Mammlian Physiology 2 Page 1 Summary: Endocrinology 4 January-12-11 21:06 Notes by Yingzhou Edward Pan Pathophysiology of the adrenal cortex Pancreas, Insulin and Diabetes Growth Hormones in males and females Gametogenesis Pathophysiology of the Adrenal Cortex Adrenal Hypofunction: Addison's Disease Failure of adrenal cortex to produce enough Adrenocortical Hormones (both Glucocorticoid & Mineralocorticoid) May be caused by destruction of the gland Or more commonly due to Atrophy of adrenal gland due to tuberculosis. Medulla atrophies too Glucocorticoid deficiency (responsible for upregulating metabolism and blood sugar levels) Decrease blood glucose levels, between meals particularly Decreased lipolysis and gluconeogenesis Lack of energy, muscular weakness and inability to take stress Mineralocorticoid deficiency (Responsible for controlling electrolyte levels, retaining sodium) Decreased retention of Na + (hyponatremia), Cl - and water in urine Decreased extracellular fluid, plasma volume and cardiac ouput Increased K + (Hyperkalemia) and H + (Acidosis) retention, since normally exchanged for Na + Patient die in shock 7 days after complete absence of mineralocorticoids Adrenal Hyperfunction: Cushing's Disease Surplus of ACTH leading to hyperplasia of Adrenal Cortex and excessive production of Glucocorticoids and Mineralocorticoids Glucocorticoid excess Increased blood glucose levels. Can lead to Adrenal diabetes Increased Insulin production. Can lead to burn out of β-cells in pancreas, leading to Diabetes Mellitus, permanent Decreased protein synthesis and Increased protein breakdown Osteoporosis from loss of protein matrix leading to eventual loss of calcium (not enough matrix) Mineralocorticoid excess Increased retention of Na + (Hypernatrimia), Cl - and water Decreased retention of K+ (hyperkalemia) and H+ (Alkalosis) Androgen & Sex hormone excess Masculinization of females Diagnosis Puffing up of face (water retention), Increased extracellular fluid and plasma volume High blood pressure due to Na+ Surgical partial removal of adrenal cortex Pancreas as an Endocrine Organ 99% Exocrine, secretion digestive juices Islet of Langerhans, compact group of cells responsible for endocrine function. Have good blood flow to them 60% β-cells: Insulin synthesis and secretion 25% α-cells: Glucagon synthesis and secretion Insulin and Glucagon are antagonist peptide hormones Insulin more important because only hormone to do its function. Glucagon's function is redundantly covered by other hormones Actions of Insulin Only hormone to decrease blood glucose levels by promoting cellular absorption of glucose Glucose is always present at 80mg/100ml, ~5mM Glucose doesn't enter cells very easily since so hydrophobic. In Liver and muscle, made into glycogen (poly-glucose) Adipose tissue, converted into fat for storage Most cells: oxidized as Energy Source Insulin Receptor on cell surface since peptide does not diffuse easily through plasma membrane Promotes usage of glucose transport proteins stored in the cytoplasm Diabetes mellitus Diabetes refers to excessive production of urine (polyurea) Diabetes Mellitus refers to polyurea caused by high blood glucose level, is the more familiar meaning of diabetes As distinct from Diabetes Insipidus, which is caused by deficiency in Antidiuretic Hormone When blood glucose levels are high (>180mg/100ml), glucose spills into urinal tract, and through osmosis, drags water with it Therefore, leads to "sweet" excessive urine Also causes thirst (Polydipsia) Increased Lypolysis, where fats are burned for fuel Body is inefficient at this process and leads to many short (4C long) fatty acids which increase blood acidity (acidosis) Fatty acids eventually burned to acetone, leading to ketosis (acetone smell in breath) Decrease in blood ph can eventually lead to coma
Mammlian Physiology 2 Page 2 Type 1 Diabetes mellitus: Insulin Dependent Diabetes Caused by deficiency in circulating Insulin, can be caused by Destruction of β-bell in pancreas, treated by Insulin injection Defective Insulin Release: treated by insulin release stimulating drug Careful administration of insulin doses Insulin overdose can result in hypoglycemia (aka Insulin Shock) where brain is starved of glucose (<20-30mg/100ml) Inject glucose immediately Juvenile Diabetes is usually type 1 and congenital, where insulin is not produced Type 2 Diabetes Mellitus: Insulin Independent Diabetes Caused by loss of sensitivity of target cells to insulin due to anterior overexposure Decrease in number of insulin receptors Associated with obesity Proper diet and exercise Decrease in caloric and glucose intake Insulin receptor count may increase as result of frequent endurance exercises Glucose Tolerance Classical test to monitor response to insulin Administration