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Endocrinology 2

Endocrinology 2. Hypoadrenal Disorders, Hyperadrenal Disorders, Therapeutic use of adrenal steroids and Endocrine Infertility By Keerthanaa Jayaraajan. Hyperadrenal disorders.

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Endocrinology 2

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  1. Endocrinology 2 Hypoadrenal Disorders, Hyperadrenal Disorders, Therapeutic use of adrenal steroids and Endocrine Infertility By Keerthanaa Jayaraajan

  2. Hyperadrenal disorders • Cushing's syndrome: list the clinical features, recall the causes, explain principles of diagnosis, recall investigations, and explain treatment options. • Conn's syndrome: list the clinical features, recall the causes, explain principles of diagnosis and recall treatment options. • Phaeochromocytoma: list the clinical features and explain the management of a patient with a phaeochromocytoma

  3. Cushing's syndrome: list the clinical features, recall the causes, explain principles of diagnosis, recall investigations, and explain treatment options. • Too much cortisol • Centripetal obesity • Red striae, thin skin and easy bruising • Stretch marks • Proximal myopathy • Hypertension and Hypokalaemia • Osteoporosis • Diabetes Clinical Features of Cushing’s Syndrome

  4. Cushing's syndrome: list the clinical features, recall the causes, explain principles of diagnosis, recall investigations, and explain treatment options. • Taking too many oral steroids NOTE: Determine whether they are on a cortisol type steroid/ testosterone • Ectopic ACTH from lung cancer • Adrenal adenoma • Cushing’s DISEASE caused by a PITUITARY gland tumour Causes of Cushing’s Syndrome

  5. Cushing's syndrome: list the clinical features, recall the causes, explain principles of diagnosis, recall investigations, and explain treatment options. • 24 hour urine collection for urinary free cortisol • Blood diurnal cortisol levels • Low dose dexamethasone suppression test (0.5mg 6 hourly for 48h) Investigations for Cushing’s Syndrome

  6. Cushing's syndrome: list the clinical features, recall the causes, explain principles of diagnosis, recall investigations, and explain treatment options. • Cushing’s disease – transphenoidal hypophyectomy • Bilateral/ Unilateral Adrenalectomy • Drug treatments- Metyrapone and Ketaconazole Treatments for Cushing’s Syndrome

  7. Cushing's syndrome: list the clinical features, recall the causes, explain principles of diagnosis, recall investigations, and explain treatment options. Treatments for Cushing’s Syndrome

  8. Cushing's syndrome: list the clinical features, recall the causes, explain principles of diagnosis, recall investigations, and explain treatment options. • Uses: • Control Cushing’s symptoms before surgery • Control Cushing’s symptoms after radiotherapy • Side effects: • 11-deoxycorticosterone has mineralocorticoid properties. Acts like aldosterone – causing hypokalaemic hypertension • Block 2 pathways- precursors funnelled into the production of adrenal androgens- causing hirsutism in women • Nausea, vomiting, dizziness • Sedation, hypoadrenalism Treatments for Cushing’s Syndrome

  9. Cushing's syndrome: list the clinical features, recall the causes, explain principles of diagnosis, recall investigations, and explain treatment options. Treatments for Cushing’s Syndrome

  10. Cushing's syndrome: list the clinical features, recall the causes, explain principles of diagnosis, recall investigations, and explain treatment options. • Uses: • Control Cushing’s symptoms before surgery • Used to be an anti-fungal but withdrawn in 2013 • Side effects: • Nausea, vomiting, abdominal pain • Alopecia • Reduced androgen production – gynaecomastia, oligospermia, impotence, decreased libido • Ventricular tachycardias • HEPATOTOXICITY – COULD LEAD TO DEATH (Monitor with regular LFTs) Treatments for Cushing’s Syndrome

  11. Conn's syndrome: list the clinical features, recall the causes, explain principles of diagnosis and recall treatment options. • Benign tumour of the zona glomerulosa • Excess aldosterone • Increased retention of sodium and excretion of potassium • Hypertension and Hypokalaemia Cause and Clinical Features of Conn’s Syndrome

  12. Conn's syndrome: list the clinical features, recall the causes, explain principles of diagnosis and recall treatment options. • Primary Hyperaldosteronism – high blood pressure and low potassium. • Exclude secondary hyperaldosteronism – RAAS should be suppressed. • Measure aldosterone. If high, measure renin and it should be suppressed by high blood pressure. • In secondary hyperaldosteronism (caused by reduced renal blood flow), renin will be increased. Diagnosis of Conn’s Syndrome

  13. Conn's syndrome: list the clinical features, recall the causes, explain principles of diagnosis and recall treatment options. • Mineralocorticoid receptor antagonist – spironolactone (Potassium sparing diuretic) – blocks sodium reabsorption and potassium excretion • Spironolactone orally active, highly protein bound and metabolised in the liver • Contraindicated in renal and hepatic disease • Side effects: • Progesterone receptor agonist – menstrual irregularities • Androgen receptor antagonist – gynaecomastia • GI irritation • Eplerenone- fewer side effects, more favourable in long-term • Then remove tumour via surgery • But if BILATERAL ADRENAL HYPERPLASIA – then stay on spironolactone/ eplerenone Treatment of Conn’s Syndrome

  14. Phaeochromocytoma: list the clinical features and explain the management of a patient with a phaeochromocytoma • Tumours of adrenal medulla- secretes catecholamines • Sudden release of lots of adrenaline : • Sudden onset of panic • Anxiety • Tachycardia • Episodic severe hypertension (usually in the young) can cause: • MI • Stroke • Ventricular Fibrillation- sudden cardiac death Clinical Features of Phaeochromocytoma

  15. Phaeochromocytoma: list the clinical features and explain the management of a patient with a phaeochromocytoma • Anaesthetic can precipitate a hypertensive crisis • To prevent unopposed alpha-mediated vasoconstriction, give alpha blocker first (phenoxybenzamine). • After giving alpha blocker, for a brief period there is unopposed vasodilatation leading to a sudden drop in blood pressure – give IV fluids • Give beta-blocker (atenolol) to prevent tachycardia Management of Phaeochromocytoma

  16. QUESTION TIME- PAST PAPER qs • What is Cushing’s Disease as opposed to Cushing’s Syndrome? • Give the clinical features of Cushing’s Disease. • List 3 non-iatrogenic causes of Cushing’s syndrome.

  17. HyPOadrenal disorders • Addison's disease: recall the synthesis of adrenocortical steroids, list the clinical features of Addison's disease, define the term Addisonian crisis and list specific features of this condition. • Congenital adrenal hyperplasia: explain the hormonal consequences of specific adrenal enzyme deficiencies, explain the clinical features and investigation of congenital adrenal hyperplasia with reference to specific enzyme deficiencies.

  18. Addison's disease: recall the synthesis of adrenocortical steroids, list the clinical features of Addison's disease, define the term Addisonian crisis and list specific features of this condition. Cholestrol 17 alpha-hydroxylase P450 SCC 17 alpha-hydroxylase 17 alpha- hydroxypregnenolone Pregnenolone Dehydroepiandrosterone 3 beta-HSD 3 beta-HSD 17 alpha-hydroxylase 17 alpha-hydroxylase 17 alpha- hydroxyprogesterone Progesterone Androstenedione 21-hydroxylase 21-hydroxylase 11-deoxycorticosterone Testosterone 11-deoxycortisol DHT 5 alpha-reductase 11 beta- hydroxylase 11 beta- hydroxylase Aromatase Corticosterone Cortisol Oestrone 17-beta oestradiol 18-hydroxylase Aldosterone Synthesis of Adrenocortical Steroids

  19. Addison's disease: recall the synthesis of adrenocortical steroids, list the clinical features of Addison's disease, define the term Addisonian crisis and list specific features of this condition. Synthesis of Adrenocortical Steroids

  20. Addison's disease: recall the synthesis of adrenocortical steroids, list the clinical features of Addison's disease, define the term Addisonian crisis and list specific features of this condition. • MOST COMMON CAUSE OF ADRENOCORTICAL FAILURE WORLDWIDE: Tuberculous Addison’s Disease • MOST COMMON CAUSE OF ADRENOCORTICAL FAILURE IN THE UK: Autoimmune Addison’s Disease • Congenital Adrenal Hyperplasia – enzyme deficiency means that adrenals cannot make hormones properly. Adrenals are stimulated and the adrenal glands become very big. Causes of Adrenocortical Failure

  21. Addison's disease: recall the synthesis of adrenocortical steroids, list the clinical features of Addison's disease, define the term Addisonian crisis and list specific features of this condition. • Darker skin and hair (ACTH is made from POMC. POMC broken down into MSH, ACTH and endorphins and enkephalins. Increased MSH (melanin-stimulating hormones) causes the increased pigmentation • Vitiligo – antibodies against melanin- suggests autoimmunity • Blood pressure falls- no aldosterone • Loss of salt in urine • Increased plasma potassium • Can cause eventual death due to severe hypotension • Sudden death due to severe hypotension- Addisonian Crisis Features of Addison’s Disease

  22. Addison's disease: recall the synthesis of adrenocortical steroids, list the clinical features of Addison's disease, define the term Addisonian crisis and list specific features of this condition. • Measure hormones at 9am. – usually high in the morning. If low, it increases suspicion of Addison’s Disease • Measure ACTH- should be really high • SynACTHen test – if they have functioning adrenals then with a 250 mg of synacthen IM, they should produce lots of cortisol. If not, suggestive of Addison’s Disease Tests for Addison’s Disease

  23. Congenital adrenal hyperplasia: explain the hormonal consequences of specific adrenal enzyme deficiencies, explain the clinical features and investigation of congenital adrenal hyperplasia with reference to specific enzyme deficiencies. 21-beta hydroxylase deficiency

  24. Congenital adrenal hyperplasia: explain the hormonal consequences of specific adrenal enzyme deficiencies, explain the clinical features and investigation of congenital adrenal hyperplasia with reference to specific enzyme deficiencies. 11-beta hydroxylase deficiency

  25. Congenital adrenal hyperplasia: explain the hormonal consequences of specific adrenal enzyme deficiencies, explain the clinical features and investigation of congenital adrenal hyperplasia with reference to specific enzyme deficiencies. 17-alpha hydroxylase deficiency

  26. QUESTION TIME • Clinical features of Addison’s Disease

  27. THERAPEUTIC USE OF ADRENAL STEROIDS • Hypoadrenalism: explain the basis of the management of syndromes of adrenal insufficiency (including Addisons disease, pituitary-dependent (secondary) adrenal insufficiency, acute adrenal insufficiency and congenital adrenal hyperplasia); explain what protective measures should be undertaken for patients with adrenocortical insufficiency. • Corticosteroids: explain the main clinical uses of exogenous corticosteroids including mode of action; recall how exogenous corticosteroids differ.

  28. Corticosteroids: explain the main clinical uses of exogenous corticosteroids including mode of action; recall how exogenous corticosteroids differ. Receptors for Corticosteroids

  29. Corticosteroids: explain the main clinical uses of exogenous corticosteroids including mode of action; recall how exogenous corticosteroids differ. Receptors for Corticosteroids

  30. Corticosteroids: explain the main clinical uses of exogenous corticosteroids including mode of action; recall how exogenous corticosteroids differ. *All drugs given ORALLY but sometimes IV/IM may be indicated. Hepatic breakdown – excreted via bile and urine Exogenous Corticosteroids

  31. Hypoadrenalism: explain the basis of the management of syndromes of adrenal insufficiency (including Addisons disease, pituitary-dependent (secondary) adrenal insufficiency, acute adrenal insufficiency and congenital adrenal hyperplasia); explain what protective measures should be undertaken for patients with adrenocortical insufficiency. Corticosteroid Replacement therapy is indicated in: • Primary adrenocortical failure • Secondary adrenocortical failure • Acute adrenocortical failure • Congenital adrenal hyperplasia • Iatrogenic adrenocortical failure Corticosteroid Replacement Therapy

  32. Corticosteroid Replacement Therapy

  33. Hypoadrenalism: explain the basis of the management of syndromes of adrenal insufficiency (including Addisons disease, pituitary-dependent (secondary) adrenal insufficiency, acute adrenal insufficiency and congenital adrenal hyperplasia); explain what protective measures should be undertaken for patients with adrenocortical insufficiency. • Additional measures in cortisol replacement: • Increase in stress • Minor illness = 2x dose • Surgery- HYDROCORTISONE IM with pre-med at 6-8h intervals. Once back to normal give ORAL HYDROCORTISONE. Corticosteroid Replacement Therapy Cautions

  34. QUESTION TIME • How would you treat an Addisonian Crisis? • What would you need to be aware about when administering high-dose hydrocortisone?

  35. Endocrine infertility • Hypothalamo-pituitary gonadal axis: Explain the abnormalities in the hypothalamo-pituitary gonadal axis (males and females) that cause primary and secondary hypogonadism. • Male hypogonadism: Explain the clinical features, causes, investigations and treatment of male hypogonadism; explain the clinical uses of testosterone including side effects. • Amenorrhoea: Define amenorrhoea, list the causes, investigations and management. • Polycystic ovary syndrome: List the diagnostic criteria, recall the clinical features, investigations and treatment of polycystic ovary syndrome (PCOS). • Prolactin: Recall the regulation of prolactin secretion; list the causes, clinical features, investigation and treatment of hyperprolactinaemia.

