By Keerthanaa Jayaraajan

Slides:



Advertisements
Similar presentations
Addison’s, Cushing’s & Acromegaly
Advertisements

Chapter 32 Disorders of Endocrine Control of Growth and Metabolism
What is Endocrinology? The study of how the body is regulated by chemicals synthesized in one region of the body which then travel elsewhere in the body.
Adrenocortical Functions - 2. Adrenocortical hypofunction Adrenocortical insufficiency may be: A.Primary B.Secondary.
Congenital Adrenal Hyperplasia (CAH) By: Anna Heideman & Angela Mullins.
Secretion: Adrenal cortex of the adrenal gland. Regulation:
Adrenal Gland.
Reproductive System. Disorders Infertility ► Infertility in males : - pretesticular or secondary hypogonadism due to hypothalamic or pituitary lesions.
The Gynaecology Clinic Michaelmas term year 2. This session will: Cover definitions of amenorrhoea and oligomenorrhoea Explain the genetic, anatomical.
Pituitary Gland: Anterior Lobe By: Galindo, Fesas, Crandall, Aquiles, Houston 7A.
Adrenal gland. ? What is the adrenal gland The adrenal glands (also known as suprarenal glands) are the triangle-shaped and orange- colored endocrine.
Congenital Adrenal Hyperplasia and Testicular Feminization Syndromes
Congenital Adrenal Hyperplasia and Testicular Feminization Syndromes
Pituitary and hypothalamic diseases Dr.Malith Kumarasinghe MBBS( Colombo)
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Chapter 60 Drugs for Disorders of the Adrenal Cortex.
HIRSUTISM. Definition  Hirsutism Excessive growth of hair in abnormal position on the body  Virilism Masculinization of female i.e. deepening of voice,
OST 529 Systems Biology: Endocrinology
The Adrenal Cortex. Basic principles of steroid endocrinology Steroid effects fall into 3 categories: –Mineralocorticoid –Glucocorticoid –Androgen/Estrogen.
Adrenal gland. ? What is the adrenal gland The adrenal glands (also known as suprarenal glands) are the triangle-shaped and orange- colored endocrine.
Top 5 Most Valuable Glands Diane Banderas and Shelby Knorr.
Adult Medical-Surgical Nursing Endocrine Module: Disorders of the Adrenal Cortex: Cushing’s Syndrome.
Biochemistry of Addison’s Disease. ANATOMICALLY: The adrenal gland is situated on the anteriosuperior aspect of the kidney and receives its blood supply.
Investigation of Infertility
Chapter 32 Disorders of Endocrine Function
Biochemistry of Addison’s Disease By Rana Hasanato, MD, KSFCC Clinical Chemistry Unit, Pathology Dept. College of Medicine, King Saud University.
1 ADRENOCORTICOSTEROIDS Major categories of action: Glucocorticoids: affecting intermediary metabolism & resistance to stress Mineralocorticoids: regulation.
MLAB 2401: Clinical Chemistry Keri Brophy-Martinez
Steroid Hormones.
Investigating infertile couple
DISORDERS OF THE ADRENOCORTICAL HORMONES Dr. Ayisha Qureshi MBBS, Mphil.
Steroid Hormones.
Male sex hormones Androgens Types: 1.Natural androgens: – Androsterone and testosterone 2.Synthetic androgens: – Testosterone propionate. – Anabolic.
Adrenal Glucocorticoids 7 أ. م. د. وحدة بشير اليوزبكي Head of Department of Pharmacology- College of Medicine- University of Mosul-2014.
By Dr. Zahoor 1. Objectives We will study 1. Pituitary gland and Hypothalamus 2. Increased Secretion of Pituitary Hormone causing disorders 3. Hyposecretion.
Investigations of infertility
THE REPRODUCTIV E SYSTEM. Functional anatomy, physiology and investigations In the male, the testis subserves two principal functions: 1.synthesis of.
Gonads:- According to both sexes, the gonads are two: Ovaries (female) secrete: –P–Progesterone –O–Oestrogen: It is the end product that can control secretion.
Zona Glomerulosa Zona Fasiculata Zona Reticularis.
Male and female sex hormones
The cortex consists of 3 layers 1 st is zona granulosa - mineralocorticoids, for example aldosterone. The inner 2 layers are zona fasiculata and zona reticularis.
Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Chapter 60 Drugs for Disorders of the Adrenal Cortex.
Hyperprolactinaemia. Introduction.  Prolactine (PRL) is secreted from the Anterior Hypophisis.  Normal blood level of PRL: IU/L or 12.5 – 25.
Addison’s Disease MS II. Endocrine2 Adrenal Glands Adrenal Medulla – Responds to SNS stimulation – Secretes catecholamines – epinephrine is the main player.
Adrenal cortex hormones Adrenal cortex Glucocorticoid secretion Aldosterone secretion Androgen secretion Adrenocortical hyperfunction Adrenocortical hypofunction.
According sex, the gonads are : Ovaries (female) secrete:
Hormones of Testes - Testosterone Lecture NO: 2nd MBBS
Congenital Adrenal Hyperplasia and Testicular Feminization Syndromes
Adrenal Androgens from Greek andro meaning male human being
King Khalid University Hospital Department of Obstetrics & Gynecology
Reproduction-Related Disorders
Disorders of the Endocrine Glands
Puberty.
Hormones of the Adrenal Cortex
Reproduction-Related Disorders
Hyperprolactinemia Is the elevation of prolactine hormone which is secreted from anterior pituitary gland.
Male hypogonadism.
DISEASES OF THE ENDOCRINE SYSTEM SUPRARENAL GLAND
Text Only in Females’ slide Only in Males’ slides Important Numbers
Human Endocrine System
Adrenal Disorders (PED474)
Parathyroid Hormone and Vitamin D: Control of Blood Calcium
PUBERTY IT IS THE TIME IN LIFE WHEN A BOY OR GIRL
CEM FICICIOGLU, M.D, Ph.D.,AA.,MBA
Alex Edwards Adrenal Disease Alex Edwards
6.6 Hormones, homeostasis and reproduction
Anjanette Acosta Physiology 3
Adrenocorticosteroids
The human nervous system Part 1 - AnswerIT
Major Hormone Secreting Glands of the Endocrine System
The Reproductive system
Presentation transcript:

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

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

Clinical Features of Cushing’s Syndrome 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 Cortisol starts to bind to receptors in the kidney to retain sodium and excrete potassium so you become hypertensive and hypokalaemic Clinical Features of Cushing’s Syndrome

Causes of Cushing’s Syndrome 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

Investigations for Cushing’s Syndrome 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) With 24 hour urine collection – patients may forget to sample urine Blood diurnal cortisol level- cortisol normally high in morning and low when asleep. So take midnight blood sample from patient- if cortisol level high, then increased suspicion for Cushing’s Syndrome Low Dose Dexamethasone Suppression Test: Steroid should suppress the HPA Axis. ACTH should stop being released leading to zero cortisol. However, in people with Cushing’s syndrome cortisol level would be abnormally high/ Further investigations would be needed to identify the cause. Investigations for Cushing’s Syndrome

Treatments for Cushing’s Syndrome 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

Treatments for Cushing’s Syndrome Cushing's syndrome: list the clinical features, recall the causes, explain principles of diagnosis, recall investigations, and explain treatment options. Metyrapone inhibits 11-beta hydroxylase. Reduces production of cortisol and aldosterone. Reduced negative feedback on pituitary gland leads to a rise in ACTH. 11-deoxycorticosterone accumulates. Treatments for Cushing’s Syndrome

Treatments for Cushing’s Syndrome 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 Control Cushing’s symptoms before surgery: Cushing’s patients have thin skin and easy bruising making them more prone to complications from surgery. So metyrapone is used to improve symptoms and promote better recovery post-op. Aim for mean serum cholesterol of 150-300nmol/L Control Cushing’s symptoms after radiotherapy as radiotherapy takes a long time to show clinical effects. Treatments for Cushing’s Syndrome

Treatments for Cushing’s Syndrome Cushing's syndrome: list the clinical features, recall the causes, explain principles of diagnosis, recall investigations, and explain treatment options. Ketoconazole inhibits Cytochrome P450 SCC. Blocks production of glucocorticoids, mineralocorticoids and sex steroids. Treatments for Cushing’s Syndrome

Treatments for Cushing’s Syndrome 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) Control Cushing’s symptoms before surgery: Cushing’s patients have thin skin and easy bruising making them more prone to complications from surgery. So metyrapone is used to improve symptoms and promote better recovery post-op. Aim for mean serum cholesterol of 150-300nmol/L Treatments for Cushing’s Syndrome

Cause and Clinical Features of Conn’s Syndrome 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

Diagnosis of Conn’s Syndrome 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

Treatment of Conn’s Syndrome 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

Clinical Features of Phaeochromocytoma 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

Management of Phaeochromocytoma 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

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.

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.

Synthesis of Adrenocortical Steroids 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 P450 SCC 17 alpha-hydroxylase 17 alpha- hydroxypregnenolone 17 alpha-hydroxylase Pregnenolone Dehydroepiandrosterone 3 beta-HSD 3 beta-HSD 17 alpha-hydroxylase 17 alpha-hydroxylase Progesterone 17 alpha- hydroxyprogesterone Androstenedione 21-hydroxylase 21-hydroxylase 11-deoxycorticosterone 11-deoxycortisol Testosterone DHT 5 alpha-reductase 11 beta- hydroxylase 11 beta- hydroxylase Aromatase Corticosterone Cortisol Oestrone 17-beta oestradiol 18-hydroxylase Aldosterone Synthesis of Adrenocortical Steroids

Synthesis of Adrenocortical Steroids 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

Causes of Adrenocortical Failure 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

Features of Addison’s Disease 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

Tests for Addison’s Disease 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

21-beta hydroxylase deficiency 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. CAH is a congenital lack of a steroid enzyme. 95% due to lack of 21-hydroxylase (autosomal recessive) Consequently if complete deficiency, person cannot make aldosterone nor cortisol. 1st day – have mother’s cortisol in you But if these hormones totally absent, can’t survive more than a day Baby loses consciousness – salt-losing Addisonian crisis on 1st day 1st thing to do – give saline Testosterone in excess – cause abnormality of genitals in females therefore more easy to spot CAH in girls than boys Cannot make cortisol. So less negative feedback on pituitary. ACTH rises. Adrenal sex steroids are also under the control of ACTH. Overflow of 17 hydroxyprogersterone funneled into sex steroid pathway. More androgens made. In children it causes: precocious puberty in boys and virilization in girls. In adult women it causes hirsutism. If partial 21-hydroxylase deficiency, slightly hypotensive and will present around puberty when they start to experience the effects of excess sex steroids- precocious puberty and hirsutism 21-beta hydroxylase deficiency

11-beta hydroxylase deficiency 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. With 11-beta hydroxylase deficiency, aldosterone nor cortisol can be made. But there is a build up of the precursor: 11-deoxycorticosterone which is an active mineralocorticoid receptor agonist (remember from the side-effects of spironolactone) As a result they act like they have a high level of aldosterone and retain lots of sodium and excrete lots of potassium, giving rise to hypokalaemic hypertension. Also build up of precursors, means more would be funneled into the sex steroid pathway leading to the production of excess steroids leading to virilisation and hirsutism in females and precocious puberty in males. 11-beta hydroxylase deficiency

17-alpha hydroxylase deficiency 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. With 17-hydroxylase deficiency, patients have a high level of aldosterone (hypertensive) but are missing cortisol (borderline hypogylcaemia and get infections recurrently because they do not have the cortisol needed to cope with the stress of the infection) and sex steroids. Consequently, they never will go through puberty. 17-alpha hydroxylase deficiency

QUESTION TIME Clinical features of Addison’s Disease

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.

Receptors for Corticosteroids Corticosteroids: explain the main clinical uses of exogenous corticosteroids including mode of action; recall how exogenous corticosteroids differ. MR does not distinguish between aldosterone and cortisol. So this can lead to problems because cortisol can stimulate the MR Receptors for Corticosteroids

Receptors for Corticosteroids Corticosteroids: explain the main clinical uses of exogenous corticosteroids including mode of action; recall how exogenous corticosteroids differ. To protect stimulation of MR by cortisol, 11-beta hydroxysteroid dehydrogenase converts it into cortisone - an inactive form that cannot stimulate the MR. But in Cushing’s you have loads of cortisol. 11-beta hydroxysteroid dehydrogenase becomes saturated. Cannot inactivate all to cortisone. Have active some active cortisol that can stimulate the MR and have aldosterone-like effects causing hypokalaemic hypertension. Receptors for Corticosteroids

Exogenous Corticosteroids Corticosteroids: explain the main clinical uses of exogenous corticosteroids including mode of action; recall how exogenous corticosteroids differ. Drug Type Features Distribution (CBG and albumin) Duration of Action Cortisol (Hydrocortisone) Glucocorticoid In high doses, causes MR activation 90-95% bound SHORTEST HALF LIFE Prednisolone Immunosuppressive Less bound than C. More than D and F HALF LIFE LONGER THAN C+F BUT SHORTER THAN D Dexamethasone Very potent – used as anti-oedema agent in brain metastases Less bound than C and P LONGEST HALF LIFE Fludrocortisone Aldosterone Analogue Aldosterone substitute Only bound to albumin NOT CBG *All drugs given ORALLY but sometimes IV/IM may be indicated. Hepatic breakdown – excreted via bile and urine Exogenous Corticosteroids

Corticosteroid Replacement Therapy 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

Corticosteroid Replacement Therapy Type of adrenal failure Cause Management Primary adrenocortical failure Addison’s Disease Chronic Adrenal Insufficiency Replacement cortisol – hydrocortisone Replacement aldosterone- fludrocortisone Secondary adrenocortical failure ACTH Deficiency – pituitary gland not working properly Replacement cortisol – hydrocortisone (titrate based on normal diurnal variations of cortisol) Acute adrenocortical failure (Addisonian crisis) Untreated Addison’s disease IV saline- improve blood pressure High dose corticosterone (also causes MR activation) Congenital adrenal hyperplasia Deficiency in steroid synthetic enzyme (95% 21-hydroxylase) Replacement cortisol- Dexamethasone (1/day) OR Hydrocortisone (2 OR 3/ day) Replacement aldosterone – fludrocortisone Monitor using 17 alpha- hydroxyprogesterone levels and clinically assessing patient for cushingoid symptoms/ hirsutism Iatrogenic adrenocortical failure Long-term, high-dose corticosteroid treatment suppresses HPA axis Increase dose of corticosteroids in stress. Wear a MedicAlert bracelet to indicate steroid dependence Corticosteroid Replacement Therapy

Corticosteroid Replacement Therapy Cautions 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

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

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.

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

Secondary Sexual Characteristics 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 - TESTIS Leydig Cells Sertoli Cells - ALSO: Development of male genital tract Maintains fertility in adulthood Anabolic effects in muscles and bones GnRH pulses from the hypothalamus stimulates pituitary LH and FSH secretion. 2 cells in testes = Sertoli cells + Leydig cells LH then stimulates Leydig cells to produce testosterone. Testosterone has negative feedback on the hypothalamus and the pituitary. FSH stimulates Sertoli cells to produce androgen binding protein and Inhibin A and B. Androgen binding proteins aid spermatogenesis by binding to testosterone. The hormone is made less lipophilic and more concentrated within the luminal fluid of the seminiferous tubule. The higher levels of testosterone enables spermatogenesis in seminiferous tubule and sperm maturation in epididymis. Inhibin has negative feedback on pituitary FSH secretion Testosterone Production of ABP Inhibin A and B Secondary Sexual Characteristics Aids spermatogenesis Normal Male HPG Axis

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

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 Hypothalamus secretes GnRH. GnRH stimulates the pituitary gland to secrete LH and FSH. LH stimulates the ovaries to produce oestradiol and progesterone. Oestrogen negatively inhibits pituitary LH and FSH secretion. NOTE difference from testosterone which inhibits BOTH the hypothalamus and the pituitary gland. FSH stimulates follicular development and inhibin. By day 10, leading follicle develops into a Graffian follicle OVARIES - Oestradiol Progesterone Follicular Development Inhibin Normal Female HPG Axis 1. Follicular Phase Day 10- leading follicle develops into a Graffian Follicle

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

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 Once oestrogen levels reach a certain point, it switches from negative to positive feedback. It increases GnRH release from hypothalamus and increases LH sensitivy to GnRH. Leads to mid-cycle LH surge. Triggers ovulation from a leading follicle. OVARIES + OVULATION Oestradiol Normal Female HPG Axis 2. Ovulation

