sign in sign up
<<
Home , Endocrinology, Permissiveness (biology)

Endocrinology and

Elisabet Stener-Victorin, Professor, PhD Reproductive and (REM) group Department of and Pharmacology Karolinska Institutet, Stockholm, Sweden [email protected] General Consepts of Endocrine Control – Greek hormaein = ”excite”

. Autocrine signalling e.g. interleukin-1 in lymphocytes

. Paracrine signalling e.g. growth and clotting factors

. Endocrine signalling all circulating Classical Endocrine Organs

Other ”non-classical” hormone e.g. . CNS . . Stomach . Small intestine . Skin . . .

Katch et al Essentials of Exercise Physiol. Figure 12.1 Hormones Controls and Regulates

. Reproduction including gamete production, fertilization, nourishment of the embryo and fetus . Growth and development . Regulates ion and water balance . Regulates cellular metabolism and energy balance . Mobilize the immun system by responding to , trauma, and emotional

. Maintance of steady states by coordinated physiological mechanisms . Contributes to homeostasis by controlling availablity of substrates and metabolism . Regulating body fluid and ion balance

Homeostasis – like thermostat in the room Body temperature ~ 37ºC Blood 4.4 – 6.1 mM Ca2+ 4.1 – 5.2 mg/dL Phosphate 0.8 – 1.5 mM How is homestasis achived?

Endocrine system : 1. 2. Hormone - 3. Target organ - response

Katch et al Essentials of Exercise Physiol. Figure 12.2 Principles for Feed-back

Negative Positive (rare)

Endocrine Endocrine cell cell A A

Target Target Endocrine Endocrine cell cell

B B

Biological effect Biological effect Principles for Feed-back and Biorythm Complex multilevel . Long feedback loop Hypo- thalamus . Active hormone regulates the hypothalamus Releasing . Short feedback loop hormone . Active hormone regulates pituitary

Target hormone Target Biorytm - Pulsatile release Endocrine . Circadian rythm () cell Endocrine cell hormone . Monthly rythm (female sex hormones) . Life rythm () Biological effect Hypothalamus –”the boss” functional connections

Fysiologi, Lännergren, Westerblad, Ulfendahl, Lundeberg och Studentlitteratur 2012. Fig. 4.4 Hormone classes

. Three main types of hormones: . Amines - Tyrosine derivatives . . Steroids 1. Amine hormones

. Derives from one or two amino acids . Eg. , hormones . Water soluble → hydrophobic → receptor in the cell membrane . Bind to G-coupled membrane receptors → modulates second messengers 2. -derived hormones

. Peptides = Proteins . E.g. and glucagon → synthesized by ribosomes as pro-hormones . Water soluble → hydrophobic → receptor in the cell membrane . Bind to G-protein coupling receptors → modulates second messengers Amine and Peptide-derived hormone receptor location 3. Steroid hormones

. All derives from . Non-water soluble → Hydrophobic . Two main types of receptors: . Steroid receptors bind to receptor in cytosol and translocate to the nucleus . Thyroid receptors bind to the receptor directly in the nucleus

. Steroid hormones e.g. . Cortisol and aldosterone . progesterone and receptor location Steroid and thyroid hormone transport

. Approx 90% bound to plasma proteins . Only the free hormone that is biological active . Free hormone and carrier-bound hormone – dynamic equilibrium

Transport protein Principle hormone(s) transported Specific -binding protein (transcortin) Cortisol, aldosterone Thyroxid-binding globulin Thyroxin, Sex hormone-binding globulin Testosterone, estrogen Nonspecific Serum albumin Most steroids, thyroxin, triiodothyronine Transthyretin (prealbumin) Thyroxin, some steroids Mechanisms of hormonal transport and bioavailability

. Circulating hormone concentration → synthesis and secretion . Protein binding – free vs bound . Only free hormones has an effect, be eliminated, and exert feed back regulation . Local enzymes in the . Converts e.g. testosterone to the more potent form: DHT . Inactivates of e.g. cortisol in the kidney . Pulsatility . E.g. cortisol . Type of receptors Hypothalamus – “the boss”

. Part of the limbic system . Control hormonal release from pituitary . Neuroendocrine and endocrine control: . (neuro) . Anterior pituitary (adeno) Hypothalamus Regulates basal body functions: . Biorhythms (suprachiasmatic nucleus) . Body temperature . . Defense – alarm – fear – aggressively . Growth . Reproduction and behavior . Delivery . (osmoreceptors) . (osmoreceptors and antidiuretic hormone, ADH) . Appetite – target organ for . Basal metabolic activity (thyroid releasing hormone) Posterior Pituitary (neurohypophysis)

. Oxytocin → synthesized in paraventricular nucleus . Stimulates milk secretion . Stimulates uterine contractions during delivery

. Arginine vasopressin = antidiurethic hormone (ADH) → synthesized in supratoptic nucleus . Regulates blood volume . ADH secretion regulated by hypothalamic osmorecetors . Main effect of ADH – decrease water and increase water absorption in the kidney

Källa: Netter. Atlas of Human Anatomy. Ciba-Geigy 1989 Anterior pituitary - adenohypophysis

Hypothalamic neurons synthesize Hypothalamus GHRH, GHIH, TRH, CRH, GnRH, PIH. Anterior lobe Superior of pituitary hypophyseal artery

GH, TSH, ACTH, FSH, LH, PRL

Marieb E, N., Hoehn, K. Human anatomy and Physiology Figure 16.4c © 2013 Pearson , Inc. Anterior pituitary – Feed-back loops

Katch et al Essentials of Exercise Physiol. Figure 12.4 Quizz https://create.kahoot.it/details/endocrinology-introduction-eng/f143a0e5-7ebb- 470f-976a-43123eb83d56

Students: . Login to Kahoot.it . Write pin code

https://www.khanacademy.org/science/health-and-medicine/human-anatomy-and- physiology/reproductive-system-introduction/v/welcome-to-the-reproductive-system Hormone release and homeostasis

. Hypothalamus . Pituitary . Growth hormone . Thyroid . . . Gonades (/testis)

Marieb E, N., Hoehn, K. Human anatomy and Physiology Figure 16.1 Regulation of anterior pituitary hormones Growth Hormone (GH) → IGF-1

. GH stimulates body growth . Important for normal body development . Metabolic effects . Protein synthesis → increase transport into cells, enhance DNA and RNA transcription, RNA translation of protein and decrease protein and amino acid . Increase blood glucose → Glycogenolys (glucose production by breakdown of ), increased gluconeogenesis and insulin production (similar to type 2 ) . Decrease glucose uptake in muscle and adipose tissue . Lipolysis (break down of fat cells) → increase concentrations of fatty acids Growth Hormone axis

• GH has a pulsatile secretion pattern • Max secretion during the first h of sleep • GH peak late puberty • Adulthood - ↓ pulsatile burst, no change in number of pulses Growth Hormone Regulation

Hypothalamus secretes growth Feedback Inhibits GHRH release Stimulates GHIH hormone—releasing Anterior release hormone (GHRH), and pituitary Inhibits GH synthesis somatostatin (GHIH) and release Growth hormone

Indirect actions Direct actions (growth- (metabolic, promoting) anti-insulin)

Liver and other tissues Produce

Insulin-like growth factors (IGFs) Effects Effects

Carbohydrate Skeletal Extraskeletal Fat metabolism

Increases, stimulates Increased protein Reduces, inhibits Increased cartilage Increased Increased blood synthesis, and formation and fat breakdown glucose and other Initial stimulus cell growth and skeletal growth and release anti-insulin effects Physiological response proliferation Result Other Hormones Affecting Growth Hormone release and homeostasis

. Hypothalamus . Pituitary . Growth hormone . Thyroid . Adrenal gland . Pancreas . Gonades (ovary/testis)

Marieb E, N., Hoehn, K. Human anatomy and Physiology Figure 16.1 Regulation of anterior pituitary hormones Thyroid Hormone (TH)

