately 2/3 of the cases this is due to ACTH oversecretion most often from a pituitary adenoma and can be cured by removal of this adenoma. Cushing's syndrome caused by an adrenal adenoma, carcinoma or bilateral nodular adrenal hyperplasia is treated by adrenal surgery. Nelson's syndrome consists of hyperpigmentation of the skin and an often aggressively growing pituitary adenoma which secretes excessive amounts of ACTH. Treatment is surgical. Conn's syndrome (primary hyperaldosteronism) is due to aldosterone hypersecretion most often from an adrenal adenoma (therapy: unilateral adrenalectomy), more seldom from bilaterally hyperplastic adrenals (therapy: spironolactone). Excessive adrenal androgen secretion is found in the adrenogenital syndrome in which defective cortisol biosynthesis leads to ACTH oversecretion and ACTH-stimulated overproduction of cortisol precursors, some of which are androgens. Treatment consists of glucocorticoids which suppress the ACTH oversecretion. Pheochromocytomas produce excessive amounts of catecholamines and cause hypertension which can be persistent as well as episodic. Therapy consists of adrenalectomy. Malignant tumors of the adrenals have a poor prognosis. Incidentally found adrenal masses ("incidentalomas") are observed at regular intervals if they are small and should be surgically removed if they have a tendency to grow or are large (greater than or equal to 5 cm phi).     

Endocrine effects of vasopressin in critically ill patients

Vasopressin, also called antidiuretic hormone, is a 9 amino-acid peptide, synthesized from a precursor containing neurophysin II, by neurones from the supra-optic and peri-ventricular nuclei, and then stored in the posterior hypophysis. Vasopressin regulates plasmatic osmolality and volaemia via V2 receptors at the levels of the kidney, and vascular smooth muscle tone via V1a arterial receptors. Both its synthesis and release from hypophysis vesicles depend on variations in plasma osmolality, volaemia, and arterial blood pressure. In addition, vasopressin interacts with the main hormonal systems involved in the response to stress, including the hypothalamic-pituitary adrenal axis, other anterior pituitary hormones, mainly prolactin and growth hormone, the renin-angiotensin system, and regulates insulin synthesis and glucose metabolism. Interestingly, during critical illness, exogenous administration of vasopressin showed little effects on the circulating levels of these various hormones, except an increase in prolactin. The absence of endocrine effects of vasopressin during critical illness is unclear and may relate to an already maximal hormonal stimulation or to down-regulation of vasopressin receptors.     

Catecholamine-resistant shock and hypoglycemic coma after cardiotomy in a patient with unexpected isolated ACTH deficiency

Isolated adrenocorticotropic hormone (ACTH) deficiency is an extremely rare disease in which ACTH-producing cells of the pituitary gland are selectively damaged. The resulting decline in ACTH production and secretion results in chronic secondary adrenocortical insufficiency. The patient in this case did not present with adrenal insufficiency symptoms prior to surgery. However, after cardiotomy under extracorporeal circulation, the patient lapsed into a catecholamine-resistant shock and hypoglycemic coma. Acute adrenal insufficiency was strongly suspected, and the patient was diagnosed with isolated ACTH deficiency after careful examination. Because the demand for cortisol increases after highly invasive surgeries, cortisol supplementation therapy is essential for patients with complications from isolated ACTH deficiency. There is a high risk of a lethal outcome when surgery is carried out without a diagnosis, as in this case. Therefore, cortisol must be supplemented without delay when acute adrenal insufficiency is suspected during the perioperative period.     

