1. MBBS- ENDOCRINES Lec:5 & 6 PITUITARY GLAND

2. Learning objectives Describe the Hypothalamo-pituitary axis List the Hormones produced by the anterior,intermediate and posterior pituitary. Functions and regulation pituitary hormones Disorders of pituitary hormones

3. Learning outcomes List the cells and state the hormones secreted by anterior and posterior pituitary Explain the role of hypothalamus in controlling anterior & posterior pituitary Explain the hypothalamic releasing & inhibitory hormones that control the anterior pituitary secretion Describe the physiology of growth Describe the actions & regulation of growth hormone Describe the regulation of secretion & actions of antidiuretic hormone & oxytocin Describe the gigantism and acromegaly.

5. Differences between exocrine and endocrine glands Exocrine glands With ducts Secretions are poured directly into cavity through duct Produce juice containing enzymes biological catalysts Secretions are in large quantity, small changes no problem Eg. Salivary glands Gastric glands Pancreatic acini Endocrine glands Without ducts Secretions are poured directly into the blood Secrete hormones Secretions are in minute quantity/ small change in secretion leads to disorders Eg.Hypothalamus Pituitary Thyroid & parathyroid Suprarenal Islets of Langerhans Ovary, Testes

6. Lobes of pituitary 1.Anterior lobe/Adenohypophysis: synthesize and secretes ACTH,LH,FSH, GH,TSH, Prolactin 2.Posterior lobe/Neurohypophysis ADH & Oxytocin 3.Intermediate lobe secretes MSH.

7. Pituitary gland has two distinctive tissues called the adenohypophysis (AP) and neurohypophysis (PP). Adenohypophysis reveals three distinctive cell types called acidophils, basophils and chromophobes. The neurohypophysis is an extension of the hypothalamus. It composed of bundles of axons from hypothalamic neurosecretory neurons intermixed with glial cells.

8. Role of hypothalamus as an endocrine gland Hypothalamus controls the activity of all the endocrine organs through its connections (vascular & neural) with pituitary gland Hypothalamo-hypophyseal portal system carries trophic hormones to the anterior pituitary Hypothalamo-hypophyseal tract ends in posterior pituitary to releases ADH & oxytocin

9. Hypothalamo-Hypophyseal System 1. Hypothalamo-hypophyseal portal system1. Hypothalamo-hypophyseal portal system – From hypothalamus to anterior pituitary – Vascular link – Route for transport of hypothalamic releasing/release inhibiting hormones from hypothalamus to anterior pituitary 2.Hypothalamo-hypophyseal Tract2. Hypothalamo-hypophyseal Tract – From hypothalamus to posterior pituitary – Neural link – Route for transport of vasopressin (ADH) and oxytocin from hypothalamus to posterior pituitary

10. Hypothalamo- Hypophyseal Portal System

11. Hypothalamus Releasing & inhibiting hormones Blood vessels (Median eminence) Hypothalamo- hypophyseal portal vessels Anterior pituitary

12. Releasing hormones Thyrotropin-releasing hormone (TRH) Corticotropin-releasing hormone (CRH) Growth hormone-releasing hormone (GHRH) Gonadotropin-releasing hormone (GnRH) Prolactin inhibitory hormone (PIH) Prolactin releasing hormone ?

13. Primary & secondary endocrine diseases Based on site of hormone defect (either increase or decreased secretion), Endocrine disorders are classified as: A) Primary Disease: If defect is in the target gland from which hormone has originated B) Secondary Disease: If defect is in the Anterior Pituitary or Hypothalamus E.g., Primary hypothyroidism means decreased secretion of thyroid hormone from the Thyroid gland Secondary hypothyroidism means deficiency of Anterior pituitary/ Hypothalamic hormone which stimulates production of thyroid hormone from the thyroid gland (defect not in the thyroid gland)

14. Releasing Hormones of Hypothalamus CRH ACTH Adrenal Cortex TRH TSH Thyroid Gland GnRH FSH,LH Gonads GHRH GH Generalized Summary Stimulating H- AP

15. Hypothalamic neurons - SON, PVN ADH & Oxytocin Stored in Posterior Pituitary Summary

16. Cell types of adenohypophysis 1. Acidophils 1. Acidophils (stain with acidic dyes) 2. Basophils 2. Basophils (stain with basic dyes) 3. Chromophobes 3. Chromophobes (do not stain with either stain)Acidophils: Somatrophs – secrete Growth Hormone (GH) Mammotrophs – secrete prolactin (PRL) Basophils : Thyrotrophs – secrete Thyroid Stimulating Hormone (TSH) Gonadotrophs – secrete Luteinizing (LH) hormone and Follicle Stimulating Hormone (FSH). Chromophobes Chromophobes – secrete adenocorticotrophic hormone (ACTH)

