Endo Flashcards
1
Q
What is the most common cell type in the anterior pituitary and what does it produce?
A
somatotrophs (50%) - growth hormone
2
Q
What are the various cell types in the anterior pituitary and what do they produce?
A
somatotrophs growth hormone
thyrotrophs - TSH
lactotrophs - prolactin
corticotrophs - ACTH
gonadotrophs -LH/FSH
3
Q
Name the 3 conditions associated with growth hormone defects
A
Gigantism = growth hormone excess in childhood/puberty
Dwarfism = growth hormone deficiency in childhood
Acromegaly = growth hormone excess after puberty; will not cause people to grow taller, grow wider instead
4
Q
Disorders of the posterior pituitary
A
Diabetes insipidus (lack of ADH)
Syndrome of inappropriate anti-diuretic hormone (SIADH) -> causes hyponatremia
5
Q
Which hormone should be replaced first with panhypopituitarism?
A
cortisol
This is because giving thyroxine first will speed up the metabolic rate, increasing the body’s steroid requirement
Lack of cortisol is life threatening
6
Q
causes of hypopituitarism
A
- Tumours
- Radiotherapy
- Infarction / haemorrhage (apoplexy)
- Trauma
7
Q
types of Pituitary tumours (size)
A
< 1cm microadenoma
> 1cm macroadenoma -> more likely to compress the optic chiasm
8
Q
types of Pituitary tumours (function)
A
Non-functioning (majority) -> visual field defect
Functioning • Prolactin (prolactinoma) • GH (acromegaly) • ACTH (Cushing’s disease) • TSH (TSHoma)
9
Q
Causes of high prolactin
A
Prolactinomas
Lactation / pregnancy
Drugs (block dopamine) - Tricyclics / antiemetics / antipsychotics
“stalk” effect - Tumour that blocks connection between hypothalamus and posterior pituitary -> blocks dopamine inhibition of prolactin
10
Q
Prolactinoma clinical features
A
- Galactorrhoea – milky discharge from breasts
- Headaches
- Mass effect
- Visual field defect
- Amenorrhoea / erectile dysfunction
Clinical features result from suppression of gonadotrophic hormones -> hypogonadrotrophic hypogonadism (negative feedback on gonadotropins)
11
Q
Prolactinoma treatment
A
Dopamine agonists (cabergoline / bromocriptine)
Surgery if there is a failure of medical therapy or with a large tumour with visual field effects
12
Q
Acromegaly
A
Pituitary tumour (macroadenoma) secreting Growth Hormone
Excessive production of GH (and IGF-1) in adults
Growth plates have fused, and therefore cannot cause increase in height
Cartilage, muscles and tendons can still grow
13
Q
Acromegaly clinical features
A
- Sweats and headaches
- Alteration of facial features
- Increased hand and feet size
- Visual impairment
- Cardiomyopathy
- Increased inter-dental space
14
Q
Acromegaly complications
A
- Hypertension
- diabetes or impaired glucose tolerance
- Increased risk of bowel cancer
- heart failure
15
Q
Acromegaly diagnosis
A
Glucose tolerance test
• Glucose load fails to suppress GH
IGF-1 level
Pituitary MRI
16
Q
Acromegaly treatment
A
surgery to debulk tumour
pituitary radiotherapy
pharmacological management
17
Q
Cushing’s disease
A
- Pituitary tumour releasing ACTH
- One of the causes of Cushing’s syndrome
• Surgery is first line treatment
18
Q
TSHoma
A
- Pituitary tumour releasing TSH
* Causes high TSH and high fT4
19
Q
Diabetes insipidus (DI)
A
- ADH deficiency – central or cranial
- lack of ADH and inability to reabsorb water
chronic excessive thirst accompanied by excessive fluid intake – polyuria
• Low urine osmolality and high plasma osmolality
Cranial DI = deficiency
Nephrogenic DI = resistance
20
Q
Hypoglycaemia
A
in DM: plasma glucos <4mmol/L
in non-DM: plasma glucose <3 mmol/L
21
Q
hypoglycaemic symptoms
A
autonomic:
- sweating
- tremors
- palpitations
- nausea
neuroglycopaenic:
- impaired concentration
- drowsiness
- slurred speech
- headache
- seizures
- coma
autonomic symptoms occur before neuroglycopenic symptoms
22
Q
Whipple’s triad
A
– Symptoms consistent with hypoglycaemia
– Low plasma glucose concentration (venous sample)
– Relief of those symptoms after the plasma glucose level is raised
23
Q
Arterial Calcium Stimulation
A
IV administered calcium stimulates insulin release from insulinoma, but not from normal beta cells.