Aldosterone secretion following non-hypotensive hemorrhage is potentiated by prior blood loss

Aldosterone is a major regulator of fluid and electrolyte balance after hemorrhage and is released from the adrenal cortex by the action of adrenocorticotropin (ACTH) and angiotensin II (AII). Past work has shown that the hemorrhage-induced release of ACTH and cortisol is potentiated by prior hemorrhage. We therefore studied the response of adrenal aldosterone secretion to repeated hemorrhage and its control by ACTH and AII. Six awake dogs with chronic lumboadrenal vein catheters were bled 10% of measured blood volume (H1) with reinfusion at 30 minutes. The hemorrhage was repeated 5 hours later (H2). Adrenal presentation rates for AII (AII-PR) and ACTH (ACTH-PR) were calculated for each sample. Control hormonal and hemodynamic parameters before each hemorrhage were not different; hemodynamic responses to H1 and H2 did not differ. Aldosterone secretion increased significantly after each hemorrhage. The increase in aldosterone secretion after H1 was associated with an early increase in AII-PR and late increase in ACTH-PR. Aldosterone secretion following H2 was greater than that following H1 and was associated with early and larger responses of AII-PR and ACTH-PR. Aldosterone secretion following H1 correlated with the AII-PR (r = 0.75; p less than 0.001), but not with the ACTH-PR. In contrast, aldosterone secretion following H2 correlated with both the AII-PR (r = 0.54; p less than 0.01) and ACTH-PR (r = 0.71; p less than 0.001) and multiple regression analysis showed a highly significant relation with both AII and ACTH (r = 0.81; p less than 0.001). The data suggest that aldosterone secretion after initial small hemorrhage occurs as a result of increased AII, whereas both AII and ACTH may contribute to the larger aldosterone secretory response to H2. Since major trauma commonly involves at least two insults separated in time (e.g., injury followed by surgery), potentiated responses of aldosterone and other pituitary-adrenal hormones (ACTH, vasopressin, and cortisol) may have important implications for the control of fluid and electrolyte balance and metabolism in injured patients.     

Anterior pituitary, thyroid, parathyroid and adrenal responses to subtotal thyroidectomy in patients with Graves' disease

Changes in the serum levels of anterior pituitary, thyroid, parathyroid, and adrenal hormones following subtotal thyroidectomy in 31 patients with Graves' disease were investigated. In 14 patients, rapid ACTH tests were performed on the preoperative and the first, third, and seventh post-operative days. Remarkable differences were not seen with regard to the changes in anterior pituitary hormones or cortisol, compared to those seen during general surgery. As to the thyroid hormones, the serum level of triiodothyronine (T3) decreased markedly after surgery and fell to half that of the preoperative value on the first postoperative day. Thereafter, a low value of T3 was maintained during the early postoperative period. Unlike T3, the serum level of thyroxine (T4) decreased gradually until the 7th post-operative day. The levels of both epinephrine and norepinephrine increased transiently during surgery, but the serum level of norepinephrine increased again on the third postoperative day. In the postoperative period, almost half the number of patients showed an inadequate cortisol response to rapid ACTH tests. It is suggested that the unique responses, such as the rise in serum norepinephrine or an inadequate response of cortisol to ACTH, or hypocalcemia, after subtotal thyroidectomy in patients with Graves' disease is largely due to the rapid decrease of T3 in the hypothyroid state, as was noted during the postoperative period.     

Anterior pituitary,thyroid, parathyroid and adrenal responses to subtotal thyroidectomy in patients with Graves’ disease

Changes in the serum levels of anterior pituitary, thyroid, parathyroid, and adrenal hormones following subtotal thyroidectomy in 31 patients with Graves’ disease were investigated. In 14 patients, rapid ACTH tests were performed on the preoperative and the first, third, and seventh postoperative days. Remarkable differences were not seen with regard to the changes in anterior pituitary hormones or cortisol, compared to those seen during general surgery. As to the thyroid hormones, the serum level of triioodothyronine (T₃) decreased markedly after surgery and fell to half that of the preoperative value on the first postoperative day. Thereafter, a low value of T₃ was maintained during the early postoperative period. Unlike T₃, the serum level of thyroxine (T₄) decreased gradually until the 7th post-operative day. The levels of both epinephrine and norepinephrine increased transiently during surgery, but the serum level of norepinephrine increased again on the third postoperative day. In the postoperative period, almost half the number of patients showed an inadequate cortisol response to rapid ACTH tests. It is suggested that the unique responses, such as the rise in serum norepinephrine or an inadequate response of cortisol to ACTH, or hypocalcemia, after subtotal thyroidectomy in patients with Graves’ disease is largely due to the rapid decrease of T₃ in the hypothyroid state, as was noted during the postoperative period.     

