Pituitary anatomy and physiology

The pituitary has been called the master gland of the body because of its central role in governing homeostasis, maintaining the reproductive cycle, and directing the activity of other glands. Housed in the sella turcica of the sphenoid bone at the base of the skull, it has important anatomic relations with the hypothalamus, visual pathways, cavernous sinus, carotid artery, and cranial nerves. The gland originates from two discrete parts of the developing embryo. Rathke's pouch, a dorsal evagination of the stomodeum, forms the anterior and intermediate lobes. The infundibulum, a ventral extension of the diencephalon, forms the posterior lobe. The anterior, intermediate, and posterior lobes of the pituitary gland function as three separate endocrine organs, each characterized by distinct cell populations, secretory products, and regulatory mechanisms. The anterior lobe secretes thyroid stimulating hormone, corticotropin, luteinizing hormone, follicle stimulating hormone, growth hormone, and prolactin. It is regulated by the hypothalamus via the portal vascular system. The posterior lobe releases oxytocin and vasopressin from axon terminals that originate in cell bodies located in the hypothalamus. The intermediate lobe is rudimentary in human beings but produces several hormones whose physiologic significance is only now being established.     

Physiology of the pituitary, thyroid and adrenal glands

The pituitary gland is made of clusters of cells producing specific hormones that control growth (growth hormones, GH), thyroid function (TH), adrenal function (ACTH), gonadal function (FSH and LH). In addition, the neurons that join the posterior pituitary (neurohypophysis) secrete vasopressin - the antidiuretic hormone involved in maintaining water balance.The negative feedback loop is the basic mechanism to control the regulation of all endocrine glands. Hypothalamic peptides - releasing hormones (e.g. TRH, CRH) reach the hypophysis via the portal venous system and induce the secretion of specific stimulating hormones (e.g. TSH, ACTH) that drive the end-target endocrine cells to secrete hormones (e.g. thyroid hormones - T3 and T4 or adrenal hormones - cortisol, DHEAS). The plasma levels of these circulating hormones inhibit the pituitary (short feedback) or the hypothalamus (long feedback) and limit the further release of releasing- and stimulating- hormones.The effects of circulating hormones on different tissues are mediated via specific receptors on the cell membrane (e.g. vasopressin receptors), in the cytoplasm (steroid receptor for cortisol) or in the nucleus (e.g. thyroid hormone receptors). Understanding the physiological effects of peripheral hormones helps understanding the mechanisms by which clinical signs and symptoms developed in diseases characterised by excessive hormone secretion (e.g. thyrotoxicosis, Cushing syndrome, phaeochromocytomas) or lack of hormone secretion (e.g. diabetes insipidus).     

Immunocytochemical localization of bioregulatory peptides in marmoset testes.

Immunocytochemical localization of neuropeptides (beta-endorphin, substance P, arginine vasopressin, oxytocin), pituitary hormones (adrenocorticotropin, prolactin, growth hormone, follicle stimulating hormone (FSH), gonadal inhibin, gastrin, and human chorionic gonadotrophin (hCG)) was carried out in marmoset testis during development. Both intensity of immunostaining and distribution of these peptides in testicular compartments viz. seminiferous tubules and Leydig cells changed dramatically during development. In vitro biosynthesis of inhibin and FSH was increased by hCG, whereas prolactin (5 micrograms) and prostatic inhibin peptide suppressed the synthesis of these hormones.     

Anterior pituitary function in the vegetative state

Anterior pituitary function tests were performed in 33 patients in the vegetative state, and the results were assessed for correlation with various clinical factors. Radioimmunoassays were employed to measure the secretion of growth hormone and cortisol during insulin tolerance testing (regular insulin, 0.15 to 0.20 U/kg), luteinizing hormone and follicle stimulating hormone under administration of luteinizing hormone-releasing hormone (100 micrograms), and thyroid stimulating hormone and prolactin under administration of thyroid-releasing hormone (500 micrograms). Impairment rate, defined as number of abnormal hormone secretions divided by number of hormones examined, was calculated for each patient. The data were statistically assessed by analysis of variance in terms of disease, sex, age, site of lesion, etiology of vegetative state, duration of illness, brain atrophy as demonstrated by computed tomography, and Hockaday's electroencephalographic (EEG) grade. The results were as follows. 1) The levels of growth hormone, luteinizing hormone, follicle stimulating hormone, cortisol, thyroid stimulating hormone, and prolactin were abnormal in 70%, 67%, 45%, 39%, 36%, and 15% of cases, respectively. 2) Anterior pituitary hormone secretion was impaired in all 33 patients, severely in 52%. 3) The impairement rate was significantly increased in patients with ruptured cerebral aneurysms, primary coma, severe brain atrophy, and abnormal EEGs. 4) The impairment rate tended to be higher in long-term vegetative patients. These results suggest that, in the vegetative state, impairment of anterior pituitary function frequently occurs at the onset of disease and worsens over time.     

Hypothalamic-pituitary dysfunction in respiratory hypoxia.

Eight hypoxic male patients with stable chronic obstructive airways disease were submitted for combined anterior pituitary function testing. All subjects showed normal growth hormone and essentially normal cortisol responses to adequate hypoglycaemia, two subjects showed delayed responses of thyroid stimulating hormone to administered thyrotrophin releasing hormone and all had basal prolactin levels within normal limits. Basal levels of luteinising hormone were significantly lower than in the group of age-matched controls (p less than 0.02) but there was a normal increment after the injection of gonadotrophin releasing hormone. Basal levels of follicle stimulating hormone were significantly lower than in the controls (p less than 0.01), and there was also a reduced response from the pituitary after injection of gonadotrophin releasing hormone (p less than 0.01). Resting levels of the thyroid hormones thyroxine and tri-iodothyronine were normal while the expected subnormal testosterone level was observed (p less than 0.05). These results show that hypoxia can produce abnormalities of hypothalamic-pituitary function and that these are primarily located in the hypothalamic-pituitary-testicular axis.     

Growth related hormones in idiopathic scoliosis. An endocrine basis for accelerated growth

In a total of 95 children with idiopathic scoliosis and 60 controls between the ages of 7 and 17 years, a prospective study of hormones related to growth and maturation was carried out. The pituitary release mechanism for growth hormone was evaluated using the propanolol/L-dopa stimulation test. In addition the blood levels of testosterone, sex hormone binding globulin, oestradiol, thyroxin, prolactin, cortisol, follicle stimulating hormone and luteinizing hormone were determined. The girls were divided into age groups and all results were evaluated according to chronological and skeletal age. The number of boys was too small (25) to allow subdivision into age groups. The girls with idiopathic scoliosis had a significantly higher response to the growth hormone stimulation test than had the controls between the ages of 7 and 12 years whereas no significant difference could be found for the older girls. In girls with a skeletal age between 9 and 12 years a significantly higher mean serum level of testosterone was found (P less than 0.05). No significant differences could be demonstrated for the remaining hormones. Growth hormone and testosterone are the most important growth factors in prepubertal and pubertal children. Thus, the present findings suggest a hormonal basis for the increased stature in children with idiopathic scoliosis which has previously been reported.     

Reproductive Hormones and Bone

Hypothalamic gonadotropin-releasing hormone (GnRH) stimulates secretion of pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which directly regulate ovarian function. Pituitary FSH can modulate osteoclast development, and thereby influence bone turnover. Pituitary oxytocin and prolactin effects on the skeleton are not merely limited to pregnancy and lactation; oxytocin stimulates osteoblastogenesis and bone formation, whereas prolactin exerts skeletal effects in an age-dependent manner. Cyclic levels of inhibins and estrogen suppress FSH and LH, respectively, and also suppress bone turnover via their suppressive effects on osteoblast and osteoclast differentiation. However, continuous exposure to inhibins or estrogen/androgens is anabolic for the skeleton in intact animals and protects against gonadectomy-induced bone loss. Alterations of one hormone in the hypothalamic-pituitary-gonadal (HPG) axis influence other bone-active hormones in the entire feedback loop in the axis. Thus, we propose that the action of the HPG axis should be extended to include its combined effects on the skeleton, thus creating the HPG skeletal (HPGS) axis.     

Hormone production in clinically nonfunctioning pituitary adenomas

Pituitary tumors in which no excess hormone secretion can be identified clinically have been considered as nonfunctioning or null-cell adenomas. Immunocytochemical data presented here suggest that many of these tumors contain subunits of the glycoprotein hormones. Of 160 patients referred for pituitary surgery, 37 (23%) had no evidence of excess hormone secretion on preoperative endocrine evaluation. Immunocytochemical staining of these tumors was carried out using antibodies specific for prolactin, growth hormone, adrenocorticotropic hormone, the beta subunits of luteinizing hormone (beta-LH), follicle-stimulating hormone (beta-FSH), and thyroid-stimulating hormone (beta-TSH), and the alpha subunit. One or more of these pituitary hormones were detected in 73% of cases. The alpha and beta subunits were detected most frequently, being found in 68% of cases; 27% had staining for one or more beta subunits and 37.9% had staining for both alpha and beta subunits. The incidence was: beta-FSH in 58%, beta-LH in 47%, beta-TSH in 33%, and the alpha subunit in 42%. Staining for multiple glycoprotein hormones was common (52%), and mixed glycoprotein hormones and prolactin cell types were found in 16% of cases. These data suggest that most apparently nonfunctioning pituitary tumors contain immunoreactive hormones and the majority of these are subunits of the glycoprotein hormones. Since the glycoprotein hormone beta subunits must combine with the alpha subunit to produce biologically active hormones, the production of the subunits alone may not have endocrine manifestations.     

Suramin inhibits gonadotropin action in rat testis: implications for treatment of advanced prostate cancer.

Suramin is being evaluated for the treatment of metastatic prostate cancer based on its inhibition of growth factor action. In addition, suramin may inhibit the endocrine control of androgen production, which was explored herein. Adult Sprague-Dawley rats were injected (i.p.) daily with varying doses of suramin. At a cumulative dose of 200 mg., suramin significantly depressed serum testosterone (p less than 0.05), and follicle stimulating hormone (p less than 0.002) levels. In vitro studies showed that suramin-mediated suppression of androgen production might be secondary to inhibition of gonadotropin action. In MA-10 cell cultures, suramin inhibited a maximum stimulatory dose of human chorionic gonadotropin with an ED50 of 4.4 microM. Studies in rat Sertoli cell cultures showed that follicle stimulating hormone action was also inhibited by suramin, with an ED50 of 8.6 microM. Using receptor binding assays with calf testis membrane, we showed that suramin inhibited 125I-hFSH binding to receptor in a dose dependent fashion with an ED50 of 10.4 microM; comparable to the ED50 of suramin inhibition of follicle stimulating hormone action in Sertoli cell culture cells. Thus the mechanism of suramin's suppression of androgen production may involve multiple sites of action, including inhibition of gonadotropin binding to its receptor and suppression of pituitary gonadotropin levels in serum. This inhibition of androgen production may be useful in the treatment of advanced prostate cancer.     

垂体激素和激素替代治疗对骨代谢调控的研究进展

既往研究多认为垂体分泌的激素通过其靶内分泌腺对骨代谢进行间接调控。但近年来,越来越多的研究发现垂体激素如生长激素、促甲状腺素、促性腺素、促肾上腺皮质素以及催产素等对骨代谢具有直接调节作用,这些激素通过作用于相应的受体,激活不同的信号通路,直接作用于成骨细胞、破骨细胞,从而发挥生物学效应,影响骨量及骨质疏松性骨折的发生率。垂体功能低下患者长期使用生长激素、糖皮质激素、性激素、甲状腺素等替代治疗亦对骨代谢有着不同的调控作用。它们也是直接与成骨或破骨细胞膜上相应的受体结合,通过基因或非基因效应,从而对骨量进行调节。本文综述了垂体激素对骨骼的直接作用及激素长期替代治疗对骨代谢的调控,旨在为疾病的早期诊断、精准个体化治疗提供一些思路。     

Growth Related Hormones in Idiopathic Scoliosis: An Endocrine Basis for Accelerated Growth

In a total of 95 children with idiopathic scoliosis and 60 controls between the ages of 7 and 17 years, a prospective study of hormones related to growth and maturation was carried out.

The pituitary release mechanism for growth hormone was evaluated using the propanolol/L-dopa stimulation test. in addition the blood levels of testosterone, sex hormone binding globulin, oestradiol, thyroxin, prolactin, Cortisol, follicle stimulating hormone and luteinizing hormone were determined. the girls were divided into age groups and all results were evaluated according to chronological and skeletal age. the number of boys was too small (25) to allow subdivision into age groups.

