Introduction to Hypothalamic Pituitary Axis PDF

Intro to the Hypothalamic- Pituitary Axis Growth Hormone Physiology BMS 200 Sept. 2023 General Outcomes Describe the functional anatomy of the vascular and non-vascular elements of the endocrine hypothalamus and the pituitary gland Explain the regulation of th...

Intro to the Hypothalamic- Pituitary Axis Growth Hormone Physiology BMS 200 Sept. 2023 General Outcomes Describe the functional anatomy of the vascular and non-vascular elements of the endocrine hypothalamus and the pituitary gland Explain the regulation of the hypothalamic-pituitary-target gland axis, considering short and long feedback loops. Describe growth hormone synthesis, transport, function and regulation, including diurnal rhythms of secretion Analyze the regulation and biological actions of somatomedins in relation to growth hormone secretion. Predict complications associated with abnormal growth hormone production and function, such as acromegaly and gigantism. Describe the synthesis, regulation of secretion, and function of prolactin, including its role in cross-talk with other hypothalamic hormones. Review: hypothalamic- pituitary system – anterior pituitary The hypothalamus secretes releasing or inhibiting hormones into 1st set of capillaries These travel down to the anterior pituitary and modulate hormone secretion from those cells Anterior pituitary hormones control a number of other endocrine glands  Thyroid, adrenal gland, gonads, liver  HPA – basic anatomy & embryology The pituitary forms when two embryological regions grow towards each other and “meet”  Rathke pouch – outgrowth from the stomodeum that grows upwards towards the developing hypothalamus (part of diencephalon) Forms the anterior pituitary  Infundibular process – inferior outgrowth from the developing hypothalamus Forms rest of the pituitary and infundibular stalk Rarely, a cyst (Rathke cleft cyst) or a tumour (craniopharyngioma) can develop from remnants of the Rathke pouch Cranial anatomy – the hypophyseal fossa Note how the pituitary is almost completely surrounded by bone (sella turcica), and how close it is to the optic chiasm  HPA – basic functional divisions: Magnocellular neurons transport peptide hormones from the cell body (fast axonal transport) to their axon terminals in the posterior pituitary  Released into the capillary plexus formed by the inferior hypophyseal artery  Hormones from magnocellular neurons need to be released in adequate concentrations to impact tissues throughout the body  Major hypothalamic nuclei – PVN, SON  HPA – basic functional divisions: Parvocellular neurons in the hypothalamus secrete small amounts of releasing hormones into the primary plexus formed by the superior hypophyseal artery  Hormones travel down the pituitary portal vein, and then are detected by adenohypophyseal cells when they reach the secondary capillary plexus  Pituicytes in the adenohypophysis then release tropic (sometimes called trophic) hormones that regulate peripheral target glands  HPA – basic functional divisions: Although the magnocellular neurons reside in (fairly) clearly- defined hypothalamic nuclei, the parvicellular neurons that release a particular “releasing hormone” are less well- defined  Magnocellular cell bodies reside in the PVN and SON (more later)  Parvicellular neurons reside in the nuclei in the table next slide… but there is significant cross- over Functional aspects of the anterior HPA axis Releasing or “Main” Anterior pituitary Pituicyte target cell inhibiting hormone hypothalamic hormone from hypothalamus nucleus (FYI) (stimulate/inhibit) Thyrotropin-releasing Paraventricular nuclei TSH (stimulate) Thyrotroph hormone (TRH) (PVN) PRL (stimulate) Luteinizing hormone- Multiple areas LH and FSH (both Gonadotroph releasing hormone stimulate) (LHRH) Corticotropin-releasing Parvicellular portion of ACTH (stimulate) Corticotroph hormone (CRH) PVN Growth hormone- Arcuate nucleus, near the GH (stimulate) Somatotroph releasing hormone median eminence (GHRH) Somatostatin (GHIH) Anterior paraventricular GH (inhibit) Somatotroph area Dopamine Arcuate nucleus PRL (inhibit) Lactotroph Hypothalamic regulation The hypothalamus receives signals from the central nervous system and messengers that travel through the bloodstream:  Situated in very close to the 3rd ventricle there are regions within the 3rd ventricular that allow somewhat selective passage of signals from blood  ventricular fluid (known as circumventricular organs) Signals can