endocrinology Flashcards
Dyslipidemia CAM treatment options
fish oil/ omega 3 fatty acid (increase risk of bleeding in combination, for both primary and secondary prevention) and plant sterols and stanols (take 2-3 weeks, GI side effects, drug interaction with ezetimide
Weight loss CAM treatment options
ephedra (banned), bitter orange, calcium (due to dietary intake), orilistat (risk of liver injury, best outcome in patients with a BMI over 27)
Diabetes CAM treatment options
chromium (caution in renal dysfunction) and vanadium (kidney toxicity, effective in DM2, increase risk of bleeding in combination)
Hypertension CAM treatment options
Garlic (allicin is active agent) and coenzyme Q-10 (statins, beta blocker, and diuretics can lower levels, increase risk of bleeding, increase T4/T8 labs)
The Pituitary Gland
The pituitary is really two separate glands of dual origin in the shape of one organ. Positioned in the sella turcica at the base of the skull, the pituitary is comprised of: 1. The anterior pituitary, or adenohypophysis, made up of the pars distalis, pars intermedia, and pars tuberalis. 2. The posterior pituitary, or pars nervosa (or infundibular process), the infundibular stem or stalk, and the median eminence. The anterior pituitary is derived embryonically from an outgrowth of endoderm called Rathke’s pouch, while the posterior pituitary is really an extension of the brain (the hypothalamus).
Pars Distalis
The anterior pituitary is composed of cells that synthesize and release growth hormone (GH), prolactin (PRL), adrenocorticotropin (ACTH) and derivatives, thyroid stimulating hormone (TSH), and two gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH). There is an extensive vasculature of small vessels/capillaries/sinusoids within the pars distalis. The hormone-secreting cells are arranged in rows around capillary endothelial cells that are fenestrated to allow rapid passage of hormones out from the various endocrine cells, but also enables diffusion towards the cells of releasing factors transported via the hypophyseal portal system (described below). This enables reasonably rapid hormonal responses by fast passage into/out of the capillary sinusoids of the anterior pituitary.
Cell types of the Pars Distalis
five types: Somatotrophs (GH)—make up about 50 % of the secretory cells. Lactotrophs (PRL)—make up about 20%. Gonadotrophs (FSH, LH) about 5-10%. Corticotrophs (ACTH), about 15-20%. Thyrotrophs (TSH), about 5-10%. These cells synthesize, store, and release respective hormones in granules. Individual cell types can be identified immunocytochemically by light microscopy using antibodies to specific hormones: In early histology three classes of cells were observed based on dye staining: acidophils (containing either GH or PRL), basophils (containing TSH, ACTH or LH and FSH) and chromophobes—cells lacking granules which are thought to be in a resting state or may have been degranulated.
Pars Tuberalis and the hypophyseal portal system
A collar of cells around the infundibular stalk contains blood vessels that lead from capillaries of the median hypothalamic eminence to small vessels/capillaries of the pars distalis. The blood entering the median eminence comes from the superior hypophyseal arteries (from the internal carotid). The capillaries of the median eminence thence lead to larger vessels in the tuberalis that deliver regulatory peptides (the releasing factors) secreted by hypothalamic neurons to the cells in the anterior pituitary. These include TSH-releasing hormone (TSH- RH), gonadotropin releasing hormone (GNRH), corticotropin releasing hormone (CRH), growth hormone releasing hormone (GHRH) and the inhibitory factors, somatostatin and dopamine. Thus, this tiny portal systems provides an intimate vascular linkage between hypothalamic neurons and endocrine cells of the anterior pituitary. Blood leaves the anterior and posterior pituitary via small hypophyseal veins.
Pars Intermedia
This part of the anterior pituitary is poorly developed in humans, consisting of colloidal cysts. Some of the cells are positive for corticotrophic hormones such as melanocyte stimulating hormone (MSH). In humans it is weakly developed and the importance of MSH and control of its secretion are not well understood.
Posterior Pituitary (pars nervosa)
The posterior pituitary is essentially an extension of the hypothalamus. The hormones, antidiuretic hormone (ADH, vasopressin) and oxytocin, are released from the ends of axons that arise from cell bodies of neurons present in the hypothalamus. They are unmyelinated and comprise a bundle that extend alongside one another within the infundibular stalk. There are also nuclei that can be observed within the posterior pituitary that are the nuclei of pituicytes, which are supportive astrocyte-like glial cells (not producing hormones). The axons expand into bulbous structures that contain neurosecretory vesicles (Herring’s bodies). Hormones are produced in the hypothalamus (in the cell bodies) as large polypeptides that undergo cleavage during vesicular transport down the axons. The prohormones are called vasopressin-neurophysin and oxytocin-neurophysin (more in physiology). Vasculature in the posterior pituitary is evident, but is not as extensive as in the anterior pituitary.
The Thyroid Gland
The thyroid is a multi-lobed gland comprised of a series of follicles, each having a single layer of epithelial cells surrounding a central chamber referred to as the colloid. The epithelial cells are producers of the colloid and ultimately the thyroid hormone group. The gland is notable for its tremendous storage capability of potential hormone in the colloid. Scattered cells between follicles produce calcitonin. Blood supply to the thyroid is via the inferior thyroid artery (from the thyrocervical trunk) and the superior thyroid artery (from the external carotid artery); drainage is from the inferior thyroid vein (to the subclavian vein) and the superior thyroid vein (to the jugular vein). Extensive vascularization around the follicles enables iodide pumping from the blood and conversion to iodine by the epithelial cells and release of the thyroid hormones into the blood. The epithelium also synthesizes and secretes the protein thyroglobulin into the interior of the follicle and takes up and digests thyroglobulin to generate the thyroid hormones. The iodide pump is very effective. Within a few minutes a major portion of radioactive iodide is taken up by the thyroid making it possible to perform partial thyroidectomies. Thyroglobulin is a large protein rich in tyrosine residues, which are the sites of iodination and modification to generate the thyroid hormones. TSH stimulates synthesis of thyroglobulin and its uptake and breakdown from the colloid with consequent release of thyroid hormone (T3 and T4, containing, respectively, 3 or 4 iodine atoms per molecule) into the blood. Colloid droplets are taken up and processed in the interior of the epithelial cells by the lysosomal system resulting in production of thyroid hormones.
Calcitonin “C” cells
have secretory granules containing calcitonin, a small protein. This hormone decreases release of calcium from bones (down regulates osteoclastic activity). It appears to act oppositely to parathyroid hormone which (below) is centrally involved in increasing blood calcium levels.
The Parathyroid Glands
The parathyroids are closely associated with the thyroid gland, and 4 to 8 may be present in any individual. They contain three main cell types: (1) Chief cells, which produce parathyroid hormone (PTH), a protein of 84 amino acids. It increases osteoclast release of calcium from bone, and increases calcium uptake in the GI tract and by the kidney, which elevates calcium levels. (2) Oxyphil cells, which contain a number of mitochondria, usually stain paler but whose functional significance remains unknown, and (3) Adipose cells. Blood vessels are seen, although are not as extensive as observed, for instance, in the anterior pituitary or islets of Langerhans.
The Adrenal Gland
The adrenal gland, like the pituitary, is a dual origin gland, housing two organs, physically distinct as the cortex and the medulla. The cortex produces and releases various steroids whereas the medulla produces and releases amino acid derived hormones including epinephrine, norepinephrine and enkephalins. Blood is delivered via the superior, middle and inferior suprarenal arteries, which branch and enter through the capsule via short cortical arteries into an outer subcapsular arterial plexus. Blood then passes via an anastomosing network of capillaries into the medullary region. Other arteries (long cortical arteries) take blood to medullary region more directly, with the blood ultimately entering a series of small capillaries/sinuosoids to the central medullary vein, which drains via the suprarenal vein.
Adrenal cortex
The cortex is divided into three layers, labeled, respectively, from outer to inner cortex layers as zones: the zona glomerulosa, the zona fasciculata, and the zona reticularis. The zones look different histologically and are associated with different classes of steroids as follows: Zona glomerulosa: mineralocorticoids, most notably aldosterone. Zona fasciculata: glucocorticoids such as cortisol. Zona reticularis: Androgens of modest potency. These cells are all involved in lipid/steroid metabolism thus are high in relative lipid content. The fasciculata is especially rich in large lipid droplets. The cells are arranged in vertical columns separated by capillaries/small sinusoids that drain to the medulla. The fasciculata and reticularis are controlled by ACTH whereas the glomerulosa is regulated through the angiotensin system. Mitochondria of cortical cells have tubular cristae characteristic of steroidogenic cells.
Adrenal medulla
The adrenal medulla contains epinephrine (adrenalin) and norepinephrine (noradrenalin) producing cells. They are arranged as clusters around venous channels/sinusoids that drain toward the central medullary vein. They are under sympathetic and parasympathetic control. Enkephalins and chromogranins are also released by these cells.
general features of endocrine organs
Most endocrine organs contain cells that derive from more than one embryonic origin. Quite generally, because endocrine glands secrete into the blood, they are vascularized with capillary networks that arise from infiltration of mesodermal cells around groups/clumps of endocrine cells that often come from different origins. The endocrine cells typically develop from early primordia as solid groups of cells that break up, often initially into cords and then smaller collective groups, or get arranged in layers infiltrated with vasculature from local mesoderm. Consequently, all endocrine organs will have a mesodermal component that gives rise to the vasculature, but not all will arise from endoderm, for example.
Development of the pituitary gland
Early in development, the neural tube and, in the head region, the primitive brain, arise from ectoderm through an infolding that pinches off is then referred to as “neural ectoderm”—and will become our brain and spinal cord. Endoderm, a tubular arrangement of cells initially, gives rise to the majority of the digestive system. However, early in development of the mouth, ectoderm comprises the stomodeum (the mouth opening) and gives rise eventually, in the upper part of the mouth, to the tissues as far back as the pharynx (the pharynx is endodermal in origin and fuses with the ectoderm of the stomodeum). In the lower part of the mouth, ectoderm gives rise to tissues about half-way along the length of the tongue. At about 4 weeks, an evagination of the lower part of the neural ectoderm of the primitive diencephalon forms the beginnings of the posterior pituitary and central portion of the infundibular stalk.
Rathke’s pouch
In embryogenesis, Rathke’s pouch is a depression in the roof of the developing mouth in front of the buccopharyngeal membrane. It gives rise to the anterior pituitary. At about 4 weeks oral ectoderm from the upper part of the mouth evaginates, which is the rathke’s pouch, comes in contact with neural ectoderm. The anterior pituitary develops from the original oral ectoderm, which pinches off from the oral epithelium, with resultant degeneration of the former “stalk” that connected the anterior pituitary with the epithelium of the mouth. During the third month, the pituitary takes on the more typical shape of the pituitary gland in the adult. The pars distalis, pars intermedia and pars tuberalis are all derived from Rathke’s pouch whereas the posterior (pars nervosa and infundibular stalk) are derived from neural ectoderm. The different cell types of the anterior pituitary that are hormone-secreting all differentiate from cells derived from Rathke’s pouch.
sella turcica
Connective tissue develops around the pituitary forming the sella turcica, the C.T. pocket that is part of the sphenoid bone in an adult. Local mesoderm infiltrates the glandular/nervous tissues of the pituitary giving rise to the vasculature of the hypophyseal portal system as well as small vessels in the posterior pituitary. Consequently, the posterior pituitary can really be thought of as an extension of the brain, where neurons are secreting hormones that are utilized systemically, whereas the anterior pituitary is really an organ derived from oral ectoderm that responds, like other organs, to blood-borne releasing factors that arrive via the blood (via the hypophyseal portal system).
Development of the thyroid/parathyroid glands
The thyroid contains cellular components that derive from the endoderm (the thyroid follicle epithelial cells), the neural crest (originally ectodermal, the calcitonin-secreting cells) and the vasculature (mesodermal). The parathyroids originate from endoderm (glandular cells) and mesoderm (vasculature), and become embedded in the thyroid, but originate from different locations along the developing pharynx.
pouches of thyroid and parathyroid
early in development, the pharynx develops in a complex way as a set of four bilateral pouches. The thyroid begins as a medial evagination of the endoderm called the thyroid diverticulum, which begins to extend at about the region between the first and second pharyngeal pouches. The components of the parathyroid develop from cells in clefts between the 3rd and 4th pouches (inferior parathyroids) and in a cleft after the 4th pouch (superior parathyroids). Another relevant group of cells early in development just after the 4th pouch (shown in the figure at the right) is the ultimobranchial body. It gets populated by cells derived from the neural crest (ectodermal in origin) and those cells give rise to the calcitonin-secreting or parafollicular cells of the thyroid. Other groups of cells among the pouch clefts, although not related to the endocrine system, give rise to the thymus, the tonsils, and the auditory tube, so this region of the pharyngeal pouches is relevant to development of a number of important organs.
thyroid diverticulum
the embryological structure of the second pharyngeal arch from which thyroid follicular cells derive. The thyroid diverticulum enlarges and descends along the pharynx with the developing thyroid initially attached via the thyroglossal duct. The thyroid gland descends to a region under the larynx, just in front of the trachea. Normally, the thyroglossal duct degenerates but pediatric cases of thyroglossal cysts occur, where portions of the thyroglossal duct may remain and become cystic, or rarely there may be a failure of the thyroid to descend properly (ectopic thyroid). In about half of individuals, a lower portion of the thyroglossal duct develops into a medial pyramidal lobe of the thyroid gland. during the descent of the thyroid, it comes in contact with the primordia of the parathyroids that arise from the clefts between the 3rd and 4th pharyngeal pouches as well as the ultimobranchial body. These become embedded in the thyroid normally and result in the parathyroids and the calcitonin-releasing cells, respectively.
development of follicular cells of the thyroid
The thyroid becomes infiltrated with mesoderm that gives rise to the vasculature. Initially, the thyroid is a solid mass of endodermal cells but they get interspersed by the infiltrating mesoderm, first to cords of cells that will become the follicular cells, then to small clumps, and then the clumps vesiculate to form the epithelia of the follicles around the follicular colloid. Meanwhile, the mesoderm differentiates into the vasculature that encircles each follicle.
Development of the adrenal cortex
The cortex originates from mesoderm. The initial primordium of the cortex originates from a group of cells of the coelomic epithelium (mesothelium) in a cleft between the region of the gut (actually the dorsal mesentery, a tissue that connects the gut to the dorsal portion of the embryo) and the urogenital ridge (also called the Wolffian body), see figure below, and recall your kidney embryology of the formation of the mesonephric duct from initial nephrotomes. At about 4 weeks, under induction by the mesonephric (or Wolffian duct), cells in the cleft proliferate and migrate into the mesenchyme just dorsal to it. They multiply and organize into a cup-like structure in roughly the same shape as the cortex of the adrenal. Between 2-3 months, another wave of cells from the coelomic epithelium at the same location enters the mesenchyme and surrounds the outer part of the cup, in another layer. The first early set of cells will become cells of the reticularis of the cortex, whereas the second group of cells that layer on the outside will differentiate into the fasciculata and the glomerulosa. Therefore, the cortical region of the adrenal is entirely mesodermal in origin. Note that after birth, a significant portion of the inner region of the early reticularis regresses.
Development of the adrenal medullary
medulla originates from the ectoderm. Cells in the medullary region come from an entirely different origin. Neural crest cells (ectoderm) migrate to a region that will become the sympathetic ganglia. Early on, these cells are called sympathogonia and some of them continue to migrate into the center of the cup that will become the medullary region of the adrenal (see Fig. above). They happen to stain yellow- brown with chrome salts hence are called chromaffin cells, and are the progenitors of the epinephrine- and norepinephrine-producing cells of the medulla. Development of the adrenal continues after birth, with the layers of the fasciculata and glomerulosa becoming more distinct, the reticularis regressing somewhat and the medulla increasing in relative volume. Vascularization occurs through infiltration of small vessels of mesodermal origin during development with blood flow from vessels entering the outer cortex and blood collecting toward and leaving via the central vein of the medulla.
types of hormones
The classic hormones fall into three categories 1) derivatives of tyrosine, 2) derivatives of cholesterol (steroids), and 3) peptides and proteins.
types of tyrosine derivative hormones
epinephrine, norepinephrine, dopamine, thyroxine
types of steroid hormones
testosterone, cortisol, estrogens, aldosterone, vit D, progesterone
types of peptides hormones
oxytocin, vasopressin, angiotensin, thyrotropine releasing hormone, gonadotropin releasing hormone
types of protein hormones
insulin, glucagon, growth hormone, ACTH, prolactin, thyroid stimulating hormone.
Peptide and Protein Hormones
The secretion of peptide and protein hormones follows the classical pathway for secretion of protein from cells. After synthesis as a pre-prohormone on ribosomes from their respective mRNAs, the hormone is targeted to the rough endoplasmic reticulum. Here the pre-prohormone is cleaved and the prohormone is transported to the Golgi apparatus where it is further processed and packaged into secretory vesicles. The endocrine organ then secretes the hormone in response to specific signals by vesicular exocytosis, in a calcium-dependent manner. A similar mechanism is used for the secretion of catecholamines like dopamine and epinephrine. Once secreted into the bloodstream, the hormone is then carried to its target organ. Most peptide and protein hormones (the exceptions are growth hormone, prolactin and Insulin-like growth factor) are transported in the blood as free hormones. As the blood contains many proteases, the half-life of these hormones is therefore limited.
Steroid Hormones
The basic precursor for all steroid hormones is cholesterol. Because the names of various steroid hormones derive from the numbering system of cholesterol, it is useful to know how the carbon atoms on a cholesterol molecule are numbered. The outline of the pathway for steroid biosynthesis will be discussed in the lecture on Adrenal gland. As steroid hormones are lipophilic and therefore membrane permeant, it stands to reason that their secretion will not be via the vesicular exocytosis as it is for protein and peptide hormones. The steroid hormones are not stored in the cell they are synthesized in and are therefore immediately released into the blood stream. Another consequence of their hydrophobicity is that they need to be carried by carrier proteins in the blood stream. In the blood, steroid hormones exist in equilibrium between free and bound forms and at any given time only a small fraction of the hormone (1-5%) exists in the free form. However, you must realize that it is the free form of the hormone that is biologically active and thus knowing total hormone levels in the blood might not be very informative. The bound form serves as an essential reservoir of the hormone. Unlike the protein and peptide hormones, steroid hormones linger in the bloodstream for a long time and have half lives in the order of many hours to days.
Measurement of Hormone levels
Measurement of plasma levels of hormones is a primary tool of the clinical endocrinologist. The two major methods for measuring hormone levels are 1) bioassays and 2) immunoassays. Bioassays measure hormone activity and in this case hormone function is measured by using an exogenous system e.g. cell lines, to measure hormone activity. Radio-immunoassays (RIA) and enzyme linked immunosorbent assays (ELISA) measure antibody binding to a specific region of the hormone. They might not be useful if an abnormal form of the hormone is being secreted by the patient.
Protein and peptide hormone actions
When protein and peptide hormones (as well as some of the hormones derived from tyrosine, like epinephrine and norepinephrine) reach their target, they bind to specific receptors on the plasma membrane of the target cells. Receptors for some hormones, e.g. epinephrine and norepinephrine, belong to the family of G-protein coupled receptors. Binding of the hormone to these receptors results in changes in the levels of intracellular second messengers like cAMP, diacylglycerol and inositol phosphates. Other hormones like growth hormone and prolactin have receptors that belong to the JAK/STAT family of receptors. Activation of these receptors results in coupling and activation of a tyrosine kinase (Janus kinase or JAK), which then causes the phosphorylation of a group of proteins called signal transducers and activators of transcription (STATs). Yet other receptors for hormones like Insulin and IGF-1 belong to a large family of protein tyrosine kinase receptors. In this case the receptors themselves are tyrosine kinases that can be activated upon hormone binding. Activation of catecholamine, protein and peptide hormones can have rapid consequences, like increased cytosolic calcium, exocytosis, phosphorylation of enzymes and ion channels. In addition, they can have effects that are slower and involve changes in gene expression. We shall discuss individual cases when we talk about individual endocrine glands.
Steroid Hormone Actions
Unlike the peptide hormones, steroid receptors are nuclear in their location. Once steroid hormones reach their target cells, they enter the cell and bind to their receptors in the cytosol or the nucleus. The receptor-hormone complexes then bind to specific hormone responsive elements (HRE) and activate transcription of specific genes.
Regulation of Hormone Secretion
Levels of various hormones, metabolites, and minerals in the body are very tightly regulated around a specific set point. This is achieved mainly by feedback loops. There are two classes of these feedback loops. One where the hormone level is the regulated variable and the other where the plasma concentration of a metabolite or a mineral acts as the regulated variable. Target hormones regulating their own secretions usually go through negative feedback loops where excess of an end hormone acts to inhibit its own production. Purely positive feedback loops are rare in biology for obvious reasons. A positive loop will lead to an unstable and often cataclysmic process. The only way a positive feedback loop can be terminated is by the exhaustion of the hormone or by an explosive event such as ovulation. An example of a positive feedback loop in endocrinology is the production of oxytocin during the birthing process. The stimulus for oxytocin secretion is the dilation of the uterine cervix. This dilation causes the release of further oxytocin thus creating a positive feedback loop that is terminated by the expulsion of the fetus and relaxation of the uterine muscles. Hormone secretion often occurs in a pulsatile fashion. In addition, the levels of many hormones are regulated by diurnal variation and thus show characteristic circadian rhythms.
hypothalamus
The hypothalamus forms the interphase between the brain and the endocrine system. The connection between the anterior pituitary and the hypothalamus consists of a very specialized structure known as the hypothalamo-hypophyseal portal system. Blood enters the median eminence through the superior hypophyseal arteries, which forms a capillary plexus. Nerve terminals of appropriate hypothalamic neurons terminate here, and their neurohormones are released into this capillary bed and then are transported via the portal system vasculature to a second capillary plexus in the anterior lobe. The ability of the plexus to have an easy access to the released hypothalamic hormones is because it lies outside the blood brain barrier. Another consequence of this specialized structure is that hormones secreted by the involved hypothalamic neurons reach the anterior lobe relatively undiluted and thus at higher concentrations than would be achieved if they had been released into the general circulation. Further, hypothalamic hormones act on a local rather than distant target. If the portal system is severed or the anterior pituitary is transplanted elsewhere (where it may even become vascularized), secretion of anterior pituitary hormones will no longer be subject to normal hypothalamic control. Hypothalamic hormones are released into the capillary plexus in the median eminence and travel a relatively short distance, for a hormone, to the anterior pituitary. Here, they regulate the secretion of hormones by the anterior pituitary into the general circulation. The hypothalamic hormones are peptides, except for dopamine (DA), which is a catecholamine, and are usually considered in relation to the anterior pituitary hormone’s secretion that they influence.
Hypothalamic hormones
Hypothalamic hormones are released into the capillary plexus in the median eminence and travel a relatively short distance, for a hormone, to the anterior pituitary. Here, they regulate the secretion of hormones by the anterior pituitary into the general circulation. The hypothalamic hormones are peptides, except for dopamine (DA), which is a catecholamine, and are usually considered in relation to the anterior pituitary hormone’s secretion that they influence.
types of hypothalamic hormone
thyrotropin releasing hormone (increases TSH and PRL), gonadotropin releasing hormone (increases LH and FSH), corticotropin releasing hormone (increases POMC and ACTH), growth hormone releasing factor (increases GH), somatostatin (decreases GH and TSH), prolactin inhibiting factor (decreases PRL). Some of these hormones stimulate while others inhibit the secretion of hormones from the anterior pituitary. In some cases, factors have been identified that stimulate and others that inhibit the secretion of the same hormone, e.g., GHRH and somatostatin stimulate and inhibit, respectively, the secretion of GH.
inputs to hypothalamus
The hypothalamus receives inputs from the thalamus, limbic system including olfactory bulb, hippocampus, habenula and amygdala, the retina, reticular activating substance and the neocortex, information regarding pain, sleep versus wakefulness, emotions, fright, rage, olfactory sensations, light reaches the hypothalamus and can affect the activity of the neurosecretory neurons.
secretion of hypothalamic hormones
Stimulus-dependent secretion of hypothalamic hormones occurs in a manner similar to neurotransmitter release. In brief, appropriate stimulation of a hypothalamic neuron will result in generation of action potentials, At the nerve terminal, calcium entry through voltage-dependent calcium channels will lead to liberation of hormone (versus neurotransmitter) from secretory vesicles. Thus, just as for neurotransmitter release, hormone secretion from hypothalamic neurons is calcium-dependent.
Cellular mechanisms of action of hypothalamic hormones
At a cellular level, the hypothalamic hormones interact with specific receptors on their appropriate target cells in the anterior pituitary. The exact intracellular signaling cascades triggered by receptor activation in the various anterior pituitary cells are the subject of much current investigation. One point of agreement is that extracellular calcium is required for the release. Involvement of calcium release from intracellular stores is still debatable. The hormones bind to their respective receptors, which in turn are coupled to various G-proteins. CRH and GHRH receptors are coupled to Gs and, upon activation, stimulate adenylate cyclase to produce cAMP in corticotrophs and somatotrophs, respectively. In contrast, the interaction of somatostatin with Gi eventually leads to a decrease in cAMP. Similarly, DA leads to a reduction in cAMP levels in lactotrophs. CRH also leads to an increase in the rate of transcription of POMC and formation of ACTH.
GnRH cellular mechanism
Gs. In gonadotrophs, GnRH receptor activation leads to the hydrolysis of membrane phosphatidyl inositol. In somatotrophs and thyrotrophs, the phosphatidylinositol cycle (in addition to adenylate cyclase activation) appears to play a role in signal transduction. For example, TRH induces this pathway in thyrotrophs as well as lactotrophs. The arachidonic acid signaling pathway is receiving attention and evidence is accumulating that implicates it in the release mechanism employed by several pituitary cells.
The role of voltage-dependent calcium and potassium channels in release of hormones
The role of voltage-dependent calcium and potassium channels in release is currently being examined. One possible mechanism is that the second messengers released upon the activation of receptors for hypothalamic hormones on pituitary cells can alter the states of various membrane ion channels and cause calcium flux from outside to mediate hormonal release from the anterior pituitary. It is also possible in the case of GnRH (and possibly GHRH and TRH) that the production of IP3 upon activation of the receptor (mediated by Gq and phospholipase C) can increase cytosolic calcium from intracellular stores and thus mediate release. In sum, although release of hormone from anterior pituitary cells is dependent upon calcium, evidence exists implicating several intracellular signaling cascades to different degrees in the various pituitary cells. Membrane conductances also appear to play a role. These intracellular cascades are probably also involved in regulating the synthesis of various pituitary hormones.
pituitary gland
The pituitary gland acts as an endocrine control center responding to neural signals, and catering to the needs of various target tissues (e.g.,thyroid, gonads, adrenal gland, bone), coordinating and regulating their functions. The gland is attached to a region of the brain (hypothalamus) by a structure known as the pituitary stalk. This anatomical connection is necessary for the functional interactions between the brain and pituitary. The pituitary consists of two major divisions, the anterior (adenohypophysis) and the posterior hypophysis (neurohypophysis). The anterior pituitary is derived from an embryological structure known as Rathke’s pouch (pharyngeal epithelium); the intermediate pituitary is also found within the adenohypophysis, but is extremely small in humans and not thought to be of functional significance. The posterior pituitary is derived from neural tissue arising from an embryological evagination of the diencephalon.
adenohypophysis
The anterior pituitary is comprised of the pars tuberalis, pars intermedia (intermediate lobe) and the pars distalis (anterior lobe). Hormone secretion is under control of the hypothalamic hormones discussed above. TRH acts on cells called thyrotrophs to stimulate the secretion of TSH; GnRH acts on gonadotrophs to stimulate the secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH); GHRH and somatostatin act on somatotrophs to stimulate and inhibit, respectively, the secretion of growth hormone (GH); CRH acts on corticotrophs to stimulate the secretion of corticotropin (ACTH) and proopiomelanocortin (POMC); prolactin inhibiting hormone (PIH, thought to be DA) and prolactin releasing factor (PRF, perhaps TRH?) act on mammotrophs to inhibit and stimulate, respectively, the secretion of prolactin (PRL). PRL and GH are polypeptide hormones; TSH, FSH and LH are glycoproteins, each comprised of an identical α-subunit and a unique β-subunit; ACTH is a derivative of a prohormone called POMC, which is cleaved in both the anterior and intermediate lobes of the pituitary to give rise to ACTH, an N-terminal fragment and β-lipotropin; subsequent cleavage of β-lipotropin generates γ-lipotropin and β-endorphin. Β-endorphin contains the sequence of metenkephalin, whereas γ-lipotropin contains the sequence of β- MSH. The post-translational processing of POMC is different in the intermediate lobe where α-MSH is predominantly generated after ACTH is further cleaved.
Pulsatile Secretion and Endocrine Rhythms
The release of hormones from the anterior pituitary is not constant over time but instead is quite varied and described as pulsatile. There are periods of higher release followed by periods of diminished release. Thus, the plasma levels show spikes or pulses. It may be that this type of secretion is directed by pulsatile secretion of the stimulating (or inhibiting) hypothalamic hormone. Evidence for this mechanism is strong for LH, FSH (GnRH pulse generator) and ACTH. Pulsatile, rather than continuous, secretion of hypothalamic hormones is the effective signal guaranteeing appropriate stimulation of the anterior pituitary. For example, a pulse of GnRH precedes the pulses of LH that are seen approximately every 90 minutes in an ovariectomized animal, giving rise to the notion of GnRH as a pulse generator for LH. GH is a more complicated case responding to both GHRH and somatostatin pulses. Endogenous pacemakers are thought to be involved in the generation of pulses of some hypothalamic hormones, e.g., GnRH pulses. Gonadal dysfunction (e.g., amenorrhea) produced by hyperprolactinemia is due to inhibition by prolactin of pulsatile secretion of GnRH. A similar mechanism has been described for CRH and corresponding ACTH release. In addition, rhythms that cycle with the period of a day exist (circadian rhythms). For example, GH secretion is elevated shortly after sleep onset, whereas ACTH is highest during the early morning hours.
neurohypophysis
The posterior pituitary is formed from the evagination of the diencephalon and is thus directly connected to the hypothalamus and brain. It consists of three parts - the median eminence, infundibular stem and the infundibular process (pars nervosa). Posterior pituitary hormones are synthesized in the hypothalamus in two nuclei- the supraoptic nucleus, which and the paraventricular nucleus. These nuclei have two cell types, both of which produce the hormones- 1) the magnocellular neurons, whose processes extend into the posterior pituitary and end in the pars nervosa and 2) the parvocellular neurons, which end at the median eminence close to the endings of hypothalamic neurons that produce the anterior pituitary regulating hormones. Thus, some of the posterior pituitary hormones can reach the anterior lobe where they can have some functions e.g. ADH can act on corticotrophs to increase ACTH production. Cortisol, regulated by ACTH, can in turn, inhibit both ADH function in the kidneys and release at the hypothalamus.
hormones secreted by neurohypophysis
The neurohypophysis secretes two nonapeptides, antidiuretic hormone and oxytocin. Both are synthesized in the cell bodies of large hypothalamic neurons known as magnocellular neurons. They are synthesized as part of a larger prohormone. The prohormone is packaged into secretory vesicles and cleaved into the hormone and a protein called neurophysin (function unknown) as the vesicles travel down the axon of the neuron to the posterior pituitary. The vesicles are released when an action potential invades the terminal, activating calcium channels. Calcium influx occurs, leading to a rise in intracellular calcium and neurosecretion.
antidiuretic hormone
ADH is secreted in response to an increase in plasma osmolarity or a decrease in blood pressure. It acts on the cells of the renal tubule and collecting ducts to alter water permeability and conserve water. At high concentrations it is a powerful pressor agent, acting to increase blood pressure; for this reason, it was originally called vasopressin. There are two kinds of ADH receptors: V1 coupled to Gq and the Phospholipase C pathway, mediates the vasopressive action of ADH and V2 coupled to Gs and the cAMP pathway regulates the effects of ADH on glomerular filtration rates in the kidney.
Oxytocin
Oxytocin is secreted in three interpersonal situations: 1. During the passage of the infant through the cervix at childbirth. 2. During sexual intercourse. 3. In response to suckling by the infant during breast-feeding. This neuroendocrine reflex can be conditioned. Oxytocin acts on the uterus around the time of birth to cause contraction of the myometrium. In the lactating woman it causes contraction of myoepithelial cells, producing milk ejection.
The Growth Hormone/Prolactin Family of Hormones
Prolactin (PRL) and growth hormone (GH) are members of the same family of hormones, and both are ~22-23 kD polypeptides of slightly less than 200 amino acids containing 2-3 disulfide bonds. PRL and GH are ~16% similar at the level of primary sequence. This class of hormones is also referred to as the somatomammotropin family. A third member of this family is placental lactogen (hPL or chorionic somatomammotropin), which has 83% amino acid identity with GH.
prolactin
This hormone distinguishes itself by the fact that the hypothalamus tonically inhibits the secretion of PRL via PIH, or DA. If the hypothalamic influences to the anterior pituitary are prevented, the adenohypophysis will secrete much larger amounts of PRL, whereas the secretion of the other anterior pituitary hormones will not increase. In some instances of hypersecretion of prolactin, administration of a dopamine agonist, such as bromocriptine, is effective in reducing the excess release of prolactin. DA reduces release and synthesis of PRL, inhibits lactotroph cell division and DNA synthesis and increase destruction of PRL containing secretory granules (crinophagy). Inhibition of cAMP formation appears to be involved in mediating these effects.
lactotrophs
The cells that secrete PRL, lactotrophs, comprise 30% of the adenohypophysis. The breast is the principal target of PRL action, where PRL plays a role in the production of milk. In cases where there are prolactin-secreting tumors, there will be inappropriate milk secretion. Reproduction is impaired, because high levels of prolactin inhibit pulsatile secretion of GnRH by hypothalamic neurons. The synthesis of peptide hormones will be discussed below for the case of GH. PRL is transported in the blood unmodified and has a short half-life of 20-30 min.
stimulation of prolactin release
In females, suckling of the breast is an effective physiological stimulus leading to release of prolactin. In addition, prolactin is released in both males and females in response to stress. Prolactin interacts with specific receptors found in the breast, liver, ovary, testis and prostate; the main site of action is the mammary gland. Prolactin receptors are members of the growth hormone/cytokine receptor families. The long form of PRL receptors and the growth factor receptors are about 620 amino acids in length. . They are single chain proteins crossing the membrane only once. Upon ligand binding, receptors dimerize, leading to the activation of the JAK/STAT pathway. Just as prolactin and growth hormone share structural homology, so do their receptors. Human PRL receptors are well stimulated by GH.
growth hormone
Growth hormone is fundamental for postnatal growth, stimulates somatic growth and regulates metabolism. GH is a peptide hormone as well as a secretory protein. At the level of the genome, the GH gene is organized into exons and introns, and the coding region spans several exons. It is thus possible to generate alternative forms of GH by splicing, and this does occur. The principal and biologically most important form consists of 191 amino acids. Similar to many other hormones, GH is synthesized as part of a prohormone. Once the signal peptide is cleaved, GH is stored in secretory granules of somatotrophs of the adenohypophysis. The synthesis of GH is evidently a major activity of the anterior pituitary, since 10% of the dry weight of the anterior pituitary is contributed by GH! Secretion of GH is under the influence of the hypothalamic hormones GHRH and somatostatin. GHRH and somatostatin stimulation of somatotrophs have opposing actions on cAMP levels; GHRH stimulation increases them, whereas somatostatin decreases them. The majority of GH circulates in an unbound form and has a half-life of 20-45 min. There is some evidence suggesting that a portion of plasma GH is bound specific binding proteins (GHBP), which are cleaved N-terminal peptides of its receptor.
production of growth hormone
Despite the sequence similarity and the fact that somatomammotropins are evolutionarily conserved genes, human GH is extremely specific for its species. Human or primate GH are the only GH’s that are active in humans. Previously, human GH isolated from cadavers was used therapeutically. In 1985, it was noted that several individuals who had been treated with “cadaver” GH acquired Creutzfeld-Jacob disease, a devastating form of spongiform encephalopathy caused by prions. Recombinant GH is now available and has become the sole source of GH replacement therapy.
growth hormone actions
At a cellular level, GH interacts with GH receptors in the plasma membrane of target cells. Both GH receptors and their signaling mechanisms are similar to that of PRL. In general, GH’s effects are anti-insulin like, i.e. glucose uptake will be decreased and plasma glucose levels will rise. Note that the increased plasma FFA is providing an alternate energy source and the increased plasma glucose is reserved for the CNS. Importantly, protein is spared. This contrasts with the actions of cortisol
actions of GH on adipose tissue
The net effect is to increase lipolysis and lead to mobilization of lipid and thus an increase in plasma free fatty acids (FFAs). Eventually, the effect of GH on fat metabolism will be evidenced by a loss in subcutaneous fat. In this action GH antagonizes the action of insulin.
actions of GH on muscle
GH has a strong anabolic action on muscle. Amino acid transport is increased, and protein synthesis is increased.
actions of GH on liver
Increased RNA, protein and glucose synthesis. Further, IGF-I will be secreted, which mediates the indirect effects. The increase in glucose levels is mainly due to an increase in gluconeogenesis and not due to glycogenolysis.
Indirect Actions of GH
In addition to its metabolic effects, GH also has effects on muscle and skeletal growth mediated by another hormone-the Insulin-like growth factor (IGF). There are two forms of IGF that have been shown to exist (IGF-I and IGF-II). Of these, IGF-I is the predominant form in postnatal tissues. The production of IGF requires both GH and insulin and occurs in a number of tissues (e.g. liver, bone marrow).
Insulin-like Growth Factor I (IGF-I)
IGF-I is structurally related to proinsulin (hence its name) and has many insulin like actions (especially in adipose tissue and muscle). IGF-I is a powerful mitogen and growth-promoting agent. Elevated IGF-I levels increase slowly from birth until puberty, when there is usually a much more pronounced elevation. Although growth hormone usually promotes secretion of IGF-I production, there are some stimuli that have different effects on GH and IGF-I levels. For example, during fasting, GH levels are elevated, while IGF-I levels are depressed. IGF receptors belong to the EGF/ Insulin receptor family. These receptors contain an inherent tyrosine kinase activity and upon ligand binding can readily phosphorylate themselves (auto phosphorylation) and other proteins of the signal transduction pathway. The major pathway activated by IGF receptors is initiated by the binding of Insulin Receptor Associated proteins 1 and 2 (IRS I&II). IRS in turn can bind to other molecules to activate either the MAP kinase pathway or transduction mediated by PI-3 kinase.
GH actions mediated via IGF-I
Bone/cartilage - Long bone growth is promoted by the stimulated proliferation of epiphyseal cartilage. After puberty, the epiphyses seal and IGF-I no longer has this effect on linear growth. Muscle - stimulates proliferation, differentiation and protein synthesis. Adipose tissue - stimulates uptake of glucose and inhibits lipolysis. This action of IGF is insulin like and antagonizes that of GH.
Control of GH secretion by products of Intermediary metabolism
Other stimuli include hypoglycemia, amino acids (arginine), low free fatty acid levels, α- adrenergic agonists (clonidine), β-adrenergic antagonists (propranolol) and estrogens. Conversely, hyperglycemia, high free fatty acid levels, obesity, α-adrenergic antagonists, β-adrenergic agonists as well as pharmacological doses of corticosteroids inhibit GH secretion. In assessing GH levels and secretion, it is important to obtain measurements several times over the course of a day. Stimulation of GH secretion by exercise or high doses of arginine is often used to assess GH status. In addition, measurement of IGF-I levels is very helpful, especially since its levels are subject to less diurnal variation.
anterior pituitary hormones and targets
TSH acts on thyroid gland epithelium. Prolactin has no direct endocrine target, but is important in lactation, menorrhea, libido, and fertility. ACTH stimulates the adrenal cortex, primarily zona fasiculata and zona reticularis. GH acts on receptors in the liver. FSH stimulates testicular Sertoli cells and ovarian granulosa cells. LH stimulates testiscular Leydig cells and ovarian theca cells. MSH acts on melanocytes in the skin and hair.
GH (somatotropin)
is counter-regulatory to insulin. It stimulates somatic growth via insulin-like growth factor (IGF-1), which is released by the liver in response to stimulation by GH. IGF-1 increases bone and cartilage growth/mass, increase protein synthesis and muscle mass, increase fat breakdown and TGA levels, and increase salt and H2O retention.
Excess growth hormone
Leads to acromegaly or gigantism. If the excessive GH secretion occurs during childhood (prior to skeletal epiphyseal closure) the disease state that results is gigantism. If the excessive GH secretion occurs during adulthood (after epiphyseal closure) the disease state that results is acromegaly.
Gigantism
Gigantism is characterized by disproportionately long limbs (increased linear bone growth), whereas acromegaly presents as conspicuous growth in the skin and soft tissues, viscera, and bones of the face, hands, and feet. Signs and symptoms of acromegaly include: Coarsening of skin/facial features. Thickening of the hands and feet. Enlargement of the jaw resulting in protrusion (prognathism). Deep voice. Impaired glucose tolerance (insulin resistance). Peripheral neuropathies (due to nerve compression). There are three treatment options for gigantism and acromegaly: Surgery or radiation, Octreotide, a somatostatin analogue that inhibits GH release from the anterior pituitary, and Pegvisomant, a GH receptor antagonist which effectively blocks IGF-1 production.
diagnosis of gigantism
Diagnosis is made based on increased insulin-like growth factor and MRI/CT imaging of a pituitary neoplasm. A growth hormone suppression test may be performed to determine whether GH production is suppressed by high blood sugar (induced by drinking a glucose solution).
thyrotropin releasing hormone
secreted from hypothalamus, targets throtroph causing increased thyroid stimulating hormone
gonadotropin releasing hormone
secreted from hypothalamus, targets gonadotroph cells, causing increased release of LH and follicle stimulating hormone
growth hormone releasing hormone
secreted from hypothalamus, targets somatortoph cells, causing increased release of growth hormone
somatostatin
secreted from hypothalamus, targets somatrotroph cells, causing decreased release of growth hormone
Corticotropin-releasing hormone (CRH)
secreted from hypothalamus, targets corticotroph cells, causing increased release of ACTH
prolactin inhibitory factor
aka Dopamine, secreted from hypothalamus, targets lactotroph cells, causing decreased release of prolactin
prolactin releasing factor
secreted from hypothalamus, targets lactotroph cells, causing increased release of prolactin
acromegaly
Acromegaly is generalized body enlargement due to excessive growth hormone production after the growth plates have fused. Acromegaly is caused by excessive growth hormone production from the pituitary gland. The most common cause is a pituitary adenoma. One key is to differentiate between acromegaly and gigantism. Gigantism occurs before fusion of the epiphyseal plates. Acromegaly occurs after the epiphyseal growth plates have fused. Acromegaly is an insidious process, often presenting after many years. Patients will experience subtle changes such as coarsening of features, changes in glove or hat size, or musculoskeletal complaints such as arthralgias due to tissue overgrowth. As with any pituitary tumor, bitemporal hemianopsia may occur due to compression of the optic chiasm. This mass effect may also cause headaches.
The hands, skull, and jaw (macrognathia) are the most affected. Patients may have hyperhidrosis (excessive sweating).
diagnosis of acromegaly
The best initial screening test for patients with suspected acromegaly is quantification of serum IGF-1 levels. The finding of NORMAL IGF-1 levels is sufficient to rule out acromegaly. Oral glucose tolerance test (OGTT) is used to confirm a diagnosis of acromegaly in patients with elevated IGF-1 due to its high level of specificity. An OGTT is considered positive when serum GH concentrations remains > 2 ng/mL (inappropriately elevated) within two hours after ingestion of 75 g glucose (normal value is
treatment of acromegaly
Transsphenoidal resection of the pituitary adenoma is the treatment of choice. Radiation therapy may be used if IGF-1 elevations persist after surgery. Somatostatin and Dopamine analogues such as octreotide and bromocriptine, respectively, may be used because of their intrinsic inhibition of GH.
adult growth hormone deficiency
Increased fat deposition; decreased muscle mass, strength and exercise capacity; increased bone loss and fracture risk; increased cholesterol levels; increased inflammatory prothrombotic markers (CRP); impaired energy and mood; decreased quality of life
diagnosis of adult onset growth hormone deficiency
insulin induced hypoglycemia (contraindicated in elderly, history of seizure disorder). GHRH-arginine is another provocative test. Low IGF-1 levels is also diagnostic.
hyperprolactinemia
physiological causes include pregnancy, suckling, sleep, stress. pharmacological reasons include estrogens (OCPs), antipsychotics, antidepressants (TCAs), antiemetics (reglan), opiates. pathological causes include pituitary stalk interruption, hypothyroidism, chronic renal/liver failure, prolactinoma (higher levels, over 150ng/dl).
prolactinoma
A benign hyperfunctioning adenoma of the anterior pituitary that secretes the hormone prolactin from the anterior pituitary. A prolactinoma is the most common pituitary tumor, accounting for approximately 30% of all hyperfunctioning pituitary adenomas.
diagnosis of prolactinoma
Signs/Symptoms: Female: Galactorrhea and Amenorrhea. Male: Loss of libido, Erectile Dysfunction, and Gynecomastia. Enlargement of the pituitary gland causing compression of optic chiasm causing bitemporal hemianopsia (loss of peripheral vision). Increased Prolactin (>200ng/mL) on labs suggests prolactinoma, but this varies depending on size of tumor. Magnetic Resonance Imaging is used to detect the prolactinoma.
treatment of prolactinomas
Dopamine agonists bromocriptine or cabergoline. Dopamine inhibits Prolactin release. This also explains why dopamine antagonists (ex: antipsychotics) cause galactorrhea (low dopamine leads to high prolactin). Transsphenoidal surgical resection for large tumors. Radiation therapy in refractory cases.
prolactin deficiency
severe pituitary (lactotrope) destruction. causes include pituitary tumors, infiltrative diseases, infectious diseases infarction, neurosurgery or radiation. presents as failed lactation in post-partum females; no known effect in males. diagnosed based on low basal PRL level
cortisol
Glucocorticoids (cortisol) are essential for the body to respond to stressful situations (fasting/hypoglycemia, injury etc.) The effects of glucocorticoids (cortisol) can be remembered using the mnemonic “Cortisol tells a BIG FIB”: Blood pressure (increases); Insulin resistance (increases); Gluconeogenesis (increases); Fibroblast activity (decreases); Inflammatory; suppression/Immunosuppression; Bone destruction. Glucocorticoids decrease bone formation through: Inhibition of osteoblast activity; Inhibition of intestinal Ca2+ absorption; Increased renal Ca2+ excretion. Cortisol regulates blood pressure through the upregulation of α1 receptors on arterioles, increasing their sensitivity to norepinephrine (NE). Cortisol excess causes an increase in arterial pressure, while cortisol deficiency causes a decrease in arterial pressure. Glucocorticoids are anti-Inflammatory/Immunosuppressive; they exert these effects through several mechanisms: The induction of synthesis of lipocortin, a phospholipase A2 inhibitor, leads to the inhibition of leukotriene and prostaglandin production . Glucocorticoids inhibit the production of IL-2, which is important for T-cell proliferation. Thus, pharmacologic doses of glucocorticoids prevent the rejection of transplanted organs. Glucocorticoids inhibit leukocyte adhesion, leading to neutrophilia (cells shifted from marginal to circulating pool). Histamine and serotonin release are inhibited by glucocorticoids. Glucocorticoids reduce the number of eosinophils. Cortisol increases insulin resistance, leading to a diabetogenic effect. Glucocorticoids increase gluconeogenesis, as well as lipolysis and protein catabolism. Cortisol decreases fibroblast activity, which plays a role in the development of striae characteristically found in Cushing syndrome.
Signs and symptoms of Cushing syndrome
Weight gain; Fat redistribution (notably moon facies, buffalo hump, truncal obesity); Hypertension; Hyperglycemia (secondary in insulin resistance); Osteoporosis; Immune suppression; Amenorrhea; Impotence; Skin changes (thinning, striae)
cushing disease
Cushing disease represents 70% of endogenous causes of excess cortisol. It is caused by an ACTH-secreting pituitary adenoma which results in increased cortisol levels. Only a primary pituitary adenoma is referred to as Cushing disease, while other etiologies of high cortisol are collectively referred to as a Cushing syndrome.
adrenal hyperplasia
Adrenal hyperplasia or adrenal neoplasias (adenoma or carcinoma) are responsible for 15% of patients with endogenous Cushing syndrome. ACTH levels are decreased due to negative feedback of cortisol on the pituitary gland. The uninvolved adrenal gland may exhibit atrophy. Adrenal hyperplasia, adenoma, or carcinoma may also present as primary aldosteronism (Conn syndrome).
ectopic ACTH production
Ectopic ACTH production, as seen in paraneoplastic syndromes, are responsible for 15% of endogenous hypercortisolemia. Important examples of paraneoplastic ACTH secretion include: Small cell carcinoma of the lung; Renal cell carcinoma; Bronchial carcinoids; Neural tumors. Bilateral adrenal hyperplasia, specifically of the zona fasciculata and zona reticularis, result from the elevated levels of ACTH.
Causes of cushing disease
Increased cortisol may be due to exogenous iatrogenic corticosteroid use, or a variety of endogenous causes including: An ACTH-secreting pituitary adenoma
Adrenal hyperplasia
Adrenal neoplasias
Paraneoplastic syndromes (e.g. renal cell carcinoma)
To determine the specific etiology of Cushing syndrome, measure ACTH levels:
If suppressed, perform an MRI to confirm an adrenal tumor
If elevated, perform a dexamethosone suppression test and CRH-stimulation test to identify the source of ACTH
Exogenous (iatrogenic) steroids are the #1 cause of Cushing syndrome. Therapeutic treatment with cortisol causes decrease pituitary secretion (negative feedback) of adrenocorticotropic hormone (ACTH).
The decreased ACTH levels can lead to bilateral adrenal atrophy.
treatment of chusing disease
If Cushing syndrome is due to a tumor, the treatment will involve excision with postoperative glucocorticoid replacement. Drug therapies, including mitotane and ketoconazole, may also be used. Mitotane is an antineoplastic agent used in the treatment of Cushing syndrome because it selectively inhibits the adrenal cortex. Ketoconazole is an antifungal which inhibits cholesterol desmolase preventing steroid hormone (cortisol) synthesis. Furthermore, it inhibits P450 enzymes.
cortisol rhythms
episodic ACTH/ cortisol secretions daily. Major ACTH/ cortisol burst in the early morning (before awakening). Cortisol Nadir 11-12pm (assuming a normal sleep wake cycle)
cortisol plasma binding
most cortisol is bound to transcortin (cortisol binding globulin- CBG). 10%-15% bound to albumin (less tightly). 5% unbound (free cortisol)
screening tests for cushing’s syndrome
Disrupted circadian rhythm can be identified from midnight salivary or serum cortisol. Increased filtered cortisol load seen in 24 hr urine free cortisol. Attenuated negative feedback seen with low dose dexamethasone suppression test.
