How do hypothalamic hormones reach the anterior pituitary gland?
A branch of the hypophyseal artery ramifies into a capillary bed in the lower hypothalamus, and hypothalmic hormones destined for the anterior pituitary are secreted into that capillary blood.
Blood from those capillaries drains into hypothalamic-hypophyseal portal veins. Portal veins are defined as veins between two capillary beds; the hypothalamic-hypophyseal portal veins branch again into another series of capillaries within the anterior pituitary.
How do hormones enter the bloodstream from the anterior-pituitary and posterior pituitary glands?
Capillaries within the anterior pituitary, which carry hormones secreted by that gland, coalesce into veins that drain into the systemic venous blood ie., the hypophyseal vein. Those veins also collect capillary blood from the posterior pituitary gland.
What is the adenohypophysis and what types of hormones does it secrete?
The anterior pituitary or adenohypophysis is a classical gland composed predominantly of cells that secrete protein hormones:
eg., GH, TRH, GnRH, insulin
What is the neurohypophysis?
The posterior pituitary or neurohypophysis is not a separate organ, but an extension of the hypothalamus. It secretes the protein hormones ADH (vasopressin) & oxytocin.
It is composed largely of the axons of hypothalamic neurons which extend downward as a large bundle behind the anterior pituitary. It also forms the so-called pituitary stalk.
What are the different regions of the adenohypophysis, aka anterior pituitary?
Pars distalis - the largest section
Pars tuberalis - a collar of tissue that usually surrounds the infundibular stalk
Pars intermedia - a narrow band that is usually separated from the pars distalis by a hypophyseal cleft
What are the different regions of the neurohypophysis, aka posterior pituitary gland?
Pars nervosa - the bulk of the posterior pituitary
Median eminence - the upper section of the neurohypophysis above the pars tuberalis
Infundibular stalk - the "stem" that connects the pars nervosa to the base of the brain
What are the types of cells that comprise the pars distalis of the adenohypophysis, aka anterior pituitary, and what do they look like when stained with haematoxylin & eosin (H&E)?
Acidophils have cytoplasm that stains red or orange
Basophils have cytoplasm that stains a bluish color
Chromophobes have cytoplasm that stains very poorly
The differential staining pattern described above is a reflection of the type of hormonal content of the cells.
In the pars distalis of the adenohypophysis, there are cells that stain in three different colour groups:
Acidophils, which stain pink or orange
Basophils, which stain bluish
Chromophobes, which stain poorly
Their colours reflect their different hormonal contents of the cells. What are the types of cells and what are the hormones produced by each type of cell?
ACIDOPHILS - cells that contain the peptide/protein hormones:
Somatotropes produce GH
Lactotropes produce PRL
BASOPHILS - cells that contain glycoprotein hormones:
Thyrotropes produce TSH
Gonadotropes produce LH & FSH
Corticotropes produce adrenocorticotrophic hormone (ACTH)
CHROMOPHOBES - Minimal or no hormonal content. Many may be acidophils or basophils that have degranulated and thereby are depleted of hormone. Some may also represent stem cells that have not yet differentiated into hormone-producing cells.
What type of trophic cells produce prolactin, where are they located, and what colour do they stain with H&E?
Lactotroph cells in the pars distalis of the adenohypophysis (anterior pituitary) produce prolactin, a peptide hormone. Lactotrophs are acidophils, staining red or orange with haematoxylin & eosin.
NB Somatotrophs, which produce GH (growth hormone), another peptide hormone, are also acidophils in the pars distalis of the adenohypophysis.
What type of pituitary trophic cells produce LH & FSH, where are they located and what colour do they stain with haematoxylin & eosin?
Gonadotrophs in the pars distalis of the adenohypophysis produce the reproductive glycoprotein hormones LH & FSH.
Gonadotrophs are basophils that stain bluish with H&E.
What types of cells produce glycoprotein hormones such as thyroid stimulating hormone (TSH) & adrenocorticotrophic hormone (ACTH)? Where are these cells located, and what colour do they stain in H&E?
The glycoproteins TSH & ACTH stimulate the thyroid & adrenal glands, so they are higher up in the hypothalamus-pituitary-adrenal axis.
They are produced & secreted by the anterior pituitary's pars distalis, by thyrotrophs (for TSH) & corticotrophs (for ACTH).
They are basophils, so they stain blue in H&E.
What is the pars tuberalis? What is its embryological origin, and what is contained in the structure?
Pars tuberalis is an extension of the adenohypophysis aka anterior pituitary, and thus its embryological origin is the same: upward evagination from oral ectoderm (vs. downward fold from neural ectoderm that forms the hypothalamus & the neurohypophysis aka posterior pituitary gland).
The pars tuberalis contains cords of epithelial cells and is filled with hypophyseal portal vessels. It reportedly contains gonadotrophs and thyrotrophs, plus other secretory cells of unknown function
What is the pars intermedia & where is it located?
The pars intermedia is closely associated with pars nervosa, aka neurohypophysis, aka posterior pituitary gland.
It is separated from the pars distalis by the hypophyseal cleft. This lobe of the pituitary shows considerable variation in size among species.
Melanocyte-stimulating hormone is the predominant hormone secreted by the pars intermedia.
The pars nervosa is comprised of three parts, starting from the part closest to the hypothalamus:
Which part is typically considered the posterior pituitary gland?
Infundibular process. This is the biggest part of the pars nervosa aka neurohypophysis.
What are the main secretory cells in the neurohypophysis aka posterior pituitary?
The bulk of the neurohypophysis is composed on largely unmyelinated axons from hypothalamic neurosecretory neurons. These axons have their cell bodies in the paraventricular and supraoptic nuclei of the hypothalamus.
These neurons secrete oxytocin (OTC) or antidiuretic hormone (ADH); ie., these are made by neurons in the hypothalamus & secreted by the posterior pituitary.
Roughly 100,000 axons participate in this process to form the posterior pituitary. In addition to axons, the neurohypophysis contains glial cells and other poorly-defined cells called called pituicytes.
What are Herring bodies?
Dilated areas or bulges in the terminal portion of axons that contain clusters of neurosecretory granules.
The granules contain oxytocin or antidiuretic hormone.
Herring bodies often are seen in association with capillaries.
What is often referred to as the "master gland" of the body?
What are the major hormones synthesized & secreted by the anterior pituitary gland aka adenohypophysis?
(name the cells that produce them, where in the anterior pituitary these cells are located, and whether they are acidophils or basophils)
FLAT PEG or FLAT PIG
Follicle Stimulating Hormone (FSH) (gonadotrophs, pars distalis, basophils)
Luteinizing Hormone (LH) (gonadotrophs, pars distalis, basophils)
Adrenocorticotropic Hormone (ACTH) (corticotrophs, pars distalis, basophils)
Thyroid Stimulating Hormone (TSH) (thyrotrophs, pars distalis, basophils)
Prolactin (lactotrophs, pars distalis, acidophils)
Interstitial-Cell Stimulating Hormone (ICSH), the male version of LH. In males, ICSH aka LH stimulates testosterone production by the Leydig cells.
Growth Hormone (somatotrophs, pars distalis, acidophils)
What are the hormones secreted by the pars nervosa aka posterior pituitary? What types of cells synthesize these hormones, and where are they located?
Oxytocin & Antidiuretic Hormone (ADH aka Vasopressin)
What are the target organs of Growth Hormone, and what are its major physiological effects?
Liver & adipose tissue
Promotes growth (indirectly), control of protein, lipid and carbohydrate metabolism
Direct effects are the result of growth hormone binding its receptor on target cells. Fat cells (adipocytes), for example, have growth hormone receptors, and growth hormone stimulates them to break down triglyceride and supresses their ability to take up and accumulate circulating lipids.
Indirect effects are mediated primarily by a insulin-like growth factor-I (IGF-I), a hormone that is secreted from the liver and other tissues in response to growth hormone. A majority of the growth-promoting effects of GH is actually due to IGF-I acting on its target cells.
How do GH & IGF-1 work together to promote growth?
GH stimulates the liver and other tissues to secrete IGF-I. IGF-I stimulates proliferation of chondrocytes (cartilage cells), resulting in bone growth.
IGF-I also appears to be the key player in muscle growth. It stimulates both the differentiation and proliferation of myoblasts. It also stimulates amino acid uptake and protein synthesis in muscle and other tissues.
What are three hormones involved in the CONTROL of GH synthesis & secretion?
Growth hormone-releasing hormone (GHRH) is a hypothalamic peptide that stimulates GH synthesis and secretion.