17. Growth hormone (GH or somatotropin) - stimulates cell growth, replication & metabolism Prolactin (PRL)-stimulates the development of mammary glands and causes milk secretion Thyroid stimulating hormone (TSH; thyrotropin) has a trophic influence on thyroid gland & triggers the release of thyroid hormones Adrenocorticotropic hormone (ACTH; corticotropin) stimulates the release of glucocorticoids & sex steroids by the adrenal gland Hormones of the Adenohypophysis

18. Follicle stimulating hormone (FSH) - stimulates follicle development and estrogen secretion in females and sperm production in males Leutinizing hormone (LH) causes ovulation and progestin production in females and androgen production in males Hormones of the Adenohypophysis

19. ACTIONS OF GROWTH HORMONE: Actions of GH are of 2 types. –DIRECT CATABOLIC actions –INDIRECT ANABOLIC actions What are Somatomedins: Are polypeptides synthesized mainly in liver Also synthesized in kidneys,cartilage & skeletal muscles. In humans, most important is Somatomedin C, also called as Insulin-like growth factor (IGF-I), secreted due to the action of GH mainly on liver & to a small extent in other organs. The Indirect actions are via the somatomedins.

20. Actions of Growth Hormone 1)Stimulation of growth of bones, cartilage & connective tissue; mediated mainly via Somatomedin C (IGF-1) a)On Bones & cartilage (Before epiphyseal closure): GH causes liver to secrete IGF-1, which in turn causes Proliferation of chondrocytes (Chondrogenesis) Appearance of osteoblasts Stimulation of DNA & RNA synthesis Collagen formation in cartilage Result- Increase in thickness of epiphyseal cartilagenous end plates. Resulting in linear skeletal growth; seen maximally during puberty & causes pubertal growth spurt.

21. GH action on bones b) After Epiphyseal closure: No increase in bone length Increase in bone thickness or widening through periosteal growth. Increased protein synthesis in most organs causing hyperplasia, hypertrophy; increased tissue mass and increased organ size

22. Site of action of IGF-1

23. Actions of GH on Metabolism 2) Actions of GH on Metabolism a)Effect of GH on Carbohydrate Metabolism: This is a direct action of GH. Does not need IGF GH is a Diabetogenic hormone ie; increases plasma glucose GH causes Hyperglycemia by increasing Hepatic glucose output Decreases peripheral utilization of glucose (Anti-Insulin Effect)

24. Metabolic actions of GH b) Effect of GH on Protein metabolism: Indirect action which requires IGF GH is a Protein Anabolic Hormone It increases protein synthesis in muscle & increases lean body mass Also increases protein synthesis in organs & increases organ size

25. Metabolic actions of GH C) On Fat metabolism: GH has a direct catabolic effect - mobilizes fat from adipose tissues by increasing lipolysis. (Does not require IGF for this action) Increases plasma free fatty acids (FFA), which are further used for Gluconeogenesis Ketogenic- Produces FFA which undergo hepatic oxidation and form ketone bodies

26. Other actions of GH Stimulates mammary growth & milk production (as it has structural similarity to PRL) Stimulates erythropoiesis Stimulates calcium absorption from GIT

27. PHYSIOLOGY OF GROWTH

28. Increase in length & size & Orderly maturational changes Factors affecting or influencing growth 1.Hormones: Growth hormone and Somatomedins, Thyroid hormones, Androgens, Estrogens, Glucocorticoids, and Insulin 2.Genetic Factors 3.Nutrition 4.Exercise 5.Communicable diseases or infections interrupt growth. 6.Stress and emotional disturbances can also interfere with growth. 7. Cultural, Socioeconomic, Environmental

29. Growth curve for a normal boy who had an illness beginning at age 5 and ending at age 7. Catch-up growth eventually returned his height to his previous normal growth curve

30. Relative importance of hormones in human growth at various ages Hormonal Effects

31. Growth of different tissues at various ages as a percentage of size at age 20

32. Regulation of GH secretion A) Role of Hypothalamus: Hypothalamus regulates GH secretion via Growth hormone releasing hormone (GHRH) and GH inhibiting hormone (GHIH / Somatostatins)

33. - Regulation of GH secretion

34. Clinical correlates of Anterior Pituitary DWARFISM: Occurs due to GH deficiency Results in Short stature/Stunted growth Causes: Panhypopituitarism (lack of all anterior pituitary hormones) Decreased GHRH Decreased IGF-1 secretion (GH receptor defect) Hypophysectomy (Removal of pituitary gland )

35. Pituitary Dwarfism GH deficiency results in proportionate short stature due to growth retardation. Individuals are referred to as Dwarfs Other associated features seen in GH deficiency are- Decreased hair growth due to decreased protein synthesis, fasting hypoglycemia, Immature genital organs leading to sexual immaturity

36. A 9- year old pituitary dwarf compared with age and sex matched control

37. Differences between : PITUITARY DWARF: HYPOTHYROID DWARF (CRETIN): Caused due to :↓ GH,↓GHRH ↓Thyroid hormone Clinical features: Plumpness, Immature face, Small genitalia Proportionate short stature Delayed skeletal & dental development ↓circulating levels of GH Gross retardation of mental & physical development Infantile body proportion, potbelly, protruded tongue Other features of hypothyroidism

38. Growth Hormone excess – Before Puberty GIGANTISM : Is seen due to overproduction of GH during adolescence, before puberty (before epiphyseal closure) – Results in excessive growth of long bones- ↑↑Height (8 ft) Clinical features: Tall stature (up to 8 ft / 2.5 mts) Large hands & feet Other associated features – Bilateral Gynaecomastia (enlargement of breasts due to structural similarity of GH to Prolactin) Coarse facial features due to increased tissue proliferation

39. 12 year old boy with Pituitary Gigantism measuring 6’5” with his mother.

40. GH excess after Puberty ACROMEGALY: Occurs due to excessive secretion of GH during adulthood (after epiphyseal closure) Causes of Acromegaly are: -Acidophilic tumor of anterior pituitary -Hypothalamic GHRH secreting tumors (Acral) Clinical features are mainly seen due to excess growth of cartilaginous & peripheral (Acral) parts & other features due to increased metabolic actions

41. Clinical features of Acromegaly Prognathism - elongation & widening of mandible Prominent eyebrow Bulbous nose Facial changes seen are described as ACROMEGALIC FACIES – thickening of skin & coarse facial features - proliferation of connective tissue resulting in facial edema Kyphosis - periosteal growth of vertebrae Enlarged hands & feet (Acral parts) - periosteal growth of metatarsals & metacarpals Increased plasma glucose levels- due to metabolic actions

42. Other features of Acromegaly Hypertrophy of soft tissues - Heart (Cardiomegaly) - Liver (Hepatomegaly) - Kidney (Renomegaly) - Spleen (Splenomegaly) - Tongue & muscles In 4% cases- Gynaecomastia (breast enlargement in males) with/without lactation- because of structural similarity of GH to PRL Visual field defects if pituitary tumor compresses Optic Chiasm

43. Sheehan’s Syndrome (Panhypopituitarism) Anterior Pituitary insufficiency commonly occurs in females with post-partum hemorrhage resulting in a clinical condition known as Sheehan’s Syndrome. Anterior Pituitary which is highly vascular, gets enlarged during pregnancy. After childbirth, pituitary undergoes infarction & necrosis due to post partum hemorrhage – giving rise to decreased levels of all the anterior pituitary hormones resulting in Panhypopituitarism Posterior Pituitary hormones are not affected as ADH & Oxytocin are synthesized by Hypothalamic neurons

44. OTHER PITUITARY HORMONES: FSH, LH – Reproductive functions in male & female TSH - Regulation of thyroxine secretion & trophic to thyroid gland ACTH- Stimulates release of Cortisol & sex steroids from adrenal cortex

45. Prolactin Prolactin (PRL) is a single chain polypeptide Receptors resemble GH receptors Structurally similar to GH Increases during pregnancy & lactation Predominant action on mammary gland Also inhibits gonadotrophic hormone secretion

46. Physiological actions of PRL PRL is responsible for Lactogenesis (initiation of lactation) & galactopoiesis (continuation of lactation) Stimulates milk production in the breasts by formation of Casein & Lactalbumin Stimulates breast development along with Estrogen during pregnancy Inhibits Ovulation by decreasing secretion of LH & FSH

47. Factors affecting PRL secretion Factors increasing PRL secretion Estrogen (during pregnancy stimulates lactotropes to secrete PRL) Breast feeding (reflex increase) TRH Dopamine antagonists Factors inhibiting PRL secretion Dopamine Bromocryptine (Dopamine agonist) Somatostatin PRL (by negative feedback)

49. Clinical aspects Hyperprolactinemia: PRL excess results from: Hypothalamic lesions – due to loss of inhibitory control of PIF (Dopamine) on PRL secretion Prolactinomas – PRL secreting tumors of Anterior Pituitary Clinical Features: Galactorrhea Amenorrhea (Lack of Menstrual cycles) because PRL inhibits release of FSH & LH In males – Gynaecomastia & Impotence Treatment: Dopamine agonists like Bromocryptine which decreases PRL secretion

50. POSTERIOR PITUITARY (NEUROHYPOPHYSIS)

52. Hormones of posterior pituitary OXYTOCIN VASOPRESSIN (Anti Diuretic hormone; ADH) SITE OF SYNTHESIS – Cell bodies of magnocellular neurons in Supraoptic nucleus (SON) & Paraventricular nucleus( PVN) of hypothalamus PVN – Predominantly Oxytocin SON- Predominantly Vasopressin

53. SECRETION Termed as – NEUROSECRETION Hormones as – NEUROHORMONES Hormones are released into the blood vessels due to - –Electrical activity in the nerve terminals –Calcium dependent exocytosis of the hormones from the nerve terminals

54. OXYTOCIN Site of synthesis Mainly PVN of Hypothalamus 1/6 th SON of Hypothalamus Actions Milk Ejection Contraction of Uterus Mechanism of action Via G proteins

55. Factors affecting oxytocin secretion Factors stimulating release: Suckling Emotions – Sight / sound of baby’s cry Dilatation of cervix (Parturition) Factors inhibiting release: Emotions- stress, fright Drugs-Alcohol, etc.

56. MILK EJECTION REFLEX Stimulus: Baby suckling the nipple (skin touch receptors around nipple) Afferent: nerves from mammary glands- via spinal cord - End on PVN (& SON) Center: PVN in hypothalamus Efferent: Action potentials travel down the nerve terminal to posterior Pituitary - Release of oxytocin into blood Oxytocin stimulates myoepithelial cells of breast to contract Effect: Ejection of milk Increased suckling - Increased stimulation Eg; for POSITIVE FEED BACK Terminated when baby stops suckling Eg; for Neuro-endocrine reflex (aff Neural, efferent endocrine)

57. Milk ejection reflex

58. EFFECT ON UTERUS Causes contraction of uterine muscle (Myometrium) that is primed by estrogen Myometrial sensitivity to oxytocin increased by estrogen, concentration of which is high in pregnancy at the end of pregnancy

59. Parturition Reflex Descent of fetus Dilatation of cervix Stimulation of stretch receptors Increased activity of afferent nerve Stimulation of PVN Release of oxytocin into blood Contraction of uterus Expulsion of fetus Positivefeedback

61. VASOPRESSIN Also called ANTIDIURETIC HORMONE Prevents diuresis Predominantly secreted by SON Nonapeptide

62. VASOPRESSIN - ACTIONS Maintenance of Osmolarity & ECF volume Acts on DCT and CD of kidney Inserts ‘aquaporins’ (water channels) & increases permeability of the tubular cells to water Increases water reabsorption

63. VASOPRESSIN Potent vasopressor But not in physiological concentrations However during hemorrhage vasopressin levels can increase – causes VASOCONSTRICTION

64. Factors affecting ADH release Factors stimulating release: Increased plasma osmolarity Hypovolemia (↓ECF volume) Pain, emotion, stress, exercise Standing Angiotensin II Factors inhibiting release : Decreased plasma osmolarity ↑ ECF volume Alcohol

65. DIABETES INSIPIDUS Decreased ADH secretion Characterized by polyuria (large volume of dilute urine) & polydipsia Central DI (Neurogenic)Central DI (Neurogenic) –↓ synthesis/ secretion of ADH –Inherited or Acquired NephrogenicDINephrogenic DI- –failure of receptors to respond to ADH –Inherited or Acquired

66. SIADH (Syndrome of inappropriate ADH secretion) Excessive secretion of ADH, despite continued renal excretion of Na + (serum Na + <110meq/L- Hyponatraemia) Increased blood volume & Hypoosmolality Increased urine osmolarity Accompanied by neurological signs-Irritability, confusion, muscular weakness, seizures