Hormonal regulation of mammary differentiation and milk secretion

The endocrine system coordinates development of the mammary gland with reproductive development and the demand of the offspring for milk. Three categories of hormones are involved. The levels of the reproductive hormones, estrogen, progesterone, placental lactogen, prolactin, and oxytocin, change during reproductive development or function and act directly on the mammary gland to bring about developmental changes or coordinate milk delivery to the offspring. Metabolic hormones, whose main role is to regulate metabolic responses to nutrient intake or stress, often have direct effects on the mammary gland as well. The important hormones in this regard are growth hormone, corticosteroids, thyroid hormone, and insulin. A third category of hormones has recently been recognized, mammary hormones. It currently includes growth hormone, prolactin, PTHrP, and leptin. Because a full-term pregnancy in early life is associated with a reduction in breast carcinogenesis, an understanding of the mechanisms by which these hormones bring about secretory differentiation may offer clues to the prevention of breast cancer.     

Routine hormone load tests are unnecessary in infertile men

A sample of 225 men examined at the Infertility Service Unit of this hospital had spermiograms, standardized in accordance with WHO guide lines, and a hormone stimulation test with injection of gonadotropin releasing hormone, thyrotropin releasing hormone, and ACTH. The serum concentrations of the following hormones were assessed: follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, oestradiol (E), thyroid stimulating hormone, cortisol, 21-desoxycortisol, 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone, dehydroepiandrosteronesulphate, androstenedione, testosterone (T), and dihydrotestosterone. The results of the spermiograms were found to be related to the concentrations of the following hormones: FSH, LH, T, and E. Thyroid and adrenal function in men without signs of endocrinological diseases failed to influence spermatic parameters.     

Effects of a low-phosphorus, low-nitrogen diet supplemented with essential amino acids and ketoanalogues on serum beta-endorphin in chronic renal failure

The effects of a vegetarian low-protein, low-phosphorus diet supplemented with essential amino acids and ketoanalogues, on the serum beta-endorphin, growth hormone, parathyroid hormone, thyroid hormones (T3 and T4), pituitary TSH and total cortisol were studied in 12 male chronic uremics. beta-Endorphin decreased, as well as growth hormone. Parathyroid hormone and T3 improved significantly, reaching almost normal values. It is hypothesized that the correction of the beta-endorphin excess may account in part for the improvement of some endocrinological and metabolic effects exerted by this dietary treatment. The possible pathophysiological mechanisms which could explain the antiendorphinic action of this treatment in uremic patients are discussed, as well as the possible beneficial endocrine and metabolic effects exerted by the fall in circulating beta-endorphin.     

Physiology of the pituitary,thyroid, parathyroid and adrenal glands

Endocrinology is the study of hormones, endocrine glands and related diseases. Understanding basic hormonal physiology is essential for surgeons to manage patients with endocrine disorders. In this article we present the fundamental physiological mechanisms related to pituitary, thyroid, parathyroid and adrenal hormonal production, secretion and action. Moreover the methods used in the investigation for hormonal disturbances associated with these glands, resulting in excess or deficient secretion, are introduced.     

Physiology of the pituitary,thyroid, parathyroid and adrenal glands

Endocrinology is the study of hormones, endocrine glands and related diseases. Understanding basic hormonal physiology is essential for surgeons to manage patients with endocrine disorders. In this article we present the fundamental physiological mechanisms related to pituitary, thyroid, parathyroid and adrenal hormonal production, secretion and action. Moreover the methods used in the investigation for hormonal disturbances associated with these glands, resulting in excess or deficient secretion, are introduced.