be detected by neurons in the hypothalamic nuclei Can sense osmolarity, glucose, signal peptides (short loop feedback, appetite mediators)… many  Extensive communication between the brainstem, limbic areas, and cortex (as already seen during our discussion of homeostatic pathways of appetite regulation) Hypothalamic & pituitary regulation Most feedback is via negative feedback  May be homeostatic or non-homeostatic mechanisms  Oxytocin release during childbirth main example of positive feedback (more in BMS 250) – cervical thinning  oxytocin release  increased uterine contractions  increased cervical thinning Definitions: Long loop: target endocrine gland  hypothalamus or pituitary Short loop: pituitary  hypothalamus We won’t discuss ultra- short Growth hormone physiology Secreted by somatotrophs in the anterior pituitary Regulated by hypothalamic secretion of somatostatin (inhibits GH release) and GHRH (stimulates GH release) Regulated by:  sleep-wake cycles Most secreted in pulses during slow wave sleep  blood sugar & arginine Secreted during hypoglycemia, can be directly detected or can be stimulated by SNS (which increases during hypoglycemia)  SNS will stimulate GHRH release and inhibit GHIH release  Also modulated by a wide range of other hormones: Dopamine, ghrelin Cortisol, thyroid hormone, androgens Growth hormone physiology Growth hormone can affect tissues via:  Direct effects on peripheral tissues Binds to a cytokine-like receptor  JAK/STAT dimerization  cellular effects  Stimulating release of IGF-1 (a somatomedin) IGFs (insulin-like growth factors) bind to receptors that function very similarly to the insulin receptor (receptor tyrosine kinases  IRS activation  PI3K activation, Ras  Raf, MAP-kinases… many) GH has a short half-life (6 – 20 minutes), but can elicit longer-lasting effects by stimulating IGF-1 release  GH stimulates IGF-1 release from the liver (and less from other sites like muscle and bone)  IGF-1 has a set of binding proteins that extend its half-life  Growth hormone secretion patterns Fig. 31-8 In the adult, GH levels are reduced as a result of smaller pulse width and amplitude rather than a decrease in the number of pulses. Rhoades’ Medical Physiology, Chapter 31, Fig 31-8 Basic feedback loops and function – GH overview GH release causes short-loop negative feedback IGF-1 feeds back on the anterior pituitary and hypothalamus (long-loop) GH effects Bone: increased bone lengthening (children, teens) and increased bone turnover and deposition  “cooperates” with IGF-1 for bone growth Adipose tissue: increased lipolysis  activation of hormone-sensitive lipase and inhibition of lipoprotein lipase (catabolic)  increased FFA availability Liver: “anti-insulin” plus anabolic through somatomedin production  IGF-1 production and release  gluconeogenesis, reduced glucose uptake  promotes hepatic glucose output Skeletal muscle: anabolic  Increased a.a. uptake, increased protein synthesis  Decreased glucose uptake (“anti-insulin”) One could accurately generalize by saying GH effects are acute and increase nutrient/energy availability  IGF seems to be more responsible for long-lasting growth effects, though GH does aid these growth effects as well IGF-1 physiology IGF-1 varies less than GH (longer half-life, fewer pulses) and seems to mediate most of the growth- promoting effects of GH  Growth rate parallels IGF-1 levels for most stages of life, and it “lasts” considerably longer than GH The IGF-1 receptor is very similar to the insulin receptor  Insulin can bind to the IGF-1 receptor with low affinity, and IGF-1 can bind to the insulin receptor with low affinity  “Cross-over” in effects is very limited except in pathological situations, though  IGF-1 IGF-1 (somatomedin) Regulated mainly by GH  Receptors are found in a wide range of tissues including muscle, cartilage, skin, kidney, brain The metabolic effects of IGF-1 are opposite to those of GH in the liver and adipose tissue  IGF-1 increases insulin sensitivity and glucose uptake in most tissues In skeletal muscle and bone, both are anabolic and increase protein synthesis and amino acid uptake Functions:  stimulates bone formation, bone turn over, collagen synthesis, linear growth  protein synthesis, glucose uptake into muscles,  neuronal survival, myelin synthesis  General mitogen (DNA, RNA and protein synthesis) Acromegaly Vast majority of cases due to a pituitary adenoma formed from somatotropes (anterior pituitary cells that secrete GH)  Rarely caused by adenomas that secrete both PRL and GH, a functional hypothalamic growth  Rarely paraneoplastic syndrome Lung cancer, adrenal adenomas, medullary thyroid cancer, pheochromocytoma (all rarely secrete GH) Clinical features are typical of what would be expected from:  Impact of GH itself – how does it impact growth? Are the impacts different at different ages? How does it impact overall energy metabolism?  