010
Pages 226-250
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
High triglycerides and low high-density lipoprotein (HDL) cholesterol are the commonest lipid abnormality seen in type 2 diabetes.
Complications
• Increased risk of CVD events
• Increased insulin resistance
Management
• With DM → the first priority in this patient is to improve the glucose control.
• JBS2 guidelines suggest that all patients with type 2 diabetes should be prescribed a
statin, even if their cholesterol is within the target range.
• If triglyceride level > 20 mmol/l that is not a result of excess alcohol or poor glycaemic
control, refer for urgent specialist review (i.e. at a regional lipid clinic).
• If triglyceride level between 10 and 20 mmol/L:
Repeat the triglyceride with a fasting test (following a meal, the chylomicron level
rises in the serum which will lead to a rise in triglyceride levels)
Look for secondary causes
Address lifestyle factors: encourage weight loss, healthy diet and exercise
Commence high-potency statins (atorvastatin, rosuvastatin) if unable to address the
triglyceride level through lifestyle measures.
Fibrates (e.g. fenofibrate).
• The best initial medical treatment for hypertriglyceridemia.
• Action: PPAR alpha receptor agonists → increasing the activity of lipoprotein lipase
• Does not reduce cardiovascular events in the presence of diabetes, while statins have.
Thus, an isolated hypertriglyceridaemia in the presence of significant cardiovascular
risk factors, in a patient not currently on a statin, should be managed with the
introduction of a statin.
• Concomitant fibrate-statin use is associated with an increased risk of myopathy.
Omega-3
• Trials of omega 3 supplementation suggest that it is associated with triglyceride
reduction of up to 38%.
• OMACOR (omega-3-acid ethyl esters) : Mode of action → Increases peroxisomal
beta-oxidation of fatty acids in the liver
• 2019 ESC/EAS Guidelines for the management of dyslipidaemias: (In high-risk patients
with TG between 1.5 and 5.6 mmol/L (135 - 499 mg/dL) despite statin treatment, n-3
PUFAs (icosapent ethyl 2 2g/day) should be considered in combination with statins
• Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA).
Nicotinic acid • it lower both cholesterol and triglyceride concentrations by inhibiting synthesis and increases HDL-cholesterol when used in doses of 1.5-3g daily. • It is recommended for use by specialists in combination with a statin, where a statin alone
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 1
Endocrinolog & Metabolism
• Add of nicotinic acid raise HDL cholesterol level by great amount
• the value of nicotinic acid is limited by its side-effects (especially vasodilatation)
• may increase blood glucose in some patients. many mechanisms have been
suggested for this:
Since nicotinic acid inhibits triglyceride synthesis, it may be that the increased
availability of free fatty acids stimulates hepatic glucose output by increasing
gluconeogenesis or replacing glucose as the primary energy source.
Higher levels of fatty acids may also block glucose uptake by skeletal muscle.
Direct effects on beta-cell function have also been postulated.
• For people with a triglyceride concentration between 4.5 and 9.9 mmol/L, optimize the management of other CVD risk factors present.
Which lipid abnormalities are most likely to be detected in a patient with type 2 diabetes?
• Small dense LDL molecules (LDL is not typically elevated in type 2 diabetes)
• ↓↓ HDL
• ↑↑Triglycerides
Question Analysis of a patient lipoprotein profile shows a deficiency of apolipoprotein C-II. All other lipoproteins are normal. Which lipid profile is most likely to be shown? Answer Elevated levels of both chylomicrons and VLDLs Apolipoprotein C-II (Apo C-II) is an essential co-factor of lipoprotein lipase, which hydrolyzes triglyceride in chylomicrons and VLDLs.
Xanthomas
• Tuboeruptive xanthomas occur in type III hyperlipoproteinaemia
• Eruptive xanthomas are associated with hyperchylomicronaemia (type I and type V
hyperlipoproteinaemia)
• Xanthoma tendinosum, which are nodular swellings of tendons, usually occur in type II
hyperlipoproteinaemia
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
____Hyperlipidaemia: management
Graphic showing choice of statin.
Statins reduce all-cause mortality (not just cardiovascular mortality) in primary prevention
Primary prevention - risk assessment
• NICE recommend use the QRISK2 CVD risk assessment tool for patients aged ≤ 84 years.
• High risk of cardiovascular disease (CVD), defined as a 10-year risk of 10% or greater.
• QRISK2 should not be used in the following situations:
Patients ≥ 85 years are already at high risk of CVD due to their age
type 1 diabetics
patients with an estimated glomerular filtration rate (eGFR) less than 60 ml/min
and/or albuminuria.
patients with a history of familial hyperlipidaemia.
• NICE suggest QRISK2 may underestimate CVD risk in the following:
people treated for HIV
Serious mental health problems
people taking medicines that can cause dyslipidaemia such as antipsychotics,
corticosteroids or immunosuppressant drugs
Autoimmune disorders/systemic inflammatory disorders such as systemic lupus
erythematosus.
• Measuring lipid levels
The samples does not need to be fasting.
repeat sample (fasting or non-fasting) before deciding on further management
In the primary prevention of CVD using statin aim for a reduction in non-HDL cholesterol of > 40%
Chapter 1
Endocrinolog & Metabolism
Primary prevention management (No established cardiovascular disease )
• If the QRISK2 10-year risk is ≥ 10% → Atorvastatin 20mg should be offered first-line +
Lifestyle changes
• People with Type 1 diabetes mellitus: atorvastatin 20 mg should be offered if type 1
diabetics who are: age ˃ 40 years, or diabetes for more than 10 years or nephropathy or
CVD risk factors.
• People with type 2 diabetes → If the QRISK2 10-year risk is ≥ 10% → atorvastatin 20
mg
• People with Chronic kidney disease (CKD): atorvastatin 20mg should be offered to all
patients with CKD
Secondary prevention management (established cardiovascular disease ) • All patients with CVD should be taking a statin in the absence of any contraindication. • Atorvastatin 80mg should be offered first-line. • Follow-up patients at 3 months: if the non-HDL cholesterol has not fallen by at least 40% → ↑the dose of atorvastatin gradually up to 80mg.
Targets of management
Total cholesterol
LDL cholesterol
Triglycerides
< 4.0 mmol/l
< 2.0 mmol/l
˂ 1.7 mmol/L
Joint British
Societies
Lipid-lowering agents
Mechanism of action and adverse effects The following table compares the side-effects of drugs used in hyperlipidaemia:
Drugs
Mechanism of action
Adverse effects
Statins
HMG CoA reductase inhibitors
Myositis, deranged LFTs
Ezetimibe
Decreases cholesterol absorption in the
small intestine
Nicotinic acid
Decreases hepatic VLDL secretion
Flushing, myositis
Fibrates
Agonist of PPAR-alpha therefore
increases lipoprotein lipase
expression
Cholestyramine Decreases bile acid reabsorption in the
small intestine, upregulating the amount
of cholesterol that is converted to bile
acid
PPAR-α agonists (The fibrate) → ↓serum triglyceride levels and ↑ HDL-cholesterol
PPAR-γ agonists (the glitazones) → ↓free fatty acid levels → ↓insulin resistance → ↓blood
glucose levels
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Headache Myositis, pruritus, cholestasis GI side-effects
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Statins
Action • Statins inhibit the action of HMG-CoA reductase, the rate-limiting enzyme in hepatic cholesterol synthesis Metabolism • Simvastatin, atorvastatin and lovastatin are mainly metabolized by cytochrome P450 (CYP) 3A4. • Fluvastatin and rosuvastatin is metabolized by CYP2C9 • Pravastatin is excreted largely unchanged.
Pravastatin may be suitable for primary prevention, but in high-risk secondary prevention patient, a stronger agent is required such as rosuvastatin.
Adverse effects
•
Myopathy: includes myalgia, myositis, rhabdomyolysis and asymptomatic raised creatine
kinase.
Occurs in up to 5%.
More common in lipophilic statins (simvastatin, atorvastatin) than relatively
hydrophilic statins (rosuvastatin, pravastatin, fluvastatin)
If only myalgia (muscle pain): continue treatment as long as creatinine
phosphokinase (CK) remain normal.
Before offering a statin, if CK levels are 5 times the upper limit of normal
(repeated 2 times), do not start statin treatment. If CK levels are raised but less than
5 times the upper limit of normal, start statin treatment at a lower dose.
Starting at a low dose and gradually titrating up can also minimise the risk of side
effects: for example, start at 5 mg of rosuvastatin.
•
Hepatotoxicity:
Occurs in ∼ 2% of patients
↑ LFTs due to the involvement of cytochrome P450 systems (CYP3A4 and CYP2C9)
in the breakdown of statins
Check LFTs at baseline, 3 months and 12 months, but not again unless clinically
indicated.
Statins should be discontinued if serum transaminase concentrations rise to and
persist at 3 times the upper limit of the reference range. If LFT are raised but less
than 3 times the upper limit of normal:
1st step: NICE advises reducing the dose in the first instance.
2nd step: Consider an alternative statin.
•
Statins may increase the risk of intracerebral haemorrhage in patients who've
previously had a stroke. For this reason the Royal College of Physicians recommend
avoiding statins in patients with a history of intracerebral haemorrhage.
This effect is not seen in primary prevention.
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 1
Endocrinolog & Metabolism
Maintain a high index of suspicion for rhabdomyolysis if muscle pain occurs after administering statins Drug interactions with statins P450 inhibitors ↑ CK and myopathy
• P450 inhibitors (e.g. HIV protease inhibitors, Macrolides (especially erythromycin and clarithromycin), Azole antifungals, Cyclosporine, grapefruit juice) → ↑ serum statins → precipitate Myopathy or rhabdomyolysis • Other lipid-lowering agents (e.g. Fibrates and Nicotinic acid) • Agents which can precipitate Myopathy or rhabdomyolysis calcium channel blockers Which statin is associated with the lowest risk of rhabdomyolysis? Fluvastatin
Lipid lowering drugs and pregnancy
• Normally in pregnancy, cholesterol can increase by up to 50%
• Omega-3 fatty acids can be used safely in pregnancy as monotherapy, and function to
decrease maternal TG levels.
• With the exception of the bile acid sequestrants (BAS) such as cholestyramine ,
cholesterol-lowering medications should be stopped prior to pregnancy
• NICE guidelines recommend stopping cholesterol-lowering medications 3 months before
attempting to conceive.
Contraindications
- Active liver disease
- Muscle disorder
- Pregnancy, breastfeeding: stop taking statins 3 months before attempt to conceive and do not restart until breastfeeding is finished.
Fibrates
Agents
• bezafibrate, fenofibrate, and gemfibrozil
Mechanism of action
• Activation of the peroxisome proliferator-activated receptor alpha (PPAR–α) → ↓ LDL, ↑
HDL, ↓↓↓ triglyceride
• Enhance lipoprotein lipase activity
Indication
• second-line drug of choice in hyperlipidemia, most effective for lowering triglycerides
Contraindications
• Renal insufficiency
• Liver failure
• Gall bladder diseases
Side effects
• Dyspepsia
• Myopathy
• Cholelithiasis (Cholesterol gallstones)
• ↑ LFTs (hepatