1. By Keerthanaa Jayaraajan
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. 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

4. 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

5. 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

6. 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

7. 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

8. 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 nmol/L
Control Cushing’s symptoms after radiotherapy as radiotherapy takes a long time to show clinical effects.
Treatments for Cushing’s Syndrome

9. 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

10. 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 nmol/L
Treatments for Cushing’s Syndrome

11. 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

12. 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

13. 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

14. 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

15. 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

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. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

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. 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

29. 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

30. 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

31. 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

32. 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

33. 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

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. 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

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
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

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
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

42. 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

43. 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…

44. 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

45. 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

46. 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

47. 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

48. 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

49. 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

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.

51. 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

52. 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

53. 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

54. *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

55. 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

56. 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

57. 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

58. 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

59. 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

60. 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

61. 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

62. 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

63. 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

64. 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

65. 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

66. 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

67. FEEDBACK
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