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

Now let’s move on to pathology… 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…

Primary Gonadal Failure 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 Klinefelters Syndrome- XYY Primary Gonadal Failure

Hypothalamic/ Pituitary Disease 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 Kallmann Syndrome – anosmia and low GnRH, testes originally undescended, stature short-normal Illness/ Underweight- due to low leptin levels which tells the body that it is not the right time to reproduce. Hypothalamic/ Pituitary Disease

Male Hypogonadism Causes 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

Male Hypogonadism Clinical Features 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

Male Hypogonadism Investigations 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

Male Hypogonadism Treatments 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

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.

Secondary Sexual Characteristics 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 - TESTIS Leydig Cells Sertoli Cells - ALSO: Development of male genital tract Maintains fertility in adulthood Anabolic effects in muscles and bones GnRH pulses from the hypothalamus stimulates pituitary LH and FSH secretion. 2 cells in testes = Sertoli cells + Leydig cells LH then stimulates Leydig cells to produce testosterone. Testosterone has negative feedback on the hypothalamus and the pituitary. FSH stimulates Sertoli cells to produce androgen binding protein and Inhibin A and B. Androgen binding proteins aid spermatogenesis by binding to testosterone. The hormone is made less lipophilic and more concentrated within the luminal fluid of the seminiferous tubule. The higher levels of testosterone enables spermatogenesis in seminiferous tubule and sperm maturation in epididymis. Inhibin has negative feedback on pituitary FSH secretion Testosterone Production of ABP Inhibin A and B Secondary Sexual Characteristics Aids spermatogenesis Normal Male HPG Axis

Clinical Uses of Testosterone Male hypogonadism: Explain the clinical features, causes, investigations and treatment of male hypogonadism; explain the clinical uses of testosterone including side effects. Testosterone increases: Lean body mass Muscle size and strength Bone formation and bone mass Libdo and potency BUT REMEMBER THAT IT DOES NOT RESTORE FERTILITY Clinical Uses of Testosterone

Side-Effects of Testosterone Male hypogonadism: Explain the clinical features, causes, investigations and treatment of male hypogonadism; explain the clinical uses of testosterone including side effects. Gynaecomastia Acne Prolonged painful erection Disturbed liver function Aggression Thickening of blood by overproduction of red blood cells – may give rise to cardiovascular complications Side-Effects of Testosterone

*NOTE: Don’t get mixed up with oligomenorrhoea (irregular long cycles) Amenorrhoea: Define amenorrhoea, list the causes, investigations and management. Amenorrhoea: absence of periods Primary Amenorrhoea – failure to develop spontaneous menstruation by 16 Secondary Amenorrhoea – absence of menstruation for 3 months in a woman who previously has had cycles *NOTE: Don’t get mixed up with oligomenorrhoea (irregular long cycles) Define Amenorrhoea

Amenorrhoea: Define amenorrhoea, list the causes, investigations and management. Pregnancy Lactation Ovarian Failure: Premature ovarian insuffiency (early menopause) Oopherectomy Chemotherapy Ovarian dysgenesis (Turner’s Syndrome) Gonadotrophin Failure: Hypothalamic/ Pituitary Disease Kallmann’s Syndrome Low BMI Post-pill amenorrhoea Hyperprolactinaemia Androgen excess: gonadal tumour Causes of Amenorrhoea

Investigations for Amenorrhoea Amenorrhoea: Define amenorrhoea, list the causes, investigations and management. Pregnancy Test LH, FSH and oestradiol Day 21 progesterone Prolactin Thyroid function tests Androgens Chromosomal Analysis (Turner’s) Ultrasound ovaries/ uterus Day 21- progesterone rises to show ovulation Investigations for Amenorrhoea

Treatment of Amenorrhoea Amenorrhoea: Define amenorrhoea, list the causes, investigations and management. Treat the cause Primary ovarian failure – HRT Hypothalamic/ Pituitary Disease – HRT for oestrogen replacement and subcutaneous LH and FSH for fertility in IVF Treatment of Amenorrhoea