Adrenal Insufficiency
Adrenal insufficiency (hypofunction) is a deficiency of adrenal hormones secondary to adrenal or hypothalamic disease. The adrenal cortex secretes: Aldosterone (Mineralocorticoid); Cortisol (Glucocorticoid); Androgens (Sex Steroids); Adrenal insufficiency may present with symptoms of all three. Causes include: Adrenal atrophy or autoimmune destruction (most common); Granulomatous infection (eg, tuberculosis) of the adrenal gland; Infarction of the adrenal gland; HIV (human immunodeficiency virus); Waterhouse-Friderichsen syndrome (due to adrenal hemorrhage secondary to severe bacterial infection, most commonly Neisseria Meningitidis); DIC (disseminated intravascular coagulation)
Addison’s Disease
Addison’s Disease (Primary adrenal insufficiency) is failure of the adrenal cortex most commonly by autoimmune destruction. Because it is autoimmune to the cortex only, ACTH levels will be significantly elevated due to no negative feedback from cortisol. Due to destruction of the adrenal gland patients will present with decreased Aldosterone and Cortisol.Important Recall: Aldosterone normally functions to reabsorb Sodium and excrete Potassium and Hydrogen Ions; Cortisol normally functions to increase Glucose. Therefore, if there is a deficiency of Aldosterone and Cortisol the patient will present with: Hyponatremia (volume contraction —> HYPOtension); Hyperkalemia; Metabolic acidosis; Hypoglycemia; Skin Pigmentation (MSH shares same precursor as ACTH and Primary Adrenal Insufficiency is a hyper-ACTH state). Other symptoms may include constipation, diarrhea, fatigue. Hyponatremia and hyperkalemia can be suggestive of primary adrenal insufficiency. The diagnosis can be made by a low morning cortisol level. Less than 5 mcg/dL is confirmatory for the diagnosis. Other causes include: Infection (fungal or bacterial); Hemorrhage; Sarcoidosis; Hemochromatosis; Lymphoma; Metastatic cancer (commonly carcinomas); Infiltrative disorders such as tuberculosis or histoplasmosis are common infective causes. Also a high infective rate in AIDS patients. Hemorrhagic adrenal infarction is common post-operatively, in sepsis (frequently in cases of meningococcal sepsis), or in any hypercoagulable state.
Secondary adrenal insufficiency
Secondary adrenal insufficiency is decreased ACTH from the pituitary due to failure of the hypothalamic-pituitary axis, leading to decreased activity of the zona fasciculata and zona reticularis. Pituitary adenomas are a common cause of suppressed ACTH. Following long-term suppression of the hypothalamic-pituitary axis with exogenous glucocorticoid therapy (i.e. prednisone), ACTH production is minimal and the adrenal cortex stops producing much endogenous cortisol. Secondary adrenal insufficiency may develop, particularly if the steroids are abruptly stopped. Metabolism in the zona glomerulosa of the adrenal cortex is NOT controlled by ACTH (it is stimulated by high potassium), so aldosterone is largely unaffected. Patients will present with profound hypoglycemia (zona fasciculata) and low testosterone (zona reticularis). There is no hyperpigmentation in secondary adrenal insufficiency because ACTH is not being produced. Pro-opiomelanocortin (POMC) is the gene that produces ACTH and melanocyte-stimulating hormone (MSH).
Tertiary adrenal insufficiency
Tertiary adrenal insufficiency is due to decreased Corticotropin-releasing hormone (CRH) from the hypothalamus. The most common cause is iatrogenicly induced by chronic corticosteroid use.
diagnosis of adrenal insufficiency
The cosyntropin stimulation test is used to differentiate primary and secondary adrenal insufficiency. Cosyntropin is a synthetic analog of ACTH. Plasma cortisol levels of greater than 20 mcg/dL are indicative of normal adrenal function and indicate hypothalamic-pituitary disease, while levels lower than this indicate non-responsiveness of the adrenals to ACTH and primary adrenal failure. Metyrapone inhibits 11-β-hydroxylase, a key enzyme on the synthetic pathway of cholesterol to cortisol. Administration of metyrapone will result in decreased synthesis of cortisol and increases in 11-deoxycortisol. The anterior pituitary will attempt to compensate by increasing ACTH production. The ACTH increase will further increase levels of 11-deoxycortisol. In adrenal insufficiency, there will be no increase in 11-deoxycortisol, as adrenal synthetic function is absent. In primary adrenal insufficiency, ACTH will increase in response to metyrapone administration, as the pituitary tries to compensate for the further reduction in cortisol synthesis. In secondary adrenal insufficiency, ACTH will not increase in response to metyrapone, as pituitary ACTH production is impaired. Shock is the most severe complication of adrenal insufficiency. This is known as adrenal crisis, and should be treated emergently in cases of high clinical suspicion. May be precipitated by stress, such as surgery or sepsis. Suspect it in a patient with chronic illness or known adrenal insufficiency who has refractory hypotension, hyponatremia, and hyperkalemia. Presents with fever, altered mental status, weakness, and vascular collapse.
treatment of adrenal insufficiency
Treatment requires repletion of adrenal hormones. Patients in adrenal crisis should receive IV glucose and corticosteroids (hydrocortisone or dexamethasone) until the shock is reversed. Vasopressors may also be used. Maintenance therapy in primary or secondary adrenal insufficiency is 5 mg prednisone every morning. Stress dosing (increased doses) of steroids are given in cases of increased stress, such as infection or surgery. Patients with primary adrenal insufficiency also require replacement of aldosterone with the aldosterone analog fludrocortisone.
causes of hypogonadotropic hypogonadism
low FSH/LH due to hypothalamic/ pituitary diseases. Causes include macroadenomas, prolactinomas, isolated GnRH deficiency (Kallman’s vs idiopathic), hemochromatosis, functional deficiency due to critical illness, OSA, starvation, meds-opiates, gluccorticoids.
causes of hypergonadotropic hypogonadism
high FSH/LH. causes include congenital anorchia, klinefelter’s syndrome, testicular injury, autoimmune testicular disease, glycoprotein tumor.
clinical features of hypogonadism
In females: anoculatory cycles (oligo/ amenorrhea, infertility), vagina dryness, dyspareunia, hot flashes, decreased libido, breast atrophy, reduced bone mineral density. In males: reduced libido, erectile dysfunction, oligospermia or azoospermia, infertility, decreased muscle mass, testicular atrophy and decrease bond mineral density, hot flashes with acute and severe onset of hypogonadism.
Clinical Presentation of Gonadotrope Adenomas
The majority of FSH/LH tumors are clinically silent (?inefficient intact LH/FSH hormone synthesis or secretion). Rare presentation (from functionally-intact FSH/LH molecules) include: ovarian hyper-stimulation syndrome (females) or macro-orchidism (males). Middle-aged patients (males >females) with macroadenomas and related mass effects (i.e., headaches, vision loss, cranial nerve palsies, and/or pituitary hormone deficiencies).
Gonadotropinoma Diagnosis
Blood tests usually showing low FSH/LH, T/E2. Pituitary MRI. Immunohistochemical analyses (+FSH, LH, or ASU staining) of the resected tumor
Thyrotropin (TSH) Elevation
Secondary causes include thyrotropic secreting pituitary tumor- very rare (less than 1% of pituitary tumors) and thyroid hormone resistance (generalized or pituitary- specific, rare conditions).
Thyrotropinoma (TSHoma)
similar clinical presentation to primary hyperthyroidism (i.e., goitre, tremor, weight loss, heat intolerance, hair loss, diarrhea, irregular menses) but also with associated mass effects (i.e., headaches, vision loss, loss of pituitary gland function) from macroadenoma. Diagnosis based on elevated free T4 and a non-suppressed TSH and pituitary MRI.
central TSH deficiency
causes include pituitary/ hypothalamic disease and/or their treatments, critical illness/ starvation- euthyroid sick syndrome, congenital defects (TSH-beta mutations, PROP1 POUF1 mutations), drug induced supraphysiologic steroids, dopamine, rexinoids. Clinical presentation is similar to primary hypothyroidism (e.g. fatigue, weight gain, cold intolerance, constipation, hair loss, irregular menses). Possible mass effects. Diagnosis is made based on low free T4 levels in the setting of a low or normal TSH.
hypopituitarism
deficiency of 1 or more pituitary hormones. Panhypopituitarism is loss of all pituitary hormones. Causes includes congenital- genetic diseases (transcription factor mutations) and acquired pituitary lesions and or their treatments (macroadenomas, pituitary surgery, radiation therapy, infiltrative, infectious, granulomatous disease, traumatic brain injury, subarchnoid hemorrhage, apoplexy. There is predictable loss of the anterior pituitary: GH, LH/FSH-> TSH, ACTH-> PRL. Clinical presentation depends on the severity of the pituitary hormone deficiencies and their rate of development. Generally similar presentation to target gland hormone deficiency with some exceptions: primary adrenal insufficiency also presents with hyperkalemia from mineralcorticoid deficiency and hyperpigmentation from ACTH. Diagnosis is based on basal and dynamic testing. Treatment involves end organ hormone replacement.
apoplexy
Clinical syndrome of headache, vision changes, ophthalmoplegia and altered mental status caused by the sudden hemorrhage or infarction of the pituitary gland. Occurs in 10-15% of pituitary adenomas; sub-clinical disease is more common. Diagnosis based on MRI or CT. Treatment includes emergent surgery is indicated for evidence of severe vision loss, rapid clinical deterioration, or mental status changes. Stress dose steroids for adrenal insufficiency.
syndrome of inappropriate anti-diuretic hormone (SIADH)
The syndrome of inappropriate anti-diuretic hormone (SIADH) is a condition of excess anti-diuretic hormone (ADH) leading to impaired water excretion and excessive water retention. SIADH should be suspected in any patient with hyponatremia, serum hypoosmolality, and urine osmolality > 100 mOsmol/kg. Patients may experience cognitive slowing and confusion, anorexia, ataxia with muscle weakness causing falls, and generalized seizures or coma. Note: these symptoms are typically only seen with severe or acute-onset hyponatremia. Physical exam is most often normal, with no evidence of fluid overload or volume depletion (normal blood pressure, skin turgor, etc.). Complications of SIADH are typically neurologic issues such as seizure or coma, due to hyponatremia.
causes of SIADH
Ectopic production of ADH, most commonly from small-cell lung carcinoma. CNS disorder or trauma, such as stroke, hemorrhage, infection, or psychosis. Pulmonary disease, particularly pneumonia. Surgery, especially transsphenoidal pituitary surgery. Drugs: cyclophosphamide, carbamazepine, SSRIs
diagnosis of SIADH
Diagnosis is made using both the clinical appearance of euvolemia and the laboratory results described below. When SIADH is suspected, the following labs should be ordered, and these results are consistent with SIADH: Serum electrolytes (sodium, potassium, bicarbonate): low sodium, normal potassium and bicarbonate; Serum osmolality: low; Urine osmolality: submaximally dilute (> 100 mOsmol/L); Urinary sodium excretion: normal, not reduced as one would expect in the setting of hyponatremia; Anion gap: reduced; Serum blood urea nitrogen (BUN): low (less then 10 mg/dL); Serum uric acid: low (less then 4 mg/dL); Blood glucose: normal value rules out hyperglycemia as cause of hyponatremia; Serum cortisol: normal value rules out adrenal insufficiency as cause of hyponatremia; Thyroid-stimulating hormone: normal value rules out hypothyroidism as cause of hyponatremia. Correction of hyponatremia after fluid restriction is indicative of SIADH. Imaging is used to find the cause of the SIADH, rather than to come to the initial diagnosis of SIADH. Chest X-ray may show small-cell lung carcinoma producing exogenous ADH. Head CT or MRI may show a brain tumor or other CNS disorder causing excessive ADH production. It may also show cerebral edema, a complication of SIADH.
treatment of SIADH
Treatment focuses on correcting the hyponatremia. First-line therapy in emergent situations is infusion of 3% hypertonic saline. Do not correct sodium levels too quickly, as rapid normalization of sodium levels can lead to central pontine myelinolysis! The goal is to raise serum sodium levels by 0.5-1 mEq/hour. Sodium levels should not be raised more than 10-12 mEq in the first 24 hours. Maximum sodium level is 125-130 mEq/L. In non-emergent situations, use fluid restriction and/or V2 receptor antagonists. Fluid restriction limits water intake, forcing the kidneys to excrete free water from plasma to maintain the fixed osmolality dictated by ADH secretion. V2 (vasopressin) receptor antagonists, the –vaptans, reduce aquaporin channels in the renal collecting ducts, thereby decreasing permeability of the duct to water and reducing the amount of water reabsorbed into the body in the collecting duct. Furosemide and other loop diuretics can also be used to increase free water excretion, but should be used in conjuction with infusion of hypertonic saline to avoid net sodium loss. Demeclocycline, an older tetracycline, can induce diabetes insipidus by interfering with the action of ADH on the collecting duct. This drug is no longer commonly used, because its onset of action can take over a week, it can be nephrotoxic in patients with liver disease, and it is no longer available in most countries. Aside from correcting the hyponatremia, further care centers on finding and treating the cause of the SIADH. This may involve surgery or chemotherapy for small-cell lung carcinoma, antibiotics for pneumonia, neurology or cardiology intervention for CNS disorder, or medication management for drug-induced SIADH.