Impact of the tumour on nearby anatomy – what neuroanatomical structures are nearby? What are the findings of increased intracranial pressure? Acromegaly Vast majority of cases due to a pituitary adenoma formed from somatotropes (anterior pituitary cells that secrete GH)  Rarely caused by adenomas that secrete both PRL and GH, a functional hypothalamic growth  Rarely paraneoplastic syndrome Lung cancer, adrenal adenomas, medullary thyroid cancer, pheochromocytoma (all rarely secrete GH) Uncommon disorder (3-4/1,000,000/year) Clinical features are typical of what would be expected from:  Impact of GH itself – how does it impact growth? Are the impacts different at different ages? How does it impact overall energy metabolism?  Impact of the tumour on nearby anatomy – what neuroanatomical structures are nearby? What are the findings of increased intracranial pressure? Acromegaly – Clinical Features Skeletal findings: If GH oversecretion begins after closure of epiphyseal plates (bone lengthening no longer possible) then the following is observed:  Increased hand and foot size, frontal bossing, mandibular enlargement  overall thickness and size of bones increases, but not height Soft tissue findings – increased growth of a wide variety of connective tissues   Larger nose, coarse facial features, deeper voice, macroglossia (obstructive sleep apnea), acanthosis nigricans, skin tags, and overall increased soft tissue thickness  Larger visceral organs – including heart, thyroid Cardiovascular complications – major source of morbidity and mortality  Cardiomyopathy: the heart increases in size Relaxation is less efficient; wall tension increases with increases in size Hypertension also increases workload Dysrhythmias are more common with cardiomegaly  Increased blood pressure (due to sodium-retaining effects of GH) Acromegaly – Clinical Features Metabolic complications:  GH is “anti-insulin”, even though IGF-1 tends to aid insulin action Results in hyperglycemia and insulin resistance due to inappropriate gluconeogenesis, downregulation of insulin signaling pathways Neurologic complications:  If the tumour grows large enough, can: Impinge on the optic nerve (at the optic chiasm  bitemporal hemianopsia) Increase intracranial pressure (headaches, eventually impacting cortical function, selected cranial nerves) Somewhat increased risk of malignancy – research not conclusive here but…  Colon polyps are more likely ( CRC), breast cancer more common, and perhaps thyroid cancer has the highest risk increase  Likely overactivation of JAK/STAT pathways or IGF-1 signaling pathways In general, mortality is increased by 3X and survival is reduced by an average of 10 years if GH secretion is not controlled  Gigantism vs. Acromegaly Gigantism has the same etiology and almost all the same clinical features/complications as acromegaly  However, GH secretion is elevated prior to closure of the epiphyseal plate  greatly increased height Prolactin Physiology Will be discussed in greater detail in 250 (as we discuss breast physiology). For now: Synthesized by the lactotrophs (15-20% of anterior pituitary); number of lactotrophs increases in response to large elevations in estrogen (most notable during pregnancy) Secretion increased during sleep and reduced during wakefulness Under tonic inhibition from dopamine released from the hypothalamus  binds to D2 receptors on the lactotrophs (also called PIH)  Somatostatin and GABA also exert inhibitory impact Stimulated by suckling and increased estrogen  Suckling  reduction of dopamine release from hypothalamus  GnRH, serotoninergic and opioidergic pathways promote release  Prolactin Releasing Factors (PRH) can also stimulate release (TRH, oxytocin, vasoactive intestinal peptide) Prolactin Function PRL receptor and PRL function: Receptor location: mammary gland, ovary, brain Function: Develop mammary glands Initiation of milk synthesis Maintenance of milk synthesis Milk synthesis is prevented during pregnancy by high progesterone levels Inhibits GnRH If PRL secretion was pathologically increased, how would that likely impact menstrual cycles?