Leo Renaud, MD PhD Professor, Medicine & Neurology, University of Ottawa

1. NSC 5404 : Session 1Hypothalamus and its regulation of anterior and posterior pituitary secretions Leo Renaud, MD PhD Professor, Medicine & Neurology, University of Ottawa Associate Director & Senior Scientist, OHRI

2. Pituitary and Hypothalamus

3. Where & what is the hypothalamus?

4. Some developmental notes: Anterior pituitary (adenohypophysis) forms from the roof of the pharynx in the embryo. Posterior pituitary develops from the floor of the third ventricle forming the stalk (infundibulum) and the posterior pituitary (neurohypophysis). Anterior pituitary has no neurons or synapses, just cells producing hormones such as growth hormone, leuteinizing hormone, follicle stimulating hormone, thyroid stimulating hormone, adrenocorticotropic hormone. Infundibulum contains axons from hypothalamic neurons that project into the posterior pituitary where they terminate near capillaries. These terminals contain hormones oxytocin and vasopressin.

5. Introduction to the Pituitary and Hypothalamus Pituitary and hypothalamus utilize synaptic communication as well as hormonal communication to regulate target cells. Pituitary and hypothalamus are the link between the nervous system and the endocrine system. Hypothalamus is also major regulator of body homeostasis 1. Homeostatic control includes regulating hunger, thirst, sex drive, sleep-wake cycles, body temperature, blood glucose. 2. Endocrine control via regulating the release of pituitary hormones. 3. Autonomic control via descending pathways to sympathetic and parasympathetic preganglionic neurons. 4. Limbic function via connections to limbic system regulating emotional behavior.

7. Functions of Selected Regions of Hypothalamus Suprachiasmatic nucleus: THE biological clock, regulates circadian rhythms. Lateral hypothalamus: feeding and arousal (orexinergic cells). Ventromedial nucleus: a “satiety center”, inhibits hunger. Anterior hypothalamus: contains osmoreceptors, triggers thirst Thermoregulation involves several systems including sweat glands, vasodilation/vasoconstriction, skeletal muscles involved in shivering and panting, and endocrine systems that control metabolic rate. Preoptic area (POA) detects increased body temp and activates systems that dissipate heat; lesions here cause hyperthermia. Posterior HT functions to conserve heat; lesions here cause poikilothermia, where body temp matches environment temp. More recent studies suggest HT functions in sexual desire/sex preference.

8. A ‘global’ view of hypothalamic pituitary functions

9. Hypothalamus: regulator of the endocrine system Figure 18.1

10. Three Methods of Hypothalamic Control over the Endocrine System Figure 18.5

11. Anatomy of the pituitary gland

12. Anatomy and Orientation of the Pituitary Gland

13. The Hypophyseal Portal System

15. Hypothalamic Control of the Anterior Pituitary • Hormonal control mechanism • Hypothalamic neurons synthesize releasing and inhibiting peptide hormones. • These are transported to axon endings in the median eminence where they are secreted into the hypothalamo-hypophyseal portal system to reach receptors that regulate the secretions of anterior pituitary hormones

16. How does the neuroendocrine axis work? • Hypothalamic parvicellular neurons synthesize release- or release-inhibiting “factors” or “hormones” (peptides) • Packaged in secretory granules, transported in axons to nerve terminal storage sites • On demand, neurons depolarize, prompting frequency-dependent exocytosis into the median eminence capillaries of the pituitary portal vessels • Transported as “hormones” to the anterior pituitary where they exit to the extracellular space • Attach to specific G-protein coupled receptors on target cells, triggering exocytosis of appropriate “hormones” that seek their peripheral glandular targets

17. Anterior Pituitary

19. Thyroid-Releasing Hormone

20. The anterior pituitary is actually a glandular structure, composed of diverse cell types that synthesize specific hormones to control specific peripheral glands or tissues:►luteinizing hormone (LH) and follicle stimulating hormone (FSH) that regulate ovarian function; ►thyroid stimulating hormone (TSH) to regulate thyroid function; ►adrenocorticotrophic hormone (ACTH) to regulate adrenal cortex function; ►growth hormone (GH) for bone and muscle; ►prolactin to stimulate milk production in the breast. :

21. Adenohypophysis: LM histology

22. Adenohypophysis: EM histology

23. GnRH  CAM CAM- dependent kinase Ca2+ Storage vesicle  LH FSH GONADOTROPIC CELL B Gq GnRH receptor q PLC q DAG Ca2+ Protein kinase C PIP2 IP3 Y Ca2+ SER Protein phosphorylation Ca2+ Figure 6. In the gonadotropes GnRH causes release of LH and FSH (B)

24. Feedback control of Endocrine Secretion

25. Feedback control of Endocrine Secretion

26. Some clinical conditions that may arise due to altered feedback or lack of hormone regulation • Too much / too little thyroxine (T4) and tri-iodothyronine (T3) results in hyper / hypothyroidism respectively • To much growth hormone secretion causes a condition called acromegaly • Excessive adrenal glucocorticoid secretion can produce Cushing’s syndrome

27. Symptoms of excess circulating thyroid hormones [thyroxine (T4) and triiodothyronine (T3)]fine tremor, heat intolerance, sweaty skin, exophthalmos, possible thyroid enlargement (goitre).

28. Excess Growth Hormone secretion → Acromegaly

29. Clinical features of excessive secretion of cortisol • Truncal obesity • Moon facies • Abdominal striae • Osteoporosis • Acne • Easy bruising • Hirsutism • Hypertension • Hyperglycemia