of 0.75 to 1.5g of glucose/kg body weight after 12 hour fasting period Blood glucose is measured every 30 minutes for 3-4 hours Normal: 80mg/100ml glucose level jump to 130mg/100ml and return to normal after 2-3 hours Diabetes: Higher initial level, higher increase and longer return period Control of Insulin Secretion Very finely control system to avoid hypoglycemia (low blood sugar) Negative feedback loop: β-cells very finely to glucose levels Response to hormonal and neural signals: Gastrin (hormone) and vagal impulse to β-cells cause insulin secretion in anticipation of food Glucagon Peptide hormone released by α-cell in pancrea Opposes insulin and increases blood glucose levels by increasing: Gluconeolysis: break down of glycogen into glucose Gluconeogenesis: production of glucose in liver Lypolysis in adipose tissue to increase fatty acids in circulation Interacts with membrane receptor and works by activating G-Protein, Adenynyl Cyclase, Cyclic AMP pathway Glucagon levels regulated by glucose levels. Secreted when glucose levels are low, not so when Glucose levels are high Not as important as insulin because glucocorticoids, epinephrine (adrenaline) and other hormones share same function Growth Hormone (GH) (Somatotropin) Single-chain Peptide hormone produced by Anterior Pituitary Gland Responsible for growth Increases protein synthesis in many tissues (liver, kidney), particularly structural ones (bone, muscle) Enhances Amino Acid uptake, increases transcription and translation of mrna Increases lypolysis rate and consumption of free fatty acids as energy source. A direct effect of Growth hormone Somatomedins Growth Hormone sometimes not immediate cause of tissue reacting Instead, cause liver to secrete other substances which then cause changes. Substances called Somatomedins Structurally similar to insulin, therefore are named Insulin-Like Hormone I and II Can bind to insulin receptor and insulin when at high concentration. Makes sense, since growth needs energy Control of Growth Hormone Release Release of GH controlled by 2 hypothalamic neurohormones: Growth Hormone Releasing Hormone (Somatoliberin) ("liberate" somato) Decreased secretion when Somatomedin levels in plasma are high Growth Hormone Inhibiting Hormone (Somatostatin) (stasis: stop, stop somato) Increased secretion during sleep and exercise Decreased secretion during stress and low blood sugar levels (hypoglycemia) Somatoliberin and Somatostatin secretion controlled by more complex system Integrated system of neural, metabolic and hormonal factors
Mammlian Physiology 2 Page 3 Pathophysiology of Growth Hormone Growth Hormone deficiency In young, lead to decreased physical growth Growth Hormone excess Often caused by adenoma of pituitary gland (benign tumour) In young: gigantism In adult: acromegaly: bones grow out of proportion, often longer and heavier - - Reproduction Primary reproductive organs: Gonads: Testes and Ovaries Accessory reproductive organ: Ducts and glands in path of sperm and eggs. Breasts are here too. Function of Gonads Gametogenesis: production of gametes: spermatozoa & ova Sex Hormone Secretion: Androgen (testosterone) in males, Estrogen & Progesterone in females All of which are steroids All sex hormones in both male and female. Difference is dosage Males: Testes produce mainly androgen and little bit of estrogen Main source of estrogen is local production by enzymatic activity Females: Ovaries produce mainly estrogen and progesterone and little androgens Main source of androgens is adrenal glands Function of Estrogen in males Stop height growth at certain age Case Study: Mutant Estrogen Receptor Recessive mutation caused formation of in-frame stop in Estrogen Receptor gene Boy's height did not plateau, instead kept growing linearly until much later Bones were very fragile and required surgery for reparations Severe osteoporosis Control of Reproductive Function Similar in both males and females Hypothalamus secretes Gonadotropin Releasing Hormone (GnRH) to Anterior Pituitary Gland Anterior Pituitary Gland secretes Follicle Stimulating Hormone (FSH) and Leutenizing Hormone (LH) Both are named for effects in female, but active in both sexes. Both are Gonadotropins FSH and LH stimulate development of spermatozoa & ova and secretion of sex steroids (androgen, estrogen, etc) Sex Steroids act on gonads (autocrine), secondary reproductive organs and rest of body (estrogen maintains bone density) Feedback mechanism through hormone called inhibin which feedbacks to anterior pituitary Male Reproductive System: Function of the testes Main functions Spermatogenesis: production of spermatozoa (natural germ cells) Steroidogenesis: production of steroid hormoness Spermatogenesis takes place in seminiferous tubues which are coiled in the testes Precursor germ cells (called spermatogonia) mature into spermatozoa takes 60 days Constant regeneration of spermatogonia through male life