Somatostatin (SS) is a peptide produced by several tissues in the body, including the hypothalamus. SS inhibits GH release in response to GHRH and to other stimulatory factors such as low blood glucose concentration.
Ghrelin is a peptide hormone secreted from the stomach. Ghrelin binds to receptors on somatotrophs and potently stimulates GH secretion.
What diseases can occur with a defect in the GH receptor in target tissue or a deficiency in GH?
What diseases can occur with excessive secretion of GH?
Giantism is the result of excessive growth hormone secretion that begins in young children or adolescents. It is a very rare disorder, usually resulting from a tumor of somatotropes.
Acromegaly results from excessive secretion of growth hormone in adults, usually the result of benign pituitary tumors. The onset of this disorder is typically insideous, occurring over several years. Clinical signs of acromegaly include overgrowth of extremities, soft-tissue swelling, abnormalities in jaw structure and cardiac disease. The excessive growth hormone and IGF-I also lead to a number of metabolic derangements, including hyperglycemia.
What is the effect of GH on metabolism?
Growth hormone has important effects on protein, lipid and carbohydrate metabolism.
Protein metabolism: In general, GH stimulates protein anabolism in many tissues. This effect reflects increased amino acid uptake, increased protein synthesis and decreased oxidation of proteins.
Fat metabolism: GH enhances utilization of fat by stimulating triglyceride breakdown and oxidation in adipocytes.
Carbohydrate metabolism: GH is one of a battery of hormones that serves to maintain blood glucose within a normal range. GH is often said to have anti-insulin activity, because it supresses the abilities of insulin to stimulate uptake of glucose in peripheral tissues and enhance glucose synthesis in the liver. Somewhat paradoxically, administration of growth hormone stimulates insulin secretion, leading to hyperinsulinemia.
What is a hormone that inhibits GH production? Where is this hormone made?
Somatostatin, made in the hypothalamus, pancreas, intestinal tract and regions of the central nervous system outside the hypothalamus.
What is TSH, where is it made, and what is the most important humoral controller of its secretion?
Thyroid stimulating hormone is produced by thyrotroph cells in the pars distalis, aka anterior pituitary. These thyrotrophs stain bluish with H&A & are thus basophils.
TSH is a glycoprotein hormone, and it binds to receptors on epithelial cells of the thyroid glands, its target organ. It stimulates the thyroid glands to synthesize and secrete thyroid hormones, such as T3 & T4, which are amines derived from the amino-acid tyrosine with iodine residues.
The most important controller of TSH secretion is thyroid-releasing hormone, or TRH, synthesized by neurons in the hypothalamus, transported to the anterior pituitary via the hypothalamic-hypophyseal portal system, where they bind to receptors on thyrotrophs.
What is ACTH, where is it made, and what does it do? What causes synthesis & secretion of ACTH?
Adrenocorticotropic Hormone is made by corticotrophs in the pars distalis aka anterior pituitary, and they bind to receptors on the adrenal gland.
They stimulate adrenal-cortex production of glucocorticoid hormones, namely cortisol.
ACTH is released in response to corticotropin-releasing hormone (CRH) from the hypothalamus.
CRH is secreted in response to many types of stress. CRH itself is inhibited by glucocorticoids/cortisol, making it part of a classical negative feedback loop.
What are the hormones, aside from ACTH, are produced from the protelolytic cleavage of the precursor protein POMC, aka "Big Mama"?
(NB some of the hormones below are only produced in the pars intermedialis lobe of the pituitary, and some are not produced in all species.)
Lipotropin: Precursor to beta-endorphin
Beta-endorphin and Met-enkephalin: Opioid peptides with pain-alleviation and euphoric effects.
Melanocyte-stimulating hormone (MSH): Known to control melanin pigmentation in the skin of most vertebrates.
What type of hormone is prolactin?
Where is it made & by what type of cells?
What colour does it stain in H&E?
How is it synthesized?
What is its major target organ & what does it do?
Prolactin is a peptide hormone synthesized & secreted by the anterior pituitary, aka the adenohypophysis, by lactotrophs in the pars distalis region.
It is also synthesized and secreted by various immune cells, the brain and the decidua of the pregnant uterus.
It stains red or orange when stained with H&E, so the lactotroph cells are acidophils.
It is synthesized as a pro-hormone, which is then cleaved to become activated.
Its main target organ is the mammary gland, where it stimulates and milk production. Note however that most tissue cells have receptors for PRL.
How is PRL synthesis & secretion inhibited?
Dopamine (DA) serves as the major prolactin-inhibiting factor or brake on prolactin secretion. Dopamine is secreted into portal blood by hypothalamic neurons, binds to receptors on lactotrophs, and inhibits both the synthesis and secretion of prolactin.
What stimulates PRL synthesis & secretion?
1. Prolactin secretion is positively regulated by thyroid-releasing hormone(TRH), gonadotropin-releasing hormone (GnRH) and vasoactive intestinal polypeptide.
2. Stimulation of the nipples and mammary gland, as occurs during nursing, leads to PRL release. This effect appears to be due to a spinal reflex arc that causes release of PRL-stimulating hormones from the hypothalamus.
3. Estrogens provide a well-studied positive control over PRL synthesis and secretion. The increasing blood concentrations of estrogen during late pregnancy appear responsible for the elevated levels of PRL that are necessary to prepare the mammary gland for lactation at the end of gestation.
Where are LH & FSH synthesized & secreted from, & by which type of cells?
What colour do they stain in H&E?
Luteinizing hormone & follicle-stimulating hormone are large glycoproteins synthesized by gonadotrophs in the pars distalis of the anterior pituitary gland. They stain bluish in haematoxylin & eosin, so they are classified as basophils.
LH & FSH are also called gonadotropins.
What are the main target organs of LH & FSH, and what do they do?
The main targets are the gonads: the testes in males and ovaries in females.
In testes, LH binds to receptors on the foamy-looking Leydig cells to synthesize the steroid hormone testosterone from cholesterol. FSH supports the function of Sertoli cells, which in turn support many aspects of sperm cell maturation.
In ovaries, LH binds to receptors on theca cells, which are stimulated to produce testosterone. The steroid hormone is then converted to oestrogen by adjacent granulosa cells.
Ovulation of mature follicles on the ovary is induced by a large burst of LH secretion known as the preovulatory LH surge. Residual cells within ovulated follicles proliferate to form corpora lutea, which secrete the steroid hormones progesterone and estradiol. Progesterone is necessary for maintenance of pregnancy, and, in most mammals, LH is required for continued development and function of corpora lutea. The name luteinizing hormone derives from this effect of inducing luteinization of ovarian follicles.
FSH stimulates the maturation of ovarian follicles.
How is LH & FHS secretion controlled/regulated?
The principle regulator is gonadotropin-releasing hormone (GnRH, also known as LH-releasing hormone).
GnRH is a peptide hormone that is synthesized and secreted from hypothalamic neurons and binds to receptors on gonadotrophs.
GnRH stimulates secretion of LH, which in turn stimulates gonadal secretion of testosterone, estrogen and progesterone. In a classical negative feedback loop, these sex steroids inhibit secretion of GnRH and also appear to have direct negative effects on gonadotrophs.
This regulatory loop leads to pulsatile secretion of LH and, to a much lesser extent, FSH. The number of pulses varies from a few per day to one or more per hour.
Besides GnRH, name two other hormones selectively stimulate and inhibit FSH secretion by the anterior pituitary?
Activin & Inhibin - both are secreted by the ovaries and testes.
Why are oestrogen & progesterone used in oral contraceptives?
Oestrogen & progesterone, as sex steroids, inhibit LH production in a negative feedback loop. Without an LH surge, the ovary cannot ovulate. Ie., an LH surge is needed to induce ovulation.
What is anti-diuretic hormone, where is it made and what type of cells synthesize it? How is it secreted?
ADH, also known as arginine vasopressin (AVP), is a hypothalamic peptide hormone produced by neurosecretory cells of the hypothalamus. It, along with Oxytocin, are the only major hypothalamic hormones to be secreted by the posterior pituitary rather than the anterior pituitary gland.
After synthesis by the hypothalamic neurons, it is packaged in secretory vesicles with a carrier protein called neurophysin, and both are released upon hormone secretion by the posterior pituitary, aka neurohypophysis.
What does ADH do to prevent dehydration?
(Recall RAAS for its effect on the vascular system).
ADH helps the body to conserve body water by reducing the loss of water in urine.
ADH binds to receptors on cells in the collecting ducts of the kidney and promotes reabsorption of water back into the circulation. In the absense of ADH, the collecting ducts are virtually impermiable to water, and it flows out as urine.