  36. Hypothalamo-pituitary gonadal axis: Explain the abnormalities in the hypothalamo-pituitary gonadal axis (males and females) that cause primary and secondary hypogonadism. Normal Male HPG Axis

  37. Hypothalamo-pituitary gonadal axis: Explain the abnormalities in the hypothalamo-pituitary gonadal axis (males and females) that cause primary and secondary hypogonadism. Hypothalamus GnRH - Pituitary Gland FSH LH - TESTIS - Leydig Cells Sertoli Cells • ALSO: • Development of male genital tract • Maintains fertility in adulthood • Anabolic effects in muscles and bones Production of ABP Inhibin A and B Testosterone Aids spermatogenesis Secondary Sexual Characteristics Normal Male HPG Axis

  38. Hypothalamo-pituitary gonadal axis: Explain the abnormalities in the hypothalamo-pituitary gonadal axis (males and females) that cause primary and secondary hypogonadism. Normal Female HPG Axis 1. Follicular Phase

  39. Hypothalamo-pituitary gonadal axis: Explain the abnormalities in the hypothalamo-pituitary gonadal axis (males and females) that cause primary and secondary hypogonadism. Hypothalamus GnRH - Pituitary Gland LH FSH - OVARIES - Oestradiol Progesterone Follicular Development Inhibin Normal Female HPG Axis 1. Follicular Phase Day 10- leading follicle develops into a Graffian Follicle

  40. Hypothalamo-pituitary gonadal axis: Explain the abnormalities in the hypothalamo-pituitary gonadal axis (males and females) that cause primary and secondary hypogonadism. Normal Female HPG Axis 2. Ovulation

  41. Hypothalamo-pituitary gonadal axis: Explain the abnormalities in the hypothalamo-pituitary gonadal axis (males and females) that cause primary and secondary hypogonadism. Hypothalamus GnRH + Pituitary Gland LH FSH OVARIES + OVULATION Oestradiol Normal Female HPG Axis 2. Ovulation

  42. Hypothalamo-pituitary gonadal axis: Explain the abnormalities in the hypothalamo-pituitary gonadal axis (males and females) that cause primary and secondary hypogonadism. Implantation? NO YES Pregnancy Endometrium shed- Menstruation Normal Female HPG Axis 3. Luteal Phase

  43. Hypothalamo-pituitary gonadal axis: Explain the abnormalities in the hypothalamo-pituitary gonadal axis (males and females) that cause primary and secondary hypogonadism. • Infertility – Inability to conceive after 1 year of regular unprotected sex (1/6 couples) • 2 major generic causes of infertility: • PRIMARY GONADAL FAILURE • HYPOTHALAMIC/ PITUITARY DISEASE Now let’s move on to pathology…

  44. Hypothalamo-pituitary gonadal axis: Explain the abnormalities in the hypothalamo-pituitary gonadal axis (males and females) that cause primary and secondary hypogonadism. • Klinefelters Syndrome • Testicular Torsion • Chemotherapy Primary Gonadal Failure

  45. Hypothalamo-pituitary gonadal axis: Explain the abnormalities in the hypothalamo-pituitary gonadal axis (males and females) that cause primary and secondary hypogonadism. • Kallmann Syndrome • Hypopituitarism • Illness/ Underweight Pituitary is unable to produce FSH and LH Hypothalamic/ Pituitary Disease

  46. Male hypogonadism: Explain the clinical features, causes, investigations and treatment of male hypogonadism; explain the clinical uses of testosterone including side effects. • Hypothalamic- Pituitary Disease (Hypopituitarism, Kallmann Syndrome, Illness/ Underweight) • Primary Gonadal Disease (Klinefelters Syndrome, Testicular Torsion, Chemotherapy) • Hyperprolactinaemia • Androgen receptor deficiency (RARE) Male Hypogonadism Causes

  47. Male hypogonadism: Explain the clinical features, causes, investigations and treatment of male hypogonadism; explain the clinical uses of testosterone including side effects. • Loss of Libido • Impotence • Small Testes • Decreased muscle bulk • Osteoporosis (REMEMBER that testosterone has anabolic actions on the bone) Male Hypogonadism Clinical Features

  48. Male hypogonadism: Explain the clinical features, causes, investigations and treatment of male hypogonadism; explain the clinical uses of testosterone including side effects. • LH, FSH and Testosterone • Prolactin • Sperm Count – Azoospermia and Oligospermia • Chromosomal Analysis • Microscopy to look at numbers and motility of sperm Male Hypogonadism Investigations

  49. Male hypogonadism: Explain the clinical features, causes, investigations and treatment of male hypogonadism; explain the clinical uses of testosterone including side effects. • Loss of Libido • Impotence • Small Testes • Decreased muscle bulk • Osteoporosis Subcutaneous gonadotrophin injections for fertility in hypothalamic/ pituitary disease Replacement Testosterone Hyperprolactinaemia – Dopamine agonist Male Hypogonadism Treatments

  50. QUESTION TIME- PAST PAPER q 2007 • Draw a diagram to show the function of male testes and how they influence the hypothalamus • Give 3 Functions of androgens in males.

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