Diabetes insipidus (DI)
Diabetes insipidus (DI) is the inability of the body to retain water, which is normally done by reabsorbing it from the urine. There are two types: central and nephrogenic.
Central diabetes insipidus
Central diabetes insipidus is caused by decreased ADH synthesis from the hypothalamus or decreased release from the posterior pituitary. Causes of central DI include: Idiopathic: Destruction of the ADH-secreting cells in the hypothalamus; Trauma; Tumors; Anorexia nervosa
Nephrogenic diabetes insipidus
Nephrogenic diabetes insipidus is caused by renal resistance to antidiuretic hormone. Causes include: Hereditary renal diseases; Drugs; Hypokalemia; Hypercalcemia. Drugs that cause nephrogenic diabetes insipidus include: Lithium; Demeclocycline (tetracycline antibiotic); Cidofovir (antiviral); Foscarnet (antiviral); Amphotericin (antifungal). Patients classically present with polyuria, polydipsia, and new-onset nocturia. In adults, onset of symptoms is usually abrupt in central DI, but more gradual in nephrogenic DI.
diagnosis of diabetes insipidus
The first step of workup is urinalysis and serum metabolic panel. Urine will be inappropriately dilute, meaning the urine osmolality will be less than the serum osmolality. Look for urine specific gravity 290 mOsm/L. Low urine and serum osmolality is characteristic of psychogenic polydipsia, not diabetes insipidus. If urine osmolality is low and serum osmolality is high, the next step is a water deprivation test. In normal physiology, decreased water intake leads to higher serum osmolality, provoking release of ADH and consequent water resorption from the urine, resulting in increased urine osmolality. No change in urine osmolality after water deprivation is diagnostic of diabetes insipidus. Once the diagnosis of diabetes insipidus is established with the water deprivation test, the next step is a DDAVP test to distinguish central DI from nephrogenic DI. DDAVP (a.k.a. desmopressin) is a synthetic form of ADH/vasopressin. In central DI, administration of DDAVP will result in increased urine osmolality, because the absent vasopressin is replaced by a synthetic analogue. In nephrogenic DI, there will be no change in urine osmolality with administration of DDAVP, since the problem is renal resistance to ADH.
treatment of diabetes insipidus
The key treatmenr in central DI is desmopressin, which can be administered IV, SQ, PO, or intranasally. Surgery may be appropriate if the condition is caused by a pituitary or hypothalamic tumor. For nephrogenic DI, the key is to treat the underlying disorder, if present. The following are helpful in symptomatic management: Hydrochlorothiazide, due to sodium excretion in the distal convoluted tubule, mild hypovolemia, and compensatory increased sodium and water reabsorption in the proximal tubule. indomethacin, an NSAID that functions by similar mechanism as hydrochlorothiazide. Amiloride in lithium-induced DI. Amiloride is a potassium-sparing diuretic that blocks lithium entry through the epithelial sodium channels in principal cells
pituitary adenomas
The two most common pituitary adenomas are prolactinoma and GH-secreting adenoma. Synaptophysin and reticulin are markers.
Overview of sellar region masses
85%+ of sellar region masses are pituitary adenomas, which although not formally graded, are equivalent to WHO grade I; almost all the other non-pituitary adenoma sellar region masses are also WHO grade I and treated by surgical resection except in instances where medical therapies are available. Some pituitary adenomas are hyperfunctioning and produce physiologically-unregulated excess of endocrine hormone(s); many are clinically non functioning and produce mass effect or visual disturbances due to compression of critical nearby anatomical structures. Most uncommon (Rathke cleft cyst), or rare, sellar region masses (pituicytoma, spindle cell oncocytoma, hypophysitis) closely mimic pituitary adenomas on neuroimaging and clinically mimic clinically non functioning pituitary adenomas in that they present with mass effects or visual disturbance. All except craniopharyngioma predominantly affect middle age adults; craniopharyngioma has two age peaks, pediatric (5-15 yrs) and middle age (45-60 yrs) adults.
Pituitary blastoma
Pituitary blastoma related to DICER1 mutation, almost always ACTH IHC(+). Pediatric/young adults occasionally get pituitary adenomas and this population is enriched for syndromic examples; very rare infantile pituitary masses are a different entity: pituitary blastoma. Almost all other pituitary adenomas SPORADIC. 85% of usual ACTH adenomas are microadenomas, most prolactinomas in premenopausal women are microadenomas. Gonadotroph are the most common type of clinically non functioning adenoma, most common adenoma type to come to surgery.
T-Pit
growth hormone factor of corticotroph tumors
Pit-1
transcription factor of somatotroph tumors
SF-1
steroidogenic factor of gonadotroph tumors
prolactinoma
A prolactinoma is the most common pituitary adenoma, which overproduces the hormone prolactin. Signs and symptoms of prolactinoma include: Impotence; Amenorrhea; Gynecomastia; Galactorrhea; Low libido; Infertility; Headache. Enlargement of the pituitary gland may also lead to compression of the optic chiasm. This results in a loss of peripheral vision known as bitemporal hemianopsia. Since prolactin provides feedback-inhibition to gonadotropin releasing hormone (GnRH), high levels of prolactin secretion in prolactinomas can suppress GnRH secretion. Prolactin inhibits its own secretion by directly increasing the release of dopamine from the hypothalamus (dopamine subsequently inhibits further prolactin secretion). Because of the physiological action of dopamine (suppressing prolactin), dopamine antagonists (notably antipsychotics) can cause galactorrhea from this loss of inhibition. The treatment for prolactinoma includes bromocriptine or cabergoline, both of which are dopamine agonists. Dopamine normally inhibits prolactin release. Bromocriptine can also be used in the treatment of Parkinson disease. Transsphenoidal surgical resection may be indicated for large tumors.
growth hormone secreting pituitary adenomas
inappropriately secretes growth hormone (GH), leading to acromegaly or gigantism. If the excessive GH secretion occurs during childhood (prior to skeletal epiphyseal closure) the disease state that results is gigantism. If the excessive GH secretion occurs during adulthood (after epiphyseal closure) the disease state that results is acromegaly. Gigantism is characterized by disproportionately long limbs (increased linear bone growth), whereas acromegaly presents as conspicuous growth in the skin and soft tissues, viscera, and bones of the face, hands, and feet. Signs and symptoms of acromegaly include: Coarsening of skin/facial features; Thickening of the hands and feet; Enlargement of the jaw resulting in protrusion (prognathism); Deep voice; Impaired glucose tolerance (insulin resistance); Peripheral neuropathies (due to nerve compression). Diagnosis is made based on increased insulin-like growth factor and MRI/CT imaging of a pituitary neoplasm. A growth hormone suppression test may be performed to determine whether GH production is suppressed by high blood sugar (induced by drinking a glucose solution). There are three treatment options for gigantism and acromegaly: Surgery or radiation; Octreotide, a somatostatin analogue that inhibits GH release from the anterior pituitary and; Pegvisomant, a GH receptor antagonist which effectively blocks IGF-1 production.
Rathke’s cleft cyst
A Rathke’s cleft cyst is a benign growth found on the pituitary gland in the brain, specifically a fluid-filled cyst in the posterior portion of the anterior pituitary gland. It occurs when the Rathke’s pouch does not develop properly and ranges in size from 2 to 40mm in diameter. Asymptomatic cysts are commonly detected during autopsies in 2 to 26 percent of individuals who have died of unrelated causes. Females are twice as likely as males to develop a cyst. If a cyst adds pressure to the optic chiasm, it may cause visual disturbances, pituitary dysfunction, and headaches. The majority of pituitary patients with chronic headaches have Rathke’s Cleft Cysts. This is believed to be caused by the constant change in volume and the drastic changes in vasopressure from fluctuations in gonadotrophs and ADH. Symptoms vary greatly between individuals. RCCs can be non-functioning, functioning, or both. Besides headaches, neurocognitive deficits are almost always present, but have high rate of immediate reversal if cyst is properly treated by being drained. They will eventually rupture if not addressed. Patients report attacks of violent headache radiating down the back of their neck. Cortisol will drop due to impact of ACTH production form apoplexy. The treatment of choice for symptomatic cysts is drainage and taking a biopsy. Radical excision is more dangerous because of the potential of damaging the patient’s pituitary function e.g. ADH storage and lowering growth hormone production.
Craniopharyngioma
Craniopharyngiomas are relatively benign (WHO grade I) neoplasms that typically arise in the sellar/suprasellar region. They account for ~1-5% of primary brain tumours, and can occur anywhere along the infundibulum (from the floor of the third ventricle, to the pituitary gland). There are two pathological types, which are said to differ not only in appearances, but also in prognosis and epidemiology. Whether or not they represent distinct entities or a spectrum of morphology remains a little controversial. They are: adamantinomatous (paediatric); papillary (adult); mixed: ~15%, but share imaging and prognosis similar to adamantinomatous. Craniopharyngiomas are believed to derive from Rathke cleft rather than squamous cell rests along the craniopharyngeal duct as was previously thought 3. This histological appearance of the two subtypes are different, accounting for the various imaging features.
Clinical presentation of craniopharyngiomas
Clinical presentation is variable on account of the variable location and size of the tumour. Presenting complaints include: headaches and raised ICP, visual symptoms (20% of children and 80% adults), hormonal imbalances, short stature and delayed puberty in children, decreased libido, amenorrhoea, diabetes insipidus, behavioural change due to frontal or temporal extension
Craniopharyngioma Adamantinomatous
This type is seen predominantly in children. It consists of reticular epithelial cells that have appearances reminiscent of the enamel pulp of developing teeth. There may be single or multiple cysts filled with thick oily fluid high in protein, blood products, and/or cholesterol, creating the so-called “machinery oil”. “Wet keratin nodules” are a characteristic histological feature. Calcification is usually present: ~90%. Adamantinomatous craniopharyngiomas is the most common form ~ 90%, and typically have a lobulated contour as a result of usually multiple cystic lesions. Solid components are present, but often form a relatively minor part of the mass, and enhance vividly on both CT and MRI. Overall, calcification is very common, but this is only true of the adamantinomatous subtype (~90% are calcified). These tumours have a predilection to be large, extending superiorly into the third ventricle, and encasing vessels, and even being adherent to adjacent structures
Craniopharyngioma Papillary
The papillary subtype is seen almost exclusively in adults and is formed of masses of metaplastic squamous cells. “Wet keratin” is absent. Cysts do form, but these are less of a feature, and the tumour is more solid. Calcification is uncommon or even rare. Papillary craniopharyngiomas tend to be more spherical in outline and usually lack the prominent cystic component; most are either solid or contain a few smaller cysts. Calcification is uncommon or even rare in the papillary subtype, a fact often forgotten
The Role of Surgery in the Treatment of Pituitary Tumors
Surgery is generally the first line of treatment for all pituitary tumors except for tumors that secrete prolactin. Tumors that secrete both prolactin and growth hormone generally are candidates for surgical intervention
steroid hormones
The major classes of steroid hormones are glucocortocoids, mineralocorticoids, and sex steroids. The three major classes of sex steroids are progestins, androgens, and estrogens. The conversion of cholesterol into the three major classes of sex steroids follows a progressive reduction in the number of carbon atoms the molecules contain. Principle sources of sex steroids include the gonads, the adrenal cortex, and the placenta. Peripheral tissues such as the skin, liver and adipose tissues play key roles in the conversion and metabolism of sex steroids. The total amounts, relative amounts, and physiologic sources of circulating sex steroids differ between males and females. The amounts of circulating estrogen and progesterone in women of reproductive age follow a monthly pattern, producing the changes in the endometrial lining of the uterus which lead to menstruation
three major classes of steroid hormones
These include the glucocortocoids such as cortisol (C-21), the mineralocorticoids such as aldosterone (C-21), and the sex steroids which include progestins (C-21), androgens (C-19), and estrogens (C-18). Like the bile salts and Vitamin D, all three major classes of steroid hormones have cholesterol as their precursor. Cholesterol is a 27-carbon steroid molecule, with all 27 carbon atoms derived from acetyl-CoA in a series of steps beyond the scope of this session. The biochemical relationships among the three major classes of steroid hormones is also addressed elsewhere. Specific gonadal cells can synthesis cholesterol de novo from co-enzyme A or derive cholesterol from low-density lipoproteins (LDL’s) in the circulation. Sex steroids can be produced in the gonads as well as in extra-gonadal tissues such as the adrenal cortex, the skin, and adipose tissue. By a process which includes a reduction in the size of the hydrocarbon side-chain and hydroxylation of the 4-ring steroid nucleus, the cholesterol molecule is converted into the steroid hormones. The initial and rate-limiting step in these reactions is catalyzed by the cholesterol side chain cleavage enzyme located in the mitochondrial membrane. This enzyme is also known as 20, 22 desmolase. The resulting structure is a 21-carbon compound known as pregnenolone. Pregnenolone is then converted into all other sex steroids.