The girls with idiopathic scoliosis had a significantly higher response to the growth hormone stimulation test than had the controls between the ages of 7 and 12 years whereas no significant difference could be found for the older girls. in girls with a skeletal age between 9 and 12 years a significantly higher mean serum level of testosterone was found (P < 0.05). No significant differences could be demonstrated for the remaining hormones.

Growth hormone and testosterone are the most important growth factors in prepubertal and pubertal children. Thus, the present findings suggest a hormonal basis for the increased stature in children with idiopathic scoliosis which has previously been reported.     

Thyroid function and endocrine abnormalities in elderly patients with severe chronic obstructive lung disease.

Serum pituitary and thyroid hormones, testosterone, and the response of pituitary hormones to thyrotrophin releasing hormone were measured in 20 inpatients (mean age 68, range 42-81 years) with severe chronic obstructive lung disease and in 15 control convalescent inpatients (mean age 73, range 57-83 years) who had normal respiratory function. No significant differences were found in total and free thyroid hormone concentrations and basal concentrations of thyrotrophin, growth hormone, and prolactin; and their increments after injection of thyrotrophin releasing hormone were similar in patients with chronic obstructive lung disease, and control patients. Three patients with chronic obstructive lung disease, however, had no thyrotrophin responses to thyrotrophin releasing hormone. In men, low testosterone concentrations were found both in patients with chronic obstructive lung disease and in controls. Luteinising hormone concentrations were higher in men with chronic obstructive lung disease (p less than 0.02), whereas concentrations of follicle stimulating hormone in the two groups were not significantly different. There was no significant correlation between arterial blood gas tensions and these hormone measurements. General effects of age and illness may be more important than direct effects of hypoxia in determining hypothalamic-pituitary function in elderly patients with chronic obstructive lung disease.     

Changes of pituitary hormones in brain death

Summary In six patients with clinical and electroencephalographic signs of brain death, pituitary hormones such as prolactin, human growth hormone (GH), luteinizing hormone (LH), and thyrotrophin (TSH) were measured in blood close to the demonstration of intracranial circulatory arrest by angiography. In addition, pituitary hormone releasing tests and an insulin test were carried out in two patients. The results showed that no patient had a general decrease in hormone levels, according to their biological half life times, which suggests there still was some function in the hypothalamus and pituitary. This was supported by the results of the stimulation tests. It is concluded that in brain death some basal parts of the brain may still be perfused despite the fact that angiography indicates circulatory arrest in these areas.     

Hormonal effects of high dose medroxyprogesterone acetate treatment in males with renal or prostatic adenocarcinoma

In 18 patients, 12 with renal and 6 with prostatic carcinoma, the gonadal, pituitary and adrenal functions were studied by measurements of steroid hormones and gonadotrophins, before and after six weeks treatment with medroxyprogesterone acetate (MPA), injected intramuscularly 500 mg per day for 5 days each week. The testosterone-oestradiol-binding globulin (TeBg) was measured and the amount of albumin and TeBg bound and unbound testosterone was calculated. Treatment with high doses of MPA caused a profound decrease in serum concentrations of testosterone, dehydroepiandrosterone sulphate (DHEAS), cortisol and TeBg. There were significant decreases in serum concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH) and oestradiol-17 beta. The serum concentration of prolactin was significantly elevated. The protein unbound testosterone fraction was lowered by MPA treatment but less than total testosterone. In conclusion, MPA therapy in high dose alters the gonadal, pituitary and adrenal functions suppressing serum concentrations of androgens, gonadotrophins, cortisol and TeBg but elevating prolactin concentration.     

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.     

Rational Design of Competitive Prolactin/Growth Hormone Receptor Antagonists

There is increasing evidence that prolactin (PRL) and growth hormone (GH) act as growth-promoters of breast tumors. Recent arguments have accumulated to suggest that when they are locally-produced within the mammary tissue, these hormones, acting by an autocrine-paracrine mechanism may have enhanced, or even specific functions compared to endocrine PRL and GH. Classical drugs blocking pituitary hormone production (dopamine and somatostatin analogs) are ineffective on extrapituitary expression of PRL/GH genes, therefore the undesirable effects of these locally-produced hormones remain a target of interest for alternative strategies. This has encouraged the development of competitive PRL and/or GH receptor antagonists, which involve engineered variants of natural receptor ligands (PRL or GH) aimed at blocking receptor activation rather than hormone production in peripheral tissues. This article overviews the rational design of this new class of molecules, their specific molecular features (receptor specificity, biological properties, etc.) and whenever available, the data that have been obtained in cell or animal models of breast cancer.     