. Two related compounds

. T4 (thyroxine); has 2 tyrosine molecules + 4 bound iodine atoms

. T3 (triiodothyronine); has 2 tyrosines + 3 bound iodine atoms . Plays a role in: . Maintenance of blood pressure . Regulation of tissue growth . Development of skeletal and nervous systems . Reproductive capabilities Action of . Metabolic Actions . Permissive Actions – on 's by increasing synthesis of β-adrenergic receptors . Growth and Development Low thyroid hormones High thyroid hormones Basal metabolism ⇓ ⇑ Carbohydrate metabolism ⇓ Gluconeogenesis ⇑ Gluconeogenesis ⇓ Glycogenolys ⇑ Glycogenolys Glycogenolys = breakdown of glycogen Protein metabolism ⇓ Synthesis ⇑ Synthesis ⇓ Proteolysis ⇑ Proteolysis Gluconeogenesis = generation of glucose from Lipid metabolism ⇓ Lipogenes ⇑ Lipogenes substrates like pyrovate, lactate, glycerol and ⇓ Lipolys ⇑ Lipolys glucogenic amino acids ⇑ Serum cholesterol ⇓ Serum cholesterol Thermogenes ⇓ ⇑ .Thyroid hormones increases metabolic rate and heat production .↑ Mitochondria .↑ blood flow, heart rate, and cardiac output .↑ .↑ Expression of NA+/K+ ATPase → ↑ neural signaling → muscle tremor ()

Parathyroid Glands and Parathyroid Hormone

. Embedded in the posterior aspect of the thyroid . Contain cells that secrete parathyroid hormone (PTH) . PTH—most important hormone in the calcium (Ca2+) homeostasis

. Calcium function – Necessary for:  Structural: Bone, teeth, connective tissue  Muscle contraction  Blood clotting  Nerve impulse transmission and stability of excitable membranes  Enzyme activity Calcium homeostasis (low blood Ca2+) stimulates parathyroid glands to release PTH.

Rising Ca2+ in blood inhibits PTH release. . PTH primary effect → ↓calcium Bone . It´s main is effect in the 1 PTH activates 2+ osteoclasts: Ca2+ . Bone: Stimulates net resorption →↑ Ca released into blood. . Kidney: ↑ Ca2+ reabsorption, inhibits 2 PTH increases Kidney Ca2+ reabsorption reabsorption of phosphate and promotes in kidney tubules. kidney activation of 3 PTH promotes kidney’s activation of vitamin D, which increases Ca2+ absorption from food.

Intestine

Ca2+ ions PTH Molecules Bloodstream Bone biggest calcium buffer

. Bone homeostasis – Dynamic process . Osteoblast . Osteocytes . Osteoclast

. Chondrocytes → synthesis of cartilage of the epiphyseal plate . IGF-1 → stimulate chondrocyte activity and bone growth Quizz https://create.kahoot.it/details/endocrinology-gh-thyroid-and-ca2/91790fee-8c0f- 4319-b8b0-eaa9fbc2e53a

Students: . Login to Kahoot.it . Write pin code

https://www.khanacademy.org/science/health-and-medicine/human-anatomy-and- physiology/reproductive-system-introduction/v/welcome-to-the-reproductive-system Hormone release and homeostasis

. Hypothalamus . Pituitary . Growth hormone . Thyroid . Adrenal gland . Pancreas . Gonades (ovary/testis)

Marieb E, N., Hoehn, K. Human anatomy and Physiology Figure 16.1 Regulation of anterior pituitary hormones Adrenal Gland Hormones – exposed to the highest concentrations of gluco- and mineralcorticoids

Hansen & Koeppen, ”Netter’s Atlas of Human Physiology, Icon Learning Systems, 2002 – cortisol –

. Metabolic effects . Proteolysis, lipolysis, gluconeogenesis—formation of glucose from fats and proteins, promotes rises in blood glucose, fatty acids, and amino acids (insulin antagonist), increased hunger . Cardiovascular effects (important for life) . Permissive effect on α1-receptors → can contract vessels . CNS . Memory, sensory integration, limbic system . Bone and Connective tissue . Stimulates bone resorption (decomposition), inhibits bone formation, inhibits K+ . uptake in the intestine, increase K+ from the kidney . Immune system . Stimulates bone resorption, inhibits bone formation, inhibits K+ . uptake in the intestine, increase K+ from the kidney

is a biochemical phenomenon in which the presence of one hormone is required in order for another hormone to exert its full effects on a target cell Cortisol – Diurnal Variation – Circadian Rhytm

• How to measure cortisol concentrations? • Saliva • 24 h urine – aldosterone –

. Change protein expression kidney, regulate long term osmotic pressure and blood volume . Cause increased absorption of sodium → increased secretion of potassium . Sodium retention → increased water absorption and thirst . Aldosterone . Most potent (90% of activity) . Corticosterone (only small response) . Loss of aldosterone leads to rapid death! Gonadocorticoids – -

. Most are androgens (male sex hormones) that are converted to testosterone in tissue cells or in females

. May contribute to . The onset of puberty . The appearance of secondary sex characteristics . Sex drive . In women – most important after menopause Regulation of glucocorticoids Hypothalamus-Pituitary-Adrenal (HPA) axis Regulation of aldosterone

Primary regulators Other factors

↓Blood volume ↑ K+ in blood Stress ↑ Blood pressure and/or blood and/or blood pressure volume

Hypo- Heart Kidney thalamus CRH Direct Anterior stimulating pituitary Renin effect Initiates cascade that produces Atrial natriuretic ACTH peptide (ANP) Angiotensin II

Inhibitory effect Zona glomerulosa of Enhanced secretion of aldosterone Targets kidney tubules

↑ Absorption of Na+ and water; increased K+ excretion

↑ Blood volume and/or blood pressure Despopoulos & Silbernagl, ”Color atlas of physiology”,ed 5, Thieme, 2003 Hormone release and homeostasis

. Hypothalamus . Pituitary . Growth hormone . Thyroid . Adrenal gland . Pancreas . Gonades (testis/ovary)

Marieb E, N., Hoehn, K. Human anatomy and Physiology Figure 16.1 Regulation of anterior pituitary hormones Circulating sex steroid hormone levels in men and women

Testosterone - male Estradiol - females

Estradiol - male Testosterone - females

Ober et al 2008 Nat Rev Genet Male hormonal (androgenic) effects 1. Development – male sexual differentiation 2. Puberty – secondary sexual changes and muscle/bone/voice/phallus(penis)/libido 3. Post-puberty – prostate growth, muscle mass sexual function

Leonidas Lundell 6 december 2014 91 Regulation of sex steroids in men

. Androgenic effects in the body: . Development of male genitalia . Male pattern hair growth . Growth of larynx and vocal cords Leyding celler → produce . Sperm production testosteron . Muscle growth . Visceral fat accumulation . Increased sexual drive and potens . Aggressive behavior

ABP = binding protein

Marieb E, N., Hoehn, K. Human anatomy and Physiology Fig 27.10 Tunica albuginea Oocyte Granulosa cells Late secondary follicle Degenerating corpus Cortex Mesovarium and luteum (corpus albicans) blood vessels

Germinal epithelium Vesicular (Graafian) Primary follicle follicles Antrum Oocyte

Ovarian Zona ligament pellucida Theca Medulla folliculi Ovulated oocyte Developing Corona corpus luteum radiata Hypothalamus-Pituitary-Ovary axis (HPO)

Källa: Human Anatomy & Physiology Av Elaine N. Marieb & Katja Hoehn Fig 27.21 Menstrual cycle

Pituitary hormones (blood)

”Ovary cycle” – follicle development

Ovary hormone (blood)

Endometrium Källa: Human Anatomy & Physiology Av Elaine N. Marieb & Katja Hoehn Fig 27.22 Quizz https://create.kahoot.it/details/hpa-axis-and-reproduction-eng/ae2c15dd-4b22- 4dd4-b89f-a6fec8404cd6

Students: . Login to Kahoot.it . Write pin code

https://www.khanacademy.org/science/health-and-medicine/human-anatomy-and- physiology/reproductive-system-introduction/v/welcome-to-the-reproductive-system Hormone release and homeostasis