Progestins
Progestins are the 21-carbon sex steroids derived from cholesterol. The progestins synthesized in the human body include pregnenolone, 17-alpha-hydroxy-pregnenolone, progesterone, and 17- alpha-hydroxy-progesterone (17-OH-P). In addition to being sex steroids, progestins are also precursors for the production of aldosterone and cortisol by the adrenal gland. Like progesterone, cortisol and aldosterone also have 21 carbons. The major circulating progestins are progesterone and 17-hydroxy-progesterone, with the former present in higher concentrations in females. Clinically, 17-hydroxy-progesterone is an excellent marker for late-onset congenital adrenal hyperplasia. Progestins affect almost all tissues in the body, most notably the uterus, the ovaries, and the breasts. Key functions of progesterone include the growth and development of the tissues and organs related to ovulation, menses, pregnancy, and lactation. Progesterone levels fluctuate during the normal menstrual cycle. Within the context of the hypothalamic – pituitary – ovarian axis, progesterone acts as a key feedback inhibitor at the levels of hypothalamus and pituitary.
Androgens
Androgens are the 19-carbon sex steroids derived from cholesterol via pregnenolone. The major androgens synthesized in the human body include testosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), dihydrotestosterone (DHT), and androstenedione. Approximately 95% of the testosterone which circulates in the male is produced in the testes. The other major source of androgens is the adrenal cortex. The majority of DHEA and conjugated DHEA-S is produced in the adrenal cortex and serves as an excellent marker of adrenal androgen activity. Physiologic levels of adrenal androgens do not appear to have significant effects on the growth of the reproductive system. Within the ovary, androstenedione from the theca calls is the precursor for ovarian estradiol production by the granulosa cells. Androstenedione is also a precursor for extraglandular estrogen formation in the liver and adipose tissues.
5-alpha-reductase
5-alpha-reductase is the enzyme which converts testosterone to dihydrotestosterone (DHT) in target cells such as those located in the prostate and skin. The biologic activity of dihydrotestosterone (DHT) is 30 to 50 times higher than that of testosterone. Dihydrotestosterone cannot be converted to estrogens.
Testosterone
Testosterone affects almost all tissues in the body. The effects are classified into two major categories: androgenic and anabolic. Androgenic impacts include the growth and development of the internal and external genitalia, the development and maintenance of secondary sex characteristics, spermatogenesis, and sexual fantasies and libido. Sebum production is an androgen dependent process. Anabolic effects can be summarized as the growth-promoting effects on somatic tissues such as bone and muscle. Within the hypothalamic – pituitary – testicular axis, testosterone acts as a key feedback inhibitor at the levels of hypothalamus and pituitary. The levels of circulating testosterone in men are relatively stable throughout most of adulthood.
Estrogens
Estrogens are the 18-carbon sex steroids derived from cholesterol via pregnenolone. Pregnenolone is converted into other progestins, and then into the androgens. Androgens are converted into the estrogens via an enzyme known as aromatase. Aromatase is present in the gonads and in various peripheral tissues including adipose tissue, liver, ands the CNS. The estrogens synthesized in the human body include estrone (E1), estradiol (E2) and estriol (E3). They have one, two, and three hydroxyl groups, respectively. Of these, estradiol is the most potent and estriol is the least. Estradiol is the major circulating estrogen and is produced by the granulosa cells of the ovary in females and by the Sertoli cells of the testes in males. Estrone is derived from androstenedione in adipose tissue. Estriol is an important placental product. Estrogens affect almost all tissues in the body, most notably the uterus, the ovaries, and the breasts. Key functions of estradiol include the growth and development of the tissues and organs related to ovulation, menses, pregnancy, and lactation. Estradiol levels fluctuate during the normal menstrual cycle. Within the context of the hypothalamic – pituitary – ovarian axis, estradiol acts as a key feedback inhibitor at the levels of hypothalamus and pituitary.
Sex steroids
Sex steroids are hydrophobic and therefore carried in the bloodstream predominantly bound to plasma proteins. These proteins include albumin, sex hormone binding globulin (SHBG), and corticosteroid binding globulin (CBG). SHBG is produced in the liver. Orally administered exogenous estrogens stimulate hepatic synthesis of SHBG. Sex steroid molecules enter target cells via passive diffusion. Testosterone and estradiol act on their target cells by binding to receptors located within the nucleus. The gene encoding for the androgen receptor is located on the X chromosome. These activated sex steroid / receptor complexes then bind to nuclear chromatin, increasing the transcription of target proteins.
hypothalamic- pituitary- gonadal axis
The hypothalamus releases a compound called gonadotropin releasing hormone (GnRH) into the portal circulation, which delivers GnRH to the anterior pituitary gland. Most of the GnRH originates in neurons of the arcuate nucleus and preoptic area of the hypothalamus. GnRH is released into the portal circulation in a pulsatile fashion. Pulsatility is key to the physiologic stimulation of the anterior pituitary as constant administration of GnRH actually suppresses the pituitary response. In adult males, approximately 8-14 pulses are released every 24 hours. In adult females, patterns of GnRH, FSH, and LH secretion vary throughout the menstrual cycle. Within the anterior pituitary, GnRH stimulates responsive cells in the anterior pituitary to release Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH). Though named for their functions in the female, LH and FSH are the primary regulators of gonadal function in both sexes. Biochemically, they are related to TSH and Human Chorionic Gonadotropin (hCG). The alpha subunits of LH, FSH, hCG and TSH are identical. The beta subunits are distinct and confer specific functional and immunologic characteristics to the intact molecule. Patterns of FSH and LH secretion change over the life cycle. In ovulatory women, the levels of FSH and LH also vary throughout the menstrual cycle, reaching their peaks shortly before ovulation. The levels of circulating estradiol and progesterone produced in response to the FSH and LH also fluctuate in a cyclic pattern. The endometrial cells which form the uterine lining responds to these fluctuations in a predictable pattern which culminates in menstrual blood flow. To stimulate FSH and LH secretion by the pituitary gonadotrophs, GnRH binds to receptors on the cell surface. LH and FSH are then released into the circulation and stimulate the production of sex steroids and inhibin. The sex steroids exert negative feedback control on the reproductive axis at both the hypothalamic and pituitary levels. Inhibin exerts negative feedback control on the reproductive axis exclusively at the level of the pituitary. At midcycle in ovulatory women, ovarian estradiol also exerts positive feedback on the pituitary gland, leading to a surge in FSH and LH.
gonadal cell types
In both sexes, gonadal sex steroid production and gametogenesis involve 2 distinct cell types working synergistically. In the testis, these are the Leydig and Sertoli cells. In the ovary, they are the theca and the granulosa cells. The theca and granulosa cells are located at the surface of the ovary in a layer known as the ovarian cortex. Both cell types are required to metabolize cholesterol into estradiol, which is the principle gonadal estrogen. The male Leydig and female theca cells are interstitial cells and have many features in common. These include the presence of LH receptors, the ability to make androgens, and the inability to make estrogens due to the absence of aromatase. The male Sertoli and female granulosa cells are immediately adjacent to the developing gametes and also have many features in common. These include the presence of FSH receptors, the ability to make inhibin, and the ability to convert androgens into estrogens due to the presence of aromatase.
Leydig cells
The Leydig cells occupy the interstitial layer surrounding the seminiferous tubules. In response to LH, Leydig cells produce around 95% of the testosterone in males. LH stimulates the rate-limiting conversion of cholesterol into pregnenolone in two ways: by increasing the amount of desmolase and by enhancing the affinity of desmolase for cholesterol. The resulting testosterone which acts on the Sertoli cells to support spermatogenesis. This testosterone also exerts negative feedback on the hypothalamic – pituitary – testicular axis at both the hypothalamic and pituitary levels.
Sertoli cells
The Sertoli cells in the male are in direct contact with the developing spermatozoa and are regarded as the as the support or nurse cells of the developing spermatozoa. Spermatogenesis requires LH, FSH, Leydig cells, Sertoli cells, and testosterone. The Sertoli cells are organized into a tubular epithelium known as the seminiferous tubule. This general structure is supported by the presence of tight gap junctions between adjacent Sertoli cells. Maturing spermatogonia are located between adjacent Sertoli Cells. Gap junctions between Sertoli cells and the adjacent spermatozoa are responsible for the maturation of those gametes. FSH binding to Sertoli cells has several effects. These include increased production of androgen binding protein, enhanced conversion of testosterone from the Leydig cells into estradiol, and the production of inhibin. The Sertoli cells are the primary source of inhibin in males. Inhibin plays an important role in the negative feedback arm of the hypothalamic-pituitary-testicular axis.
theca cells
The theca cells are located in the ovarian stroma surrounding the follicles and are similar to the Leydig cells in the male. In response to LH secretion, theca cells produce progesterone and androgens. Theca cells lack aromatase and therefore the capacity to produce estrogens. Androstenedione from the theca cells must therefore diffuse into nearby granulosa cells for estrogen to be produced.
ovarian granulosa cells
The ovarian granulosa cells are in direct contact with the oogonia and are similar to the Sertoli cells in the male. The gametes and their surrounding granulosa cells are called primordial follicles. In reproductive age women, one follicle, called the dominant follicle, matures each month. Oogenesis and ovulation require LH, FSH, granulosa cells, theca cells, testosterone and estradiol. Granulosa cells lack the enzyme which converts progesterone into androgens. Progesterone from the granulosa cells must therefore diffuse to the theca cells where it is converted into androstenedione. Theca cells lack aromatase, so the resulting androstenedione diffuses back to the granulosa cells for conversion to estradiol.