Changes in serum levels of LH, FSH, prolactin, testosterone, and cortisol associated with season and mating in male pygmy goats

Four male pygmy goats were used in a study designed to determine the effects of season on serum hormone (luteinizing hormone, follicle stimulating hormone, prolactin, testosterone, and cortisol) levels, testis size and libido, and the effects of mating on serum hormone profiles. Seasonal peaks were observed for prolactin in July, luteinizing hormone and follicle stimulating hormone in September, and testosterone in October. Luteinizing hormone peak frequency was greatest in September and was increased by mating activity in the months immediately preceding the breeding season. Scrotal circumference did not vary with season and libido showed no consistent seasonal pattern. Mating appeared to raise all hormone levels except during the months when these hormones were seasonally elevated. When episodic releases of luteinizing hormone occurred, they were associated with subsequent rises in serum testosterone levels. On some mating days, when episodic releases of luteinizing hormone were absent, changes in testosterone levels were highly correlated with changes in cortisol levels. It was concluded that both season and mating influence reproductive hormone levels in male pygmy goats.     

Thyroid and parathyroid hormones and calcium homeostasis

The thyroid gland is under the control of thyroid stimulating hormone (TSH) from the pituitary. It secretes thyroxine (T4) and triiodothyronine (T3). Iodine is essential for the synthesis of thyroid hormones. T4 is probably converted to T3 in peripheral tissues. Thyroid hormones have a role in growth and development but their principal effect is the control of basal metabolic rate. Deficiency or excess affects all the tissues of the body, reducing or increasing the metabolic rate, resulting in hypothermia or hyperthermia, respectively. Deficiency during development produces mental retardation. Lack of iodine leads to thyroid swelling (goitre) caused by continuing stimulation by TSH. Calcium is one of the most tightly controlled ions in the body; abnormalities can produce muscle paralysis. Bone is the major store of calcium. Calcium reabsorption by the kidney is controlled by parathyroid hormone (PTH) produced by the parathyroid glands, which lie in the posterior part of the lobes of the thyroid gland. PTH secretion is controlled by blood calcium concentrations. Phosphate metabolism is intimately bound up with the control of calcium levels, as is the metabolism of vitamin D, which stimulates the absorption of calcium from the gastrointestinal tract and, in part, from the kidney.     

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.     

Preoperative preparation of patients with pituitary gland disorders

This paper presents the most common disorders of pituitary function: acromegaly, hypopituitarism, diabetes insipidus and syndrome similar to diabetes insipidus, in terms of their importance in preoperative preparation of patients. Pituitary function manages almost the entire endocrine system using the negative feedback mechanism that is impaired by these diseases. The cause of acromegaly is a pituitary adenoma, which produces growth hormone in adults. Primary therapy of acromegaly is surgical, with or without associated radiotherapy. If a patient with acromegaly as comorbidity prepares for non-elective neurosurgical operation, then it requires consultation with brain surgeons for possible delays of that operation and primary surgical treatment of pituitary gland. If operative treatment of pituitary gland is carried out, the preoperative preparation (for other surgical interventions) should consider the need for perioperative glucocorticoid supplementation. Panhypopituitarism consequences are different in children and adults and the first step in diagnosis is to assess the function of target organs. Change of electrolytes and water occurs in the case of pituitary lesions in the form of central or nephrogenic diabetes insipidus as a syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Preoperative preparation of patients with pituitary dysfunction should be multidisciplinary, whether it is a neurosurgical or some other surgical intervention. The aim is to evaluate the result of insufficient production of pituitary hormones (hypopituitarism), excessive production of adenohypophysis hormones (acromegaly, Cushing's disease and hyperprolactinemia) and the influence of pituitary tumours in surrounding structures (compression syndrome) and to determine the level of perioperative risk. Pharmacological suppressive therapy of the hyperfunctional pituitary disorders can have significant interactions with drugs used in the perioperative period.