Distinguishes focal (Insulinoma) from diffuse disease
24
Q
causes of non-diabetic fasting hypoglycaemia
A
Remember: causes of non-diabetic fasting hypoglycaemia = ExPLAIN
- Ex = exogenous drugs
- P = pituitary insufficiency
- L = Liver failure
- A = Addison’s disease/Autoimmune
- I = Islet cell tumours (insulinoma)
- N = non-pancreatic neoplasms
25
Impaired glucose tolerance
a period of increased insulin resistance
Usually develops due to combination of lifestyle and genetic factors
Insulin signalling impaired at cellular level
Pancreas is overworking to try and keep the blood glucose within a normal range
26
Pathogenesis of type 2 diabetes
1) Insulin resistance + beta cell compensation
2) Beta cell failure - decreased insulin production
3) increased blood glucose
27
Which drugs act as insulin sensitisers?
metformin
| pioglitazone
28
Mechanism of action: metformin
Inhibits mitochondrial glycerophosphate dehydrogenase in the liver, activates AMPK
acts as an insulin sensitising agent and reduces hepatic gluconeogenesis
29
Which diabetes therapies cause weight gain?
insulin
sulphonylureas
thiazolidinediones
30
Which diabetes therapies may cause hypoglycaemia?
insulin
| sulphonylureas
31
incretin effect
the difference in insulin response between orally delivered and intravenously delivered glucose.
32
Which diabetes therapies cause weight loss?
GLP-1 receptor agonists
| SGLT-2 inhibitors
33
Which GLP-1 receptor agonist has proven cardiovascular benefits?
liraglutide
34
Which SGLT-2 inhibitors have proven cardiovascular benefits?
empagliflozin
| canagliflozin
35
Diabetes mellitus
A metabolic disorder characterized by chronic hyperglycaemia with disturbed carbohydrate, protein and fat metabolism resulting from defects in insulin secretion and/or insulin action
36
Symptoms of Hyperglycaemia
Glycosuria - Depletion of Energy Stores
o Tired, weak, weight loss, difficulty concentrating, irritability
Glycosuria - Osmotic Diuresis
o Polyuria, polydipsia, thirst, dry mucous membranes, reduced skin turgor, postural hypotension
Glucose Shifts - Swollen Ocular Lenses
o Blurred vision
37
DKA symptoms
```
nausea
vomiting
abdominal pain
heavy/rapid breathing
acetone breath
drowsiness
coma
```
38
Diagnostic Criteria for DM
Fasting blood glucose
o > 7: diabetes
OGTT (oral glucose tolerance test) 2 hr glucose
o > 11.1: diabetes
Need 2 abnormal tests, or 1 + symptoms
```
Symptoms
Polydipsia
Fatigue
Polyuria
Blurred vision
Thrush (oral/genital)
```
HbA1c >48 (6.5%)
39
Pathogenesis of type 1 diabetes
Type 1 diabetes results from autoimmune destruction of the insulin-producing beta cells in the islets of Langerhans.
Occurs in genetically susceptible individuals and is probably triggered by one or more environmental agents.
40
MODY
any of several hereditary forms of diabetes mellitus caused by mutations in an autosomal dominant gene disrupting insulin production
"monogenic diabetes"
most common is a mutation of hepatic nuclear factor 1-alpha -> results in deficiency of one of the islet transcription factors
41
Gestational diabetes mellitus
Carbohydrate intolerance with onset, or diagnosis during pregnancy
* Fasting venous plasma glucose ≥ 5.1 mmol/l, or
* One hour value ≥ 10 mmol/l, or
* Two hours after OGTT ≥ 8.5 mmol/l
Women become very resistant to their own insulin, mainly in the third trimester of pregnancy
If the threshold for insulin is already very high, this pushes the woman over to hyperglycaemia
42
Risk factors for Gestational diabetes mellitus
```
o high BMI >30
o previous macrosomic baby
o previous gestational diabetes
o family history of diabetes
o ethnic prevalence of diabetes
```
all women with risk factors should have an OGTT at 24 to 28 weeks
43
What are some causes of Secondary Diabetes?
Pancreatitis
Pancreatic Carcinoma
CF
Haemochromatosis
Any excess of counter-regulatory hormones (e.g. GH/cortisol)
Drug induced
- Anti Psychotics – Clozapine/Olanzapine
- Glucocorticoids/Tacrolimus/Ciclosporin
44
Most common Auto-antibodies in Type 1 DM
* ICA (islet cell antibody)
* I-A2 (insulinoma-associated antigen-2)
* GAD65 (glutamic acid decarboxylase 65)
45
Basal insulin
Basal = maintains some constant insulin in circulation
• Usually administered once daily = long acting
Different versions
– glargine
– detemir (twice daily)
– Tresiba
46
Bolus insulin
Dose of insulin changes depending on the amount of carbohydrates ingested
-e.g. humulin S (short-acting)
If you have no carbs, you shouldn’t necessarily need bolus insulin
Patients are encouraged to use carb counting
1 unit of short acting insulin for 10g of carbohydrate
47
Advantages of Insulin pens
More convenient and easier to transport
more accurate dosages
Easier to use for those with impairments in visual and fine motor skills
Less injection pain
Can be used without being noticed
48
Continuous Subcutaneous Insulin infusion (CSII)
continuous infusion of a short-acting insulin driven by mechanical force and delivered via a needle or soft cannula under the skin
can improve glycaemic control and quality of life
49
Hypoglycaemia and driving
CBG (capillary blood glucose) > 5mmol/l before driving, carry CHO, identifiers
Remember: at least five to drive!
50
precipitants of ketoacidosis
* new onset diabetes
* MI
* Infection
* Steroids
* CSII Pump failure
* Substance abuse
* Deliberate omission of Insulin dose
51
Treatment of DKA
Hypovolaemia - Intravenous fluid
• restoration of circulatory volume: crystalloid
• clearance of ketones: 10% dextrose – Give dextrose to stop FFA catabolism
Insulin deficiency - Intravenous insulin. Will cause fall in glucose and potassium
Hypokalaemia - Intravenous potassium
52
Hyperglycaemic Hyperosmolar State (HHS)
Complication of diabetes mellitus in which high blood sugar results in high osmolarity without significant ketoacidosis
RELATIVE insulin deficiency
53
Hyperglycaemic Hyperosmolar State precipatants
* Infection (majority)
* Poor compliance
* Drugs
54
HHS treatment
Strategies are broadly the same as DKA, but all need to be administered with much more caution due to comorbidities and the potential for over-rapid replacement
Fluid
Insulin (if glucose doesnt fall with fluid alone)
K+ - NB: Chronic renal impairment may make the patient less able to excrete potassium
LMWH - Hypercoagulable due to severe dehydration
Foot protection – ulceration is common
55
How does thyroid hormone circulate in the blood?
Free (0.5%) / bound (99.5%)
Bound to thyroid binding globulin, transthyretin and albumin
56
Primary hypothyroidism
High TSH and low T4
Disease is in the thyroid gland
Treat with thyroxine
57
Secondary hypothyroidism
Low TSH and low T4
Pituitary cause of disease
May also have other pituitary axis hormone deficits
NB: Make sure their cortisol is okay before commencing thyroxine treatment
58
Primary hyperthyroidism
Low TSH and high T4
59
Sick euthyroidism
low TSH and low T4
Effect on thyroid hormones with other illness (e.g. malignancy), but not fundamental thyroid disease
60
Investigation of thyroid function
```
Measure:
o TSH
o free T4
o total T3
o TSH receptor antibodies
o TPO - thyroid peroxisomal antibody
```
* Primary hypothyroidism – High TSH and low T4
* Secondary hypothyroidism – Low TSH and low T4
61
radioiodine uptake scan
Used for investigation of hyperthyroidism
different conditions will cause different uptake patterns
62
Causes of hyperthyroidism
Auto-immune (Graves’ disease)
Toxic adenoma – solitary nodule over secreting thyroid hormones
Multinodular goitre - can be either:
o toxic multinodular goitre (causes hyperthyroidism)
o non-toxic (does not make too much thyroid hormone)
Thyroiditis (acute early phase) - generally caused by an attack on the thyroid, resulting in inflammation and damage to the thyroid cells
Excess administration of thyroxine (e.g. abuse for weight loss)
Pituitary adenoma
Other hormones acting as TSH - hCG
63
Which symptoms are specific to graves' disease?
Graves’ Ophthalmopathy - autoimmune inflammatory disorder of the orbit and periorbital tissues
Dermopathy
- red, swollen skin, usually on the shins and tops of the feet.
- texture may be similar to an orange peel
64
Characteristics of Graves’ Ophthalmopathy
```
o Lid retraction / lag and periorbital oedema
o Proptosis (30%) = Exophthalmos
o Diplopia (10%) = double vision
```
65
Pathophysiology of of Graves’ Ophthalmopathy
Autoantibodies target the fibroblasts in the eye muscles, which can differentiate into adipocytes.
Fat cells and muscles expand and become inflamed.
inflammation causes deposition of collagen / glycosaminoglycans in the muscles -> enlargement and fibrosis
increase in volume of the intraorbital contents within the confines of the bony orbit
Veins become compressed, and are unable to drain fluid, causing oedema
66
Thyroid acropachy
soft-tissue swelling of the hands and clubbing of the fingers
67
Treatment of hyperthyroidism
* Antithyroid drugs
* Surgery – will lead to hypothyroidism
* Radioiodine - will probably lead to hypothyroidism
68
How does thyroid hormone circulate in the blood?
Free (0.5%) / bound (99.5%)
Bound to thyroid binding globulin, transthyretin and albumin
69
Primary hypothyroidism
High TSH and low T4
Disease is in the thyroid gland
Treat with thyroxine
70
Secondary hypothyroidism
Low TSH and low T4
Pituitary cause of disease
May also have other pituitary axis hormone deficits
NB: Make sure their cortisol is okay before commencing thyroxine treatment
71
Primary hyperthyroidism
Low TSH and high T4
72
Sick euthyroidism
low TSH and low T4
Effect on thyroid hormones with other illness (e.g. malignancy), but not fundamental thyroid disease
73
Investigation of thyroid function
```
Measure:
o TSH
o free T4
o total T3
o TSH receptor antibodies
o TPO - thyroid peroxisomal antibody
```
* Primary hypothyroidism – High TSH and low T4
* Secondary hypothyroidism – Low TSH and low T4
74
radioiodine uptake scan
Used for investigation of hyperthyroidism
different conditions will cause different uptake patterns
75
Causes of hyperthyroidism
Auto-immune (Graves’ disease)
Toxic adenoma – solitary nodule over secreting thyroid hormones
Multinodular goitre - can be either:
o toxic multinodular goitre (causes hyperthyroidism)
o non-toxic (does not make too much thyroid hormone)
Thyroiditis (acute early phase) - generally caused by an attack on the thyroid, resulting in inflammation and damage to the thyroid cells
Excess administration of thyroxine (e.g. abuse for weight loss)
Pituitary adenoma
Other hormones acting as TSH - hCG
76
Thyrotoxicosis symptoms
```
o Weight loss
o Tachycardia
o Tremor
o Hypertension
o Heat intolerance
o Palpitations
o Diarrhoea
o Sweating
```
77
Which symptoms are specific to graves' disease?
Graves’ Ophthalmopathy - autoimmune inflammatory disorder of the orbit and periorbital tissues
Dermopathy
- red, swollen skin, usually on the shins and tops of the feet.
- texture may be similar to an orange peel
78
Characteristics of Graves’ Ophthalmopathy
```
o Lid retraction / lag and periorbital oedema
o Proptosis (30%) = Exophthalmos
o Diplopia (10%) = double vision
```
79
Pathophysiology of of Graves’ Ophthalmopathy
Autoantibodies target the fibroblasts in the eye muscles, which can differentiate into adipocytes.
Fat cells and muscles expand and become inflamed.
inflammation causes deposition of collagen / glycosaminoglycans in the muscles -> enlargement and fibrosis
increase in volume of the intraorbital contents within the confines of the bony orbit
Veins become compressed, and are unable to drain fluid, causing oedema
80
Thyroid acropachy
soft-tissue swelling of the hands and clubbing of the fingers
81
Treatment of hyperthyroidism
* Antithyroid drugs (carbimazole, PTU)
* Surgery – will lead to hypothyroidism
* Radioiodine - will probably lead to hypothyroidism
82
Radioiodine therapy for Graves’ Disease
* Destroys thyroid tissue by beta emission
* May worsen eye disease – ensure steroid cover and avoid hypothyroidism
* Defer conception for at least 4 months
* Hypothyroidism is main side effect. May be transient in first 6 months
83
Causes of hypothyroidism
Autoimmune thyroid disease (Hashimotos)
Thyroiditis – Viral and often painful
Thyroidectomy
Following radio iodine therapy
Drug-induced
o Amiodarone
o Lithium
o Sunitinib
Pituitary disease – secondary hypothyroidism
Severe iodine deficiency
84
Signs and Symptoms of hypothyroidism
```
Symptoms of hypothyroidism
• Weight gain
• Depression
• Lethargy
• Constipation
• Cold intolerance
• Poor concentration
• Hoarseness
• Menorrhagia - menstrual periods with abnormally heavy or prolonged bleeding
```
```
Signs of hypothyroidism
• Weight gain
• Bradycardia
• Lethargy
• Dry skin
• Coarse, thin hair
• Anaemia
• Slow relaxing reflexes
• May have goitre
```
85
Treatment of hypothyroidism
Mainstay is levothyroxine
o usually 75-150 mcg per day
o Generally need 1.7-2.0 micrograms / kg / day (with no gland whatsoever)
o Best taken on an empty stomach
86
Signs/symptoms of Neonatal hypothyroidism/cretinism
```
o Coarse facial features
o Large fontanelles
o Umbilical hernia
o Mottled, cool, and dry skin
o Developmental delay
o Pallor
o Myxedema
o Goitre
```
87
Jod Basedow phenomenon
iodine induced hypERthyroidism
88
Wolff Chaikoff effect
iodine induced hypOthyroidism
89
Amiodarone thyroid disease
type 1: autoimmune thyrotoxicosis
o treatment with high dose carbimazole
type 2: destructive thyroiditis
o treatment with glucocorticoids
90
What does hypertension + hypokalaemia suggest?
What tests would you perform and what results do you expect?
Primary Aldosteronism (CONN’S SYNDROME)
Aldosterone - high
Renin - low
ARR = aldosterone renin ratio - increased. Disproportionate amount of aldosterone to renin in the blood
suppression testing: IV saline load will fail to suppress aldosterone
Adrenal CT scan
91
CONN’S SYNDROME
Primary Aldosteronism
most common cause of secondary HTN. Usually caused by single adrenal adenoma (or bilateral hyperplasia)
Patients present with severe HTN and hypokalaemia
92
Management of primary aldosteronism
Surgical
• Unilateral laparoscopic adrenalectomy if the patient has an adrenal adenoma
Medical
• Use MR antagonists (spironolactone or eplerenone)
93
Cushing’s Syndrome
Excess cortisol secretion
ACTH dependent (ACTH will be high)
• Pituitary adenoma = Cushing’s Disease
• Ectopic ACTH
• Ectopic CRH
ACTH independent (ACTH will be low)
• Adrenal adenoma
• Adrenal carcinoma
• Nodular hyperplasia
94
Clinical features of cortisol excess
* Centripetal obesity
* Prone to HTN/hyperglycaemia
* Easy bruising (thin skin)
* Moon face
* Striae
* Proximal myopathy - muscle wasting in arms/legs
* buffalo hump
* abdominal striae
95
Diagnosis of Cushing’s syndrome
1) Establish cortisol excess:
Perform two of the following:
• 24 hr Urinary free cortisol
• Dexamethasone suppression test
• Late night salivary cortisol
2) Determine underlying cause. If cortisol is abnormal, determine the origin -> CRH stimulation test
• low ACTH - problem with the adrenal gland (ACTH-independent)
• high ACTH - ACTH dependent Cushing’s (pituitary)
96
Management of Cushing’s syndrome
Surgical
o Trans-sphenoidal pituitary surgery
o Laparoscopic adrenalectomy
o Removal of ACTH source
97
IATROGENIC CUSHING’S SYNDROME
* COMMONEST CAUSE OF CORTISOL EXCESS
* Cushingoid appearance but low plasma cortisol
* Due to prolonged high dose steroid therapy
• Causes chronic suppression of pituitary ACTH production and adrenal atrophy. Patients become steroid dependent
98
Clinical presentation and management of secondary adrenal insufficiency
Skin pale (no elevated ACTH, therefore no pigmentation)
No electrolyte abnormalities as aldosterone production is intact (regulated by RAAS)
Treat with hydrocortisone replacement (fludrocortisone unnecessary)
99
symptoms of Congenital Adrenal Hyperplasia
Female
• masculinisation of female genitalia due to excess exposure to androgens in utero
• Usually presents earlier in girls
Male
• Adrenal crisis (Hypotension, hyponatraemia)
• Early virilization
100
treatment of Congenital Adrenal Hyperplasia
mineralocorticoid and glucocorticoid replacement with the aim to normalize androgen production
101
PHAEOCHROMOCYTOMA
Catecholamine secreting tumours of the adrenal medulla
102
Symptoms/ signs of phaeochromocytoma
Hypertension (intermittent in 50%)
Episodes of headache, palpitations, pallor and sweating
Also tremor, anxiety, nausea, vomiting, chest or abdo pain
* Crises last about 15 minutes
* Often well in between crises
103
Paraganglioma
extra-adrenal neural crest cell tumours. Can secrete catecholamines
e.g. sympathetic ganglia
104
Phaeochromocytoma diagnosis and treatment
Measure 24 hour urinary catecholamines and metabolites
CT scan of adrenals
Adrenalectomy is treatment of choice
NB: Need pre-operative treatment with α1 +/- β1 antagonists to block effects of catecholamine surge
Alpha-blockade initially - doxazosin
Then beta blocker if tachycardic - bisoprolol
105
* 21-year-old female
* ‘unwell’ for few months
* Weight loss
* Amenorrhoea
* Acutely unwell over past 48 hours with vomiting and diarrhoea
```
On examination:
• Dark skin
• Dehydrated
• Hypotensive
• Low Na, high K
```
Adrenal insufficiency
106
Causes of Primary adrenal insufficiency
o Addison’s disease
o Adrenal TB/malignancy
o Congenital Adrenal Hyperplasia = neonatal form
o Autoimmune destruction
107
Causes of secondary adrenal insufficiency
Due to lack of ACTH stimulation of the adrenal glands
Iatrogenic (excess administration of exogenous steroid)
Pituitary/hypothalamic disorders (tumours, surgery, radiotherapy)
108
Treatment Issues (Androgen Replacement)
* Mood (aggression/behaviour change)
* Libido issues
* Increased haematocrit
* Possible prostate effects
* Acne, sweating
* Gynaecomastia
109
Clinical Features of Addison’s Disease
```
o Anorexia, weight loss
o Fatigue/lethargy
o Dizziness and low BP
o Abdominal pain, vomiting, diarrhoea
o Skin pigmentation
```
110
Diagnosis of adrenal insufficiency
SHORT SYNACTHEN TEST
very elevated ACTH levels
High renin -> renin activation due to hypotension
low aldosterone -> Low Na, high K
Adrenal autoantibodies may be present
111
Management of primary adrenal insufficiency
* Untreated, this is a fatal condition
* Do not delay treatment to confirm diagnosis
* Hydrocortisone as cortisol replacement
* Fludrocortisone as aldosterone replacement
Patient education:
o ‘sick day rules’ – double oral hydrocortisone for 3 days when unwell
o Cannot stop suddenly - will cause adrenal crisis
o Need to wear identification
112
Clinical presentation and management of secondary adrenal insufficiency
Skin pale (no elevated ACTH, therefore no pigmentation)
No electrolyte abnormalities as aldosterone production is intact (regulated by RAAS)
Treat with hydrocortisone replacement (fludrocortisone unnecessary)
113
Clinical Features of Male Hypogonadism
```
Child/Young Adult
• Slow growth in teens
• No pubertal growth spurt
• Small testes & phallus
• Lack of 2° sexual development
```
```
Adult
• Depression/low mood
• Poor libido
• Erectile problems
• Poor muscle bulk/power
• Poor energy
```
* Sparse body/facial hair
* Gynaecomastia
* Gynoid weight gain
* Great head hair
* Short phallus
* Small testes – abnormal consistency to palpation
114
Orchidometer
tool used to determine at what point in development the testes are. 20-25ml = adult
115
Testing for male hypogonadism
Sex steroid deficiency?
• Testosterone - measure in early morning
• LH & FSH - possible pituitary cause
Fertility?
• Semen analysis
116
Hypogonadal hypogonadism
Primary Gonadal Failure
i.e. testicular cause of hypogonadism
117
Hypogonadotrophic Hypogonadism
Secondary gonadal failure
i.e. Hypothalamic-Pituitary Problem
Characterised by:
• Low testosterone
• Low LH/FSH
NB: Determine prolactin levels – possible prolactinoma
• Prolactin suppresses LH and FSH
118
Kallmann’s Syndrome
Commonest form of isolated gonadotrophin deficiency
• Isolated LH and FSH deficiency
Failure of cell migration of GnRH cells to hypothalamus from Olfactory placode
characterized by delayed or absent puberty and an impaired sense of smell (aplasia/hypoplasia of olfactory lobes)
119
PRIMARY GONADAL DISEASE: DIFFERENTIAL DIAGNOSIS
Klinefelters syndrome
Cryptorchidism
Trauma/chemotherapy/radiotherapy causing leydig cell/seminiferous tubule failure
Myotonic dystrophy
120
Klinefelter’s Syndrome
Commonest genetic cause of male hypogonadism
XXY
Clinically manifests at puberty
• Poor growth and delayed puberty
• Increased LH & FSH – but seminiferous tubules regress & Leydig cells do not function normally
low testosterone and elevated oestrogen levels
121
Male Hypogonadism Treatment
Androgen Replacement Therapy
• Oral
• IM = sustanon
• Topical – NB: need to be careful to make sure that other people don’t come into contact with the testosterone gel
NB: will not reach high enough testicular androgen levels to treat infertility
Fertility Treatment
• Need to stop androgen replacement therapy
• hCG
• Recombinant LH & FSH
• GnRH pumps – overstimulate pituitary to get enough endogenous testosterone production
122
Treatment Issues (Androgen Replacement)
* Mood (aggression/behaviour change)
* Libido issues
* Increased haematocrit
* Possible prostate effects
* Acne, sweating
* Gynaecomastia
123
24 yr old female
• Complains of facial hair growth / male pattern
• No periods in last 6 months, acne worse recently
• No prescribed or OTC medications
• Weight going up
• FHx Type 2 Diabetes
PCOS
124
Causes of primary amenonorrhoea
GU malformations
Chromosomal abnormalities - Turner's syndrome (XO)
Pituitary/hypothalamic disorders- secondary hypogonadism
125
Causes of secondary amenonorrhoea
```
Premature ovarian failure
PCOS
Pituitary tumour (prolactinoma)
```
Weight loss
drugs (opiates)
stress
thyroid dysfunction
126
Hirsutism
Excess hair growth in a male pattern due to increased androgens and increased skin sensitivity to androgens
Vast majority of cases are due to PCOS
127
symptoms of anovulation
o Amenorrhoea
o Oligomenorrhoea – infrequent periods
o irregular cycles
128
symptoms of hyperandrogenism in women
o Hirsutism
o Acne
o Alopecia
129
Symptoms of PCOS
Classic presentation is with symptoms of anovulation
o Amenorrhoea
o Oligomenorrhoea – infrequent periods
o irregular cycles
Associated with symptoms of hyperandrogenism
o Hirsutism
o Acne
o Alopecia
Polycystic ovaries on USS
Typically presents during adolescence
130
PCOS
Commonest cause of anovulatory infertility
Typical endocrine features are raised testosterone and LH
Associated with metabolic abnormalities and increased risk of type 2 diabetes
Defined by:
- Clinical and/or biochemical signs of hyperandrogenism
- Oligo- and/or anovulation
131
GONADOTROPHINS in PCOS
Increased LH concentration
- Increased androgen production from theca cells under influence of LH
- I.e. LH drives some of the phenotype that we see
Decreased FSH
- Low constant levels result in continuous stimulation of follicles without ovulation
- Decreased conversion of androgens to oestrogens in granulosa cells
132
Which androgen is predominantly produced in the adrenal glands in females?
DHEA-s (95%)
133
What would cause high calcium and suppressed PTH?
malignancy
drugs
granulomatous disease
134
What would cause high calcium and high PTH?
primary hyperparathyroidism
lithium
Familial hypocalciuric hypercalcemia
135
What is the significance of decreased sex-hormone binding globulin (SHBG) in PCOS?
Insulin resistance causes increased insulin production to maintain glucose homeostasis
This results in decreased SHBG and increased androgen levels
Results in increased free testosterone
o SHBG is a carrier protein produced in liver
o binds testosterone in the circulation, stopping it from becoming biologically active
Increased testosterone leads to clinical symptoms of PCOS
136
Treatment of PCOS
weight loss is main strategy. Other strategies have limited efficacy and more side effects.
Insulin sensitizers (metformin):
• Decreased LH levels
• Increased SHBG
• and hence decreased FAI (free androgen index)
Ovarian Androgen Suppression:
- OCP
- AR antagonists (spironolactone)
-Finasteride for 5 alpha reductase inhibition to reduce peripheral conversion
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24 yr old female
• Complains of facial hair growth / male pattern
• No periods in last 6 months, acne worse recently
• No prescribed or OTC medications
• Weight going up
• FHx Type 2 Diabetes
PCOS
138
Functions of calcium
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muscle contraction
bone growth/remodelling
hormone secretion
second messenger in signalling
enzyme cofactor
```
139
what is the effect of albumin on plasma calcium levels?
If a patient has a low albumin concentration, the TOTAL [Calcium] will also be low but the FREE [Calcium] may be quite normal
Albumin is a negative acute phase reactant, i.e. it decreases in inflammation
Many ill people thus have decreased albumin, and therefore decreased total [calcium]
Calcium is thus adjusted for the low [albumin]
140
What impact does acid-base balance have on plasma calcium?
Alkalosis causes ionized calcium to bind to albumin more strongly.
This causes a decrease in the ionized calcium and may trigger symptoms of hypocalcemia.
- cramps
- paraesthesia
- perioral numbness
141
Effect of PTH
In response to a decrease in iCa, PTH:
1) Stimulates calcium REABSORPTION in renal tubule (DCT) and excretion of phosphate
2) Stimulates formation of 1,25 DHCC in kidney, which enhances calcium ABSORPTION from gut and bone RESORPTION
3) Promotes bone RESORPTION
Overall effect → rise in iCa back to normal
142
Role of vitamin D
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increases absorption of calcium from the gut
increases bone resorption
reduces insulin resistance
immunomodulation
increased muscle strength
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143
What form of vitamin D is measured in Clinical Vitamin D Assays?
25-hydroxycholecalciferol (25HCC)
144
Hypercalcaemia symptoms
Remember: Bones, stones, abdominal moans, and groans
Moans = depression/confusion, fatigue
Bones = bone pain, muscle weakness, osteopaenia
Stones = predisposed to nephrocalcinosis/nephrolithiasis
Abdominal Groans = vomiting, constipation
Also increased thirst and polyuria
Bradycardia and hypertension
145
ECG changes in hypercalcaemia
* Can predispose to dysrhythmia
* Shortened QTc interval
* Bradycardia
146
Causes of Hypercalcaemia
1) Hyperparathyroidism – adenoma of parathyroid gland (in rare cases a carcinoma)
- high calcium and high PTH
2) Malignancy
- Tumour produces PTH related peptide
- Lung cancer, breast cancer, multiple myeloma
- high calcium and suppressed PTH
3) vitamin D toxicity
- Least common cause
147
What would cause high calcium and suppressed PTH?
production of PTHrP by a tumour
-Lung cancer, breast cancer, multiple myeloma
drugs
granulomatous disease
148
What would cause high calcium and high PTH?
primary hyperparathyroidism
lithium
Familial hypocalciuric hypercalcemia
149
By what mechanisms can malignancy lead to hypercalcaemia?
1) Osteolytic metastases and myeloma
- bone metastases break down bone and release calcium
2) Tumour secretion of PTHrP
- squamous cell lung cancer; oesophageal cancer; renal cell carcinoma; breast cancer
3) Tumour production of 1,25 dihydroxycholecalciferol
- Occurs in lymphoma
150
Management of hypercalcaemia
Stop offending / contributing medications
1) Rehydration - isotonic (0.9%) saline infusion
• hypovolaemic -> exacerbates hypercalcemia by impairing renal clearance of calcium
• see if this works before starting other treatments
2) loop diuretic -> Promote calciuria
3) Bisphosphonate Therapy
• Inhibit bone resorption
• useful in hypercalcaemia of malignancy
• Zolendronic acid is most commonly used
4) Steroids
• Inhibit vitamin D production
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* 62-year-old female
* Sees GP with polyuria, polydipsia, constipation
* History spans several months
* Previous hospital admission with renal colic
* BP/HR normal
* Glucose /eGFR normal
* Calcium 2.9 mmol/L (NR 2.2-2.58)
* PTH 28 pmol/L (N=1.0-6.8)
Primary Hyperparathyroidism
152
Management of Primary Hyperparathyroidism
Observation if no end-organ damage or unfit for surgery
• Annual bone profile
• renal function + urinary calcium
• DEXA and renal US every 3 years
Surgery - Parathyroidectomy in patients who have:
• Calcium > 3.0 mmol/L
• Hypercalciuria
• age under 50 years
• end organ damage - Osteoporosis, renal stones
Medical treatment only indicated if not fit for surgery
• Calcium sensing receptor agonists (Cinacalcet)
153
Complications of parathyroidectomy
Mechanical
• Vocal cord paresis
• Haematoma causing tracheal compression
Metabolic
• Transient hypocalcaemia
154
Causes of Vitamin D Deficiency
Primary / Nutritional causes
o Lack of sunlight exposure
o nutritional deficit
```
Secondary causes
1) Deficient absorption
o Partial gastrectomy
o Small bowel malabsorption
o Pancreatic disease (fat-soluble vitamin)
```
2) Chronic Renal Failure
o Impaired conversion to 1,25-DHCC
3) Enzyme inducing drugs, e.g. anticonvulsants
155
Osteomalacia
Failure to ossify bones in adulthood as a result of Vitamin D deficiency
156
Signs/symptoms of osteomalacia
bone pain - can be localised or generalised, but is particularly prevalent in the groin/lower legs
proximal myopathy
Waddling gait
Difficulty rising from a chair
hypocalcaemia
157
Findings in osteomalacia
* Low calcium
* low phosphate
* High alkaline phosphate = high bone turnover
* Low 25HCC = vitamin D deficiency
* elevated PTH
• Looser zones on xray = pseudofractures
158
Vitamin D Deficiency - treatment
Cholecalciferol (D3)
Alfacalcidol (i.e. active Vit D)
- In renal impairment, cannot activate vitamin D stores
- In hypoparathyroidism (cannot activate Vit D in gut)
- Higher risk of hypercalcaemia
159
Amiodarone and TFTs
1) inhibits T4→T3 conversion – which in the pituitary results in a mild raise in TSH
2) can induce hypothyroidism- in 1st year of treatment
3) can induce hyperthyroidism – due to increased iodine intake or destructive thyroiditis
patients on amiodarone have:
elevated/high normal fT4
low normal fT3
initially a high TSH – normalises within a few months.
160
Thyrotoxicosis vs hyperthyroidism
Thyrotoxicosis = syndrome resulting from excessive free t4 and/or T3.
Can occur without hyperthyroidism – e.g. stored hormone released from a damaged gland or excess hormone replacement
Hyperthyroidism = thyroid over activity resulting in thyrotoxicosis.
161
Thyrotoxicosis causes
Primary – i.e. driven by the thyroid
Graves’ disease
Toxic Multinodular Goitre
Toxic Adenoma
Secondary
TSH secreting pituitary adenoma (rare) – ‘TSHoma’
Gestational Thyrotoxicosis – high levels of hCG in 1st trimester (resembles TSH)
162
What investigations can help determine the cause of thyrotoxicosis?
Antibodies +/- nuclear medicine scan (=Thyroid scintigraphy)
163
Thyroid scintigraphy patterns
1) Diffuse uptake with suppression of background activity = Graves’
2) Irregular Uptake – Multi Nodular Goitre
3) Hot Nodule – Toxic Adenoma
4) Reduced uptake- thyroiditis eg viral.
164
What are the 2 treatment regimens for thyrotoxicosis?
1) A reducing regimen where higher doses are started at initiation of treatment, then as the patient becomes euthyroid the dose is reduced, maintaining a euthyroid state.
2) Block and Replace – Commence with blocking medication, then when patient is euthyroid add in Thyroxine. Smoother biochemical control, ideal where there is concern of hypothyroidism with thyroid eye disease. Avoid in pregnancy.
165
What are features of thyroid eye disease are specific to Graves’ disease?
1) Grittiness and redness
2) Conjunctival oedema
3) Periorbital oedema
4) Proptosis and exophthalmos (proptosis secondary to endocrine cause). Lower sclera visible
5) Ophthalmoplegia (paralysis of the muscles within or surrounding the eye)
NB: Lid lag (slowed lid closing) and lid retraction (upper sclera visible) are the result of excess sympathetic activity and are not specific to Graves’ disease.
166
What factors increase the risk of developing Graves’ opthalmopathy?
```
Smoking
Male Sex
Age
Radioactive iodine treatment
Signs of thyroid eye disease
```
167
Treatment of Graves’ ophthalmopathy
Grittiness – artificial tears
Eyelid – tape eyelids at night to avoid corneal damage, surgery if risk of exposure keratopathy
Proptosis – steroids, radiotherapy may need orbital decompression
Optic neuropathy - steroids, radiotherapy may need orbital decompression
Ophthalmoplegia – orbital decompression, orbital
muscle surgery.
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Myxoedema
denote severe hypothyroidism
there is accumulation of hydrophilic mucopolysaccharides in the dermis and other tissues
Leads to the thickened facial features and doughy skin.
Other tissues also affected:
Dull, expressionless face, sparse hair, periorbital puffiness, macroglossia
Pale, cool, skin which is rough and doughy
Pericardial effusion
Megacolon/ intestinal obstruction
Cerebellar ataxia
Prolonged relaxation phase of deep tendon reflexes
Peripheral neuropathy
169
Myxoedema Coma
state of decompensated hypothyroidism
occurs in patients with long-standing, undiagnosed hypothyroidism and is usually precipitated by infection, cerebrovascular disease, heart failure, trauma, or drug therapy
170
Subclinical hyperthyroidism
low levels of TSH but normal levels of T3 and T4
171
Subclinical hypothyroidism
elevated TSH value (on at least 2 occasions) with
| normal T4 hormone levels.
172
Autoimmune Polyendocrine Syndrome Type 2
Autoimmune condition affecting several endocrine glands
Triad of:
o Addison’s
o AI thyroiditis
o T1DM
More common in females
Presents in adulthood
Polygenic
173
DKA diagnosis
1) hyperglycaemia (blood glucose >11.1)
2) metabolic acidosis (bicarbonate <15mmol/L) = anion gap metabolic acidosis.
3) ketosis/ketonuria
174
What could cause high ketone levels other than DKA?
starvation
175
DKA pathophysiology
Insulin deficiency results inlipolysis -provides the substrate for ketone production from the liver.
Ketones (β hydroxyl butyrate, acetoacetate, acetone) are excreted by the kidneys and buffered in the blood initially but eventually this system fails and acidosis develops.
Hyperglyceamia occurs due to unregulatred gluconeogensis and glycogenolysis.
Reduced peripheral glucose utilisation associated with Insulin deficiency exacerbates hyperglycaemia -> activation of counterregulatory hormones
osmotic diuresis produced by hyperglycaemia and ketonuria causes hypovolaemia