Control of anterior pituitary hormone release
Release of hypothalamic hormones (releasing factors) under CNS control via neurotransmitters (NE, DA, GABA, 5HT, ACh). Release of anterior pituitary hormones (trophic hormones) is controlled by hypothalamic hormones (either releasing or inhibiting factors) that are synthesized in and released from peptidergic neurons. They are then delivered via portal circulation to the pituitary gland for release into the systemic circulation where they act on endocrine glands to regulate production of hormones that perform ultimate regulatory functions
Control of posterior pituitary hormone release
Synthesized in peptidergic neurons in the hypothalamus and then transported to the neuronal terminal in the posterior lobe of pituitary. Neuronally released into the systemic circulation and act directly on target tissues to perform regulatory functions
Applications of Hypothalamic-Pituitary-Target Organ Hormones in Endocrine Pharmacology
Diagnostic tools: Testing for site of disorder along hypothalamic-pituitary-target organ axis in hypo- or hyperfunctional endocrine states. Often use hypothalamic releasing factors or pituitary trophic factors. Management of hypofunction: Hormone replacement (physiologic) therapy for deficiency states. Management of hyperfunction: Suppression of hormone synthesis or effect (nonhormonal agents). Alteration of normal endocrine states: Interference with normal function in order to achieve desired state, e.g., oral contraceptives or anabolic steroids (supraphysiologic doses). Control of nonendocrine disorders: Drug therapy for variety of diseases using pharmacologic doses of hormones, e.g., glucocorticoids for inflammatory diseases
Growth Hormone (aka GH, Somatropin) Structure / Pharmacokinetics
191 amino acid peptide with 2 sulfhydryl bridges. Produced with recombinant DNA technology: Somatropin (Humatrope, Serostim, Genotropin, Nutropin, Saizen, Norditropin) matches native GH amino acid sequence. Somatrem (Protropin), which was formerly available, has additional methionine AA. Circulating t1/2 of 25 min. Can be given IM, peak levels in 2-4 hrs, active levels persist 36 hrs
Growth Hormone (aka GH, Somatropin) Pharmacodynamics
Release increased by GHRH, exercise, hypoglycemia, dopamine, l-DOPA, arginine. Decreased by somatostatin and paradoxically decreased by dopamine agonists in acromegaly. Produces anabolic and metabolic effects: Positive nitrogen balance, stimulation of lipolysis, increased free fatty acids and blood glucose. At pharmacologic doses GH works indirectly to stimulate synthesis of insulin-like growth factors (IGF-1, IGF-2 in growth plate cartilage and liver) promoting linear and skeletal muscle growth
Growth Hormone (aka GH, Somatropin) Uses
Recombinant human growth hormone now available; until 1985 only source was human cadaver, use was discontinued due to possible prion contamination [Creutzfeldt-Jakob disease]. Replacement therapy in children with deficiency. Given daily at bed time via SC injection (more effective, mimics natural release pattern) or 3 times a week IM - SR preparations for weekly SC injection are in development. Yearly cost $10,000-50,000 depending on patient’s weight. Use in children with idiopathic short stature is controversial. Response to GH is highly variable with responders showing only modest growth increase. Scant evidence that short stature is substantial psychosocial burden to most short children. Any psychosocial benefit must be weighed against cost (∼ $50,000 per inch) and possible adverse effects. If growth hormone insensitive (receptor mutation - Laron dwarf) can treat with recombinant IGF-1 (Mecasermin-Increlex); concern with hypoglycemia, so carb intake prior to injection. Treatment of poor growth due to Turner’s syndrome, Prader-Willi syndrome, and chronic renal insufficiency. Growth hormone deficiency in adults (most commonly due to pituitary tumor or consequences of its treatment - surgery and/or radiation). Treatment of wasting or cachexia in AIDS patients. Patients with short bowel syndrome dependent on total parenteral nutrition
Growth Hormone (aka GH, Somatropin) Illicit Uses
Use by athletes to increase muscle mass and improve performance despite lack of controlled studies and in violation of regulations (banned by IOC / MLB) and standard medical practice NOTE: Many oral preparations containing “stacked” amino acids that reportedly stimulate GH release have been marketed as nutritional supplements. Again, validation in controlled trials is lacking, but they are part of multibillion dollar anti-aging and performance-enhancing programs. Use by healthy elderly for “anti-aging” effects. General consensus from limited studies suggests GH use is associated with small changes in body composition and increased rates of adverse events (edema, joint pain, muscle pain, carpal tunnel syndrome, skin numbness and tingling - may also increase growth of pre-existing malignant cells and increase the possibility of developing diabetes). Cannot be recommended
Growth Hormone (aka GH, Somatropin) Side Effects
Generally safe when used for replacement in children. Insulin resistance and glucose intolerance may occur. Slight increased risk for idiopathic intracranial hypertension (pseudotumor cerebri) Rarely pancreatitis, gynecomastia, nevus growth. Misuse in athletes: Acromegaly, arthropathy, visceromegaly, extremity enlargement
Growth Hormone Releasing Hormone (GHRH) Structure
Linear peptide - 44 amino acids. Synthetic analogs [GHRH44, GHRH40, and GHRH29] are easier to synthesize and cheaper - available for investigational use
Growth Hormone Releasing Hormone (GHRH) Pharmacology
Rapidly stimulates GH synthesis and secretion via binding to GPCR coupled to Gs -> increasing cAMP and Ca++ levels in somatotrophs - no receptor down-regulation with continuous stimulation. Ghrelin is a 28 AA peptide that also stimulates GH release via a different GPCR. It is secreted predominantly by endocrine cells in stomach and also stimulates appetite and increases food intake. Acts in complex manner to integrate functions of GI tract, hypothalamus, and pituitary. Dominant inhibitory regulator is somatostatin. Growth hormone also acts as own feedback inhibitor. Effective given intravenously, intranasally, subcutaneously. Adverse effects rare, facial flushing (IV), antibody formation with continued use
Growth Hormone Releasing Hormone (GHRH)
Sermorelin (Geref)-GHRH29 withdrawn from US market in 2008. Diagnostic evaluation of patients with idiopathic GH deficiency. Potential use in GH-deficient children (preserves feedback at pituitary level - smaller molecule than GH, less expensive); potentially fewer side effects. However, synthetic human growth hormone is now usually used for treatment of GH deficiency. For approximately two-thirds of GH deficient children, the deficiency may be secondary to inadequate GHRH release. Tesamorelin (Egrifta) is a GHRH analog available for use in HIV patients with lipodystrophy secondary to use of highly active retroviral therapy (HAART) - reduces excess abdominal fat
Somatostatin (aka SST, Growth Hormone-Inhibiting Hormone, Somatotropin Release-Inhibiting Factor) Pharmacology
Present in hypothalamus, nervous system, gut, endocrine and exocrine glands - function varies. Inhibits GH release via GPCR coupled to Gi decreasing cAMP levels and activating K+ channels. Decreases secretion of gastric enzymes and acid - decreased GI motility - suppresses release of
serotonin and gastroenteropancreatic peptides. Reduces insulin and glucagon release - complex effects on blood glucose. Interferes with TRH ability to release TSH
Somatostatin Pharmacokinetics of Somatostatin and Analogs
Somatostatin: T1/2 following exogenous administration only 3-4 min limiting therapeutic usefulness - kidney has significant role in clearance. Octreotide (Sandostatin): plasma t1/2 ∼ 90 min (duration ∼ 12 hrs); given SC every 6-12 hours. Octreotide (Sandostatin LAR depot) given intramuscularly every 4 weeks Lanreotide (Somatuline depot) given subcutaneously every 4 weeks
Pituitary Uses of Somatostatin Analogs
Treats excess of growth hormone. Acromegaly (adults - rare, most commonly due to pituitary somatotroph adenoma) and gigantism (children - extremely rare). Surgical resection preferred unless adenoma does not appear fully resectable, patient has high surgery risk, or does not choose surgery. Long-acting somatostatin analog is preferred pharmacotherapy - utilized after response seen to SC octreotide. Dopamine agonists may inhibit GH secretion in some patients, but not as effective as SST analogs. Cabergoline is preferred agent for adjuvant management of acromegaly with advantage of oral administration. GH receptor antagonist: Pegvisomant (Somavert) is a mutated GH molecule with polymers attached to extend its half-life. Binds to receptor, blocking GH access, but does activate signaling transduction. Single daily dose administered subcutaneously.
Non- Pituitary Uses of Somatostatin Analogs
Control of bleeding from esophageal varices and GI hemorrhage - direct action on vascular smooth muscle to constrict splanchnic arterioles. Fewer side effects than vasopressin. Carcinoid tumors, VIP-secreting tumors, glucagonoma, gastrinoma. Symptoms of WDHA syndrome (watery diarrhea, hypokalemia, achlorhydria)
Somatostatin
Transient deterioration in glucose tolerance (hyperglycemia) then subsequent improvement. Abdominal cramps, loose stools. Cardiac effects include sinus bradycardia (25%) and conduction disturbances (10%)
Prolactin pharmacodynamics
Prolactin release is under inhibitory control by hypothalamic dopamine at D2 receptors. Main stimulus for release is suckling - causes 10-100-fold increase within 30 min. Stimulates milk production if appropriate levels of insulin, estrogens, progestins, and corticosteroids are present. Stimulates proliferation and differentiation of mammary tissue during pregnancy. Inhibits gonadotropin (FSH/LH) release and/or ovarian response to these hormones - related to lack of ovulation during breastfeeding
Uses of Prolactin
Hypoprolactinemia - No preparation available for prolactin deficiency. Hyperprolactinemia (prolactinomas) - These pituitary adenomas are the most amenable to pharmacotherapy because of the availability of dopamine agonists that both decrease secretion and reduce tumor size. All available as oral preparations. Bromocriptine [Parlodel] - prototype agent of long-standing use. Ergot derivative that also activates D1 receptors. Frequent side effects include nausea-vomiting, headache, and postural hypotension; less frequently can see psychosis or insomnia. Cabergoline [Dostinex] - has become preferred agent for hyperprolactinemia. More selective for D2 receptor and more effective in reducing prolactin secretion. Better tolerated, less nausea, but may cause hypotension and dizziness. Concern with higher doses and valvular heart disease (agonist action at 5HT2B receptors). Quinagolide - non ergot D2 agonist not approved for use in US
Vasopressin (aka Antidiuretic Hormone, ADH) Pharmacodynamics
Critical role in control of water content throughout body via actions on cells in distal nephron and collecting tubules in kidney. Released from supraoptic nuclei of hypothalamus. Main stimulus for release is rising blood osmolality. Also released in response to a decrease in circulating blood volume Recall that release can be inhibited by alcohol. Renal actions are mediated by V2 receptors (GPCRs coupled to Gs). Main effect is to increase the rate of insertion of water channels (aquaporins) into luminal membraneincrease water permeabilityleading to an antidiuretic effect. Also activates urea transporters and increases Na+ transport in distal nephron. Non-renal V2 actions include release of coagulation factor VIII and von Willebrand’s factor. ADH-vasopressin actions at V1 receptors (GPCRs coupled to Gq). Mediates vasoconstriction of vascular smooth muscle. BUT pressor responses occur in vivo only at much higher concentrations than those that produce maximal antidiuresis
Desmopressin
ADH analog that is more stable to degradation, t1/2 ∼ 1.5-2.5 hrs
Pharmacologic Therapy of Posterior Pituitary Hypofunction Diseases
Central Diabetes Insipidus - can result from head injury (trauma or surgery), pituitary tumors, cerebral aneurysm, or ischemiainadequate ADH secretion from posterior pituitary Desmopressin is treatment of choice. Nasally 1-2/day individualized to response. ADRs: may cause nasal irritation. Orally 2-3/day (bioavailability 5-10%), particularly useful in patients with sinusitis from nasal preps. ADRs: GI symptoms, asthenia, mild elevation of live enzymes. ADRs: Headache, nausea, abdominal cramps, allergic reactions, water intoxication. Chlorpropamide (1st generation sulfonylurea). Potentiates action of small or residual amounts of ADH - mechanism not clear. Option for patients intolerant (side effects-allergy) to desmopressin. Other drug options: Carbamazepine, clofibrate (not in US), thiazides, NSAIDs. Nephrogenic Diabetes Insipidus - can be congenital or drug-inducedinadequate ADH actions. Congenital: Diverse receptor and aquaporin mutations are known. Drug-induced: Lithium: reduces V2-receptor mediated stimulation of adenylyl cyclase. As many as 1/3 of patients treated with Li+ may develop nephrogenic diabetes insipidus. Demeclocyline (tetracycline antibiotic): mechanism not completely understood but possibly acts via block of ADH binding to receptor. Treatment: Low salt, low protein diet. Thiazide diuretics: Paradoxically reduce the polyuria of patients with DI. Mechanism not completely understood but antidiuretic effect parallels ability to cause natriuresis - used in doses that mobilize edema fluid. NSAIDs: Since prostaglandins attenuate ADH-induced antidiuresis, inhibition of PG synthesis by indomethacin may relate to the antidiuretic response seen. Indomethacin has greatest efficacy among NSAIDs. Thiazides and indomethacin are also used as combined therapy
Pharmacologic Therapy of Posterior Pituitary Hyperfunction Diseases
Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH) - incomplete suppression of ADH secretion under hypoosmolar conditions. Produced by multitude of disorders including malignancies, pulmonary diseases, CNS trauma- infections-tumors. Drug classes most commonly implicated. Psychotropic agents: SSRIs, haloperidol, tricyclic antidepressant. Sulfonylureas (chlorpropamide). Vinca alkaloids chemotherapy. Methylenedioxy methamphetamine (MDMA). Treatment of hyponatremia. Restriction of free water intake is initial conservative approach. Demeclocyline inhibits ADH effect on distal tubule and has been preferred drug in patients with inadequate response to conservative measures. V2 receptor antagonist - potential therapeutic advance for hyponatremia (also tried in HF). Tolvaptan (Samsca®) - oral route, but use limited by cost, increase in thirst. Conivaptan (Vaprisol®) - IV infusion (useful in hospitalized SIADH patients) - if severe symptomatic hyponatremia present, conivaptan can be given with hypertonic saline (3%), permitting a more rapid initial correction. BUT: Warning against too rapid correction of hyponatremia cerebellar pontine myelinolysisserious consequences and fatalities. Both are eliminated by CYP3A4 and associated with variety of drug-drug interactions
V1 Receptor-Mediated [Vasopressin (Pitressin)] Therapeutic Applications
Attenuates pressure and bleeding in esophageal varices via vasoconstriction of splanchnic arterioles - octreotide better tolerated and now preferred if drug used ± endoscopy. Used as a vasopressor for treatment of patients with severe septic shock. Alternative to epinephrine in ACLS protocol for shock-refractory ventricular tachycardia / fibrillation (long duration of action may have adverse effects on survival)
V2 Receptor-Mediated Therapeutic Applications
Option in nocturnal enuresis - oral desmopressin [DDAVP]: 30% of children are full responders and 40% have a partial response. Von Willebrand’s disease (elevates von Willebrand factor) and moderate hemophilia A (elevates factor VIII) - IV desmopressin
Somatropin
Growth Hormone (recombinant)
Mecasermin
Insulin-like Growth Factor-1 (recombinant IGF-1)
Octreotide
Somatostatin Analogs
Lanreotide
Somatostatin Analogs
Cabergoline
Dopamine Agonists
Bromocriptine
Dopamine Agonists
Pegvisomant
GH Receptor Antagonist
Cabergoline
Dopamine Agonists
Bromocriptine
Dopamine Agonists
Desmopressin
ADH analog
Chlorpropamide
ADH analog. Like other sulfonylureas, chlorpropamide acts to increase the secretion of insulin, so it is only effective in patients who have some pancreatic beta cell function.
Hydrochlorothiazide
Thiazide diuretics
Indomethacin
NSAIDs
Demeclocycline
It is officially indicated for the treatment of various types of bacterial infections. It is used as an antibiotic in the treatment of Lyme disease, acne, and bronchitis. Resistance, though, is gradually becoming more common, and demeclocycline is now rarely used for infections. It is widely used (though off-label in many countries) in the treatment of hyponatremia (low blood sodium concentration) due to the syndrome of inappropriate antidiuretic hormone (SIADH) when fluid restriction alone has been ineffective. Physiologically, this works by reducing the responsiveness of the collecting tubule cells to ADH. The use in SIADH actually relies on a side effect; demeclocycline induces nephrogenic diabetes insipidus (dehydration due to the inability to concentrate urine)
Tolvaptan
ADH-V2 receptor antagonists