. Hypothalamus . Pituitary . Growth hormone . Thyroid . Adrenal gland . Pancreas . Gonades (testis/ovary)

Marieb E, N., Hoehn, K. Human anatomy and Physiology Figure 16.1 Endocrine pancreas Exocrine Secretes bicarbonate ions and digestive enzymes

Endocrine 1. α-cells secrete glucagon and increase glucose release from the liver 2. β-cells secrete insulin, pro-insulin, C-peptide and amylin – decrease blood glucose 3. δ-cells secrete somatostatin – inhibits secretion of insulin and glucagon and inhibit GI-tract 4. F-cells secrete pancreatic poly peptide (PP) – inhibits gastric acid secretion Glucose homeostasis

. Glucose the most important energy source . Tight regulation under several hormones: . GH . Cortisol . . Insulin . Glucagon

Katch et al Essentials of Exercise Physiol. Figure 12.9 Main function of insulin

Katch VL, Mc Ardle WD and Katch FI., Essentials of Exercise Physiology 4th Edition Fig. 12.10 Main function of glucagon and somatostatin

. Glucagon: Increase blood glucose . Somatostatin: Inhibit glucagon and insulin and GI-tract

Katch VL, Mc Ardle WD and Katch FI., Essentials of Exercise Physiology. 4th Edition Fig. 12.10 Insulin dependent and insulin independent glucose uptake

IR

Glukos p -Tyr IRS-1

PI3-K Muskel AS160 . Mitochondrial biogenesis Contraction – insulin GLUT-4 Akt . Oxidative stress independent

Insulin Resistance

Normal β-cell Abnormal β-cell function function

Compensatory Relative insulin deficiency Normoglycemia Insulin resistance in peripheral target tissues

.Muscle .Liver . ↓GLUT4 transloc. . ↓Glycogen synthesis . ↓Glucose uptake . ↓Glycogen synthesis . ↓Glucose oxidation

.Liver .Adipose tissue . ↑Gluconogenesis . ↑Lipogenesis . ↑Lipolysis . ↑TG . ↑FFA

International Diabetes Federation (IDF) 2005

1. Visceral : Waist ≥ 94 cm (men) and waist ≥ 80 cm (women)

and at least 2 of the following: 1. High triglycerides: >1,7 mmol/L 2. Low HDL-cholesterol: < 1,03 mmol/L (men) <1,29 mmol/L (women) 3. Blood pressure ≥130/85 or medication 4. Fasting plasma glucose ≥5,6 mmol/L or diagnosed type 2 diabetes Classification of diabetes mellitus according to WHO, 1999

. Type I diabetes (insulin-dependent diabetes mellitus (IDDM) . Insulin deficiency → caused by destruction of the B cells in . autoimmune (autoimmune positive) . idiopathic (autoimmune negative) . Type 2 diabetes (non insulin-dependent diabetes mellitus (NIDDM) . Insulin resistance and impaired insulin secretion . Genetic component stronger for type 2 diabetes compared with type 1 . Other specific types of diabetes (e.g.) . Genetics disruption of B cell function . Genetic dysfunction of insulin effects . (PCOS, , Cushing) . Disease in exocrine pancreas . Infection diseases . Pharmacological induced diabetes . Quizz https://create.kahoot.it/details/pancreas-ir-and-diabetes-eng/6c909d3a-a1cc- 4452-8bcd-076483d60eb3

Students: . Login to Kahoot.it . Write pin code

https://www.khanacademy.org/science/health-and-medicine/human-anatomy-and- physiology/reproductive-system-introduction/v/welcome-to-the-reproductive-system

Questions? [email protected] Questions?

[email protected] Endocrinology and Reproduction Part 2

Elisabet Stener-Victorin Professor Department of Physiology and Pharmacology Group: Reproductive Endocrinology and Metabolism Understand function in the different hormonal systems by dysfunction i.e. endocrine disorders:

• , , acromegaly • Cretinism • Goiter • Hyperthyroidism • • • Cushings syndrome and Cushings disorder • and Type 2 diabetes • Polycystic Ovary Syndrome • Hypothalamic insufficiency