Mammlian Physiology 2 Page 4 Critical cells for Spermatozoa Maturation Leydig cells Outside seminiferous tubules Produce androgens in reponse to Leutenizing Hormone Sertoli cells Located within seminiferous tubules Intimately inolved in sperm maturation: they envelop germ cells through their development Produce Androgen Binding Protein and Inhibin in response to Follicle Stimulating Hormone Spermatogenesis Requires very high concentration of androgens within seminiferous tubules Androgen Binding Protein help maintain concentration to levels 10 times higher than circulating levels Testicular Androgen synthesis regulation 2 negative feedback loops 1. Hypothalamic-Pituitary-Leydig cell axis, double-negative feedback Androgen secreted by Leydig cells negative feedbacks to Hypothalamus and Anterior pituitary, decreasing both Gonadotropin Releasing Hormone but also FSH and LH 2. Hypothalamic-pituitary -seminiferous-tubules axis Inhibin secreted by sertoli cells inhibit Follicle Stimulating Hormone secretion at Anterior Pituitary No positive feedback regulation in males Female Reproductive System: Function of the Ovaries Main Functions Production of mature eggs (ova) Production of sex steroid hormones At birth, single ovary contains 2 million oocytes (non-proliferating germ cells) which is life supply Number drops to 400 000 by puberty Primordial Follicles Fundamental reproductive structure of ovaries Small oocyte surrounded by Granulosa cells Primordial Follicle can begin to grow into Primary follicle as result of unknown initializing event As far as we know, it is independent of Anterior Pituitary, thus not caused by LH or FSH Growth leads to development of chambers in which the fully grown oocyte grows Several Follicles grow this way, but only one will release its oocyte (Ovulation) Others will degenerate (Atresia) Follicular Growth: Development of suitable oocytes and a new endocrine organ Several Primordial Follicles begin to develop, each forming a Zona Pellucida Zone Pellucida has no cells, but is rich in glycoproteins Primordial to Primal Follicle Influenced by Follicle Stimulating Hormone and Estrogen Estrogen causes formation of LH Receptors on Granulosa Cells Granulosa cells proliferate and begin to form 2+ distinct layers Primal to Secondary (aka Antral) Follicle Change is caused by FHS and LH Now has receptors for FSH, LH and Estrogen Formation of Antrum, chamber containing secretion of Granulosa cells Formation of Theca Interna cells from stroma (external supportive) cells Theca Interna cells cooperate with Granulosa cells to produce more estrogen Notice that it sets itself up to react what it produces. Boosting own activity Clearly not a down-regulating mechanism Secondary to Mature Follicle Also called Graafian Follicle or Late Secondary Follicle Change caused by FSH and LH Granulosa cells secrete more Follicular Fluid into Antrum Outcome of Follicular Development
Mammlian Physiology 2 Page 5 Outcome of Follicular Development Of all the follicles that develop, only 1 will eventually ovulate, giving rise to an egg Ovulation Is the release of the egg by one of the many follicles that develop It is not clear how the ovulation events take place Possible proteolysis of ovarian wall of Mature Graafian Folicle (aka Mature Follicle) And increased intrafollicular pressure Follicular Atresia Refers to the degeneration of all other follicles Lutenization and the Corpus Luteum "lutenization" refers to the formation of the Corpus Luteum After ovulation, the follicle becomes Corpus Luteum Main function is to secrete progesterone and estrogen Corpus Luteum is mainly what is left over of follicle, namely, theca cells and Granulosa Cells The point of the corpus luteum is to act as a timer It will continue to secrete progesterone and estrogen, which aids in maintaining appropriate environment to promote fertilization of the egg If no fertilization occurs, the Corpus Luteum will begin to degenrate through luteolysis This is because the corpus luteum is really constantly degenerating The decrease in progesterone and estrogen levels will onset the beginning of the next menstrual cycle Note that the degeneration of the corpus luteum is fairly sudden, taking place over just 3 days If fertilization occurs, then corpus leuteum will grow into corpus luteum of pregnancy This is detected by the presence of Human Chorionic Gonadotropin, which are secreted by the trophoblasts that are formed after fertilization In this situation, the function of the corpus luteum is to continue secreting high amounts of estrogen and progesterone until the placenta is formed and becomes ready to take over this function