ADH stimulates water reabsorbtion by stimulating insertion of "water channels" or aquaporins into the membranes of kidney tubules. These channels transport solute-free water through tubular cells and back into blood, leading to a decrease in plasma osmolarity and an increase osmolarity of urine.
What role does ADH play in the regulation of blood pressure, for example in haemorrhage or during exercise?
High concentrations of ADH cause widespread constriction of arterioles, which leads to increased arterial pressure. It was for this effect that the name vasopressin was coined. It has a pressor effect.
(see notes on RAAS)
How is ADH secretion from the posterior pituitary controlled?
The most important variable regulating ADH secretion is plasma osmolarity, or the concentration of solutes in blood. Osmolarity is sensed in the hypothalamus by neurons known as an osmoreceptors, and those neurons, in turn, stimulate secretion from the neurons that produce antidiuretic hormone.
When plasma osmolarity is below a certain threshold, the osmoreceptors are not activated and secretion of ADH is suppressed. When osmolarity increases above the threshold, the osmoreceptors recognize this as their cue to stimulate the neurons that secrete ADH.
Another potent stimulus of antidiuretic hormone is nausea and vomiting, both of which are controlled by regions in the brain with links to the hypothalamus.
What are the most common & important diseases associated with deficiency in ADH secretion or failure of the kidney to respond to ADH?
Hypothalamic or "Central" Diabetes insipidus results from a deficiency in secretion of antidiuretic hormone from the posterior pituitary. Causes of this disease include head trauma, and infections or tumors involving the hypothalamus. This can be treated with exogenous ADH.
Nephrogenic diabetes insipidus occurs when the kidney is unable to respond to antidiuretic hormone. Most commonly, this results from some type of renal disease, but mutations in the ADH receptor gene or in the gene encoding aquaporin-2 have also been demonstrated in affected humans. This is basically untreatable.
What are the major hormones synthesized by the neurons of the hypothalamus and secreted by the pituitary gland?
Oxytocin ( (secreted by posterior pituitary)
Gonadotropin-Releasing Hormone (GnRH)
Growth-hormone Releasing Hormone (GHRH)
Corticotropin-Releasing Hormone (CRH)
ADH (secreted by posterior pituitary)
Thyroid-releasing Hormone (TRH)
* remember that hypothalamic hormones are "releasing" while pituitary hormones are "stimulating"
What is oxytocin? Where is it made, by what types of cells, and from where is it secreted? What type of hormone is it?
Oxytocin is a hypothalamic peptide hormone that only differs by two amino-acid residues from ADH but has completely different functions and target tissues.
OTC, along with ADH, is secreted by the posterior pituitary gland. OTC is also secreted within the brain and from a few other tissues, including the ovaries and testes.
Like ADH, OTC is packaged into granules and secreted along with carrier proteins called neurophysins.
Its major target organs are the ovaries and testes. In females, it stimulates milk ejection ("let-down") and uterine contractions (Fergusson Reflex).
How does Oxytocin cause milk letdown?
Milk is initially secreted into mammary alveoli, from which it must be ejected for consumption or harvesting. Mammary alveoli are surrounded by smooth muscle (myoepithelial) cells which are a prominant target cell for oxytocin. Oxytocin stimulates contraction of myoepithelial cells, causing milk to be ejected into the ducts and cisterns.
How does Oxytocin stimulate uterine contractions toward the end of gestation/at the start of parturition?
During the later stages of gestation, there is an increase in abundance of OTC receptors on uterine smooth muscle cells, which is associated with increased "irritability" of the uterus. OTC is released during labour when the fetus stimulates the cervix and vagina, and it enhances contraction of uterine smooth muscle to facilitate parturition or birth. (Fergusson Reflex)
In cases where uterine contractions are not sufficient to complete delivery, veterinarians sometimes administer oxytocin ("pitocin") to stimulate uterine contractions.
What is the most important control for secretion of oxytocin from the posterior pituitary?
Physical stimulation of the nipples or teats. The act of nursing or suckling is relayed within a few milliseconds to the brain via a spinal reflex arc. These signals stimulate oxytocin-secreting neurons, leading to release of oxytocin.
The burst of OTC released at birth is also triggered by abruptly declining concentrations of progesterone.
OTC neurons are repressed by catecholamines (eg, adrenalin), which are released from the adrenal gland in response to many types of stress, including fright.