Diagnostic Criteria for PCOS Polycystic ovary syndrome: List the diagnostic criteria, recall the clinical features, investigations and treatment of polycystic ovary syndrome (PCOS). Need 2 of the following: Polycystic ovaries on the ultrasound scan Oligoovulation/ Anovulation Clinical/ Biochemical evidence of androgen excess: increased growth of hair in a male pattern Diagnostic Criteria for PCOS

Clinical Features of PCOS Polycystic ovary syndrome: List the diagnostic criteria, recall the clinical features, investigations and treatment of polycystic ovary syndrome (PCOS). Hirsutism Menstrual cycle disturbance Increased BMI Clinical Features of PCOS

Polycystic ovary syndrome: List the diagnostic criteria, recall the clinical features, investigations and treatment of polycystic ovary syndrome (PCOS). Associated with increased cardiovascular risk and insulin resistance making them more prone to diabetes METFORMIN CLOMIPHENE – anti-oestrogenic effect. Bind to oestrogen receptors in hypothalamus thus blocking negative feedback and leading to an increase in GnRH and gonadotrophin secretion. (Kick starts HPG axis) GONADOTROPHIN THERAPY FOR IVF Treatment of PCOS

Regulation of Prolactin Secretion Prolactin: Recall the regulation of prolactin secretion; list the causes, clinical features, investigation and treatment of hyperprolactinaemia. Dopamine has a negative effect on prolactin release. TRH has a milk stimulatory effect on prolactin release. Normal physiological effect: stimulates production of milk in lactating women. Dysregulated prolactin – reduces GnRH pulsatility and switches off gonadal function by LH actions on the ovaries/ testes Regulation of Prolactin Secretion

Causes of hyperprolactinaemia Prolactin: Recall the regulation of prolactin secretion; list the causes, clinical features, investigation and treatment of hyperprolactinaemia. Dopamine Antagonists – anti-emetics and anti-psychotics Prolactinoma PCOS Stalk compression due to pituitary adenoma Hypothyroidism Oestrogens (OCP), Pregnancy, Lactation Idiopathic Anti-emetics generally used in the short term so not much of a problem but anti-psychotics used in the long term so more of a problem Causes of hyperprolactinaemia

Clinical Features of hyperprolactinaemia Prolactin: Recall the regulation of prolactin secretion; list the causes, clinical features, investigation and treatment of hyperprolactinaemia. Galactorrhoea Reduced GnRH pulsatility and LH actions on ovaries/testes leads to Hypogonadism Prolactinoma – headache and visual field defect BITEMPORAL HEMIANOPIA At the optic chiasm, the fibres from the inner (nasal) part of both retinae cross Light from the left visual field will hit the right part of the retina and vice versa Because of the crossing over, all the light from the left visual field is detected by the right side of the brain A pituitary tumour could protrude out of the sella turcica and disrupt the fibres coming from the nasal parts of the retinae This means that you lose the temporal part of the visual field Clinical Features of hyperprolactinaemia

Investigations for hyperprolactinaemia Prolactin: Recall the regulation of prolactin secretion; list the causes, clinical features, investigation and treatment of hyperprolactinaemia. History and examination Are they on phenothiazines/ metoclopramide? Serum prolactin Thyroid function tests – caused by hypothyroidism? MRI if pituitary adenoma suspected Investigations for hyperprolactinaemia

Treatments for hyperprolactinaemia Prolactin: Recall the regulation of prolactin secretion; list the causes, clinical features, investigation and treatment of hyperprolactinaemia. Treat the cause: if pituitary adenoma – transphenoidal hypophysectomy (rare) / if caused by drugs stop them/ treat hypothyroidism etc. Dopamine agonists: bromocriptine, cabergoline (decreases size of tumour if caused by prolactinoma) Treatments for hyperprolactinaemia

QUESTION TIME- PAST PAPER q 2008 What is the diagnostic criteria for PCOS? Why does hyperprolactinaemia cause infertility? Name a class of drug to treat hyperprolactinaemia

FEEDBACK Thanks for listening! Hope it was useful, if you have any questions about this presentation or med school in general, don’t hesitate to email me at: kj416@ic.ac.uk. I am always happy to help! I would really appreciate it if you could take 2 minutes to fill in the feedback forms. I would love to know what things you guys liked and did not like so that I can give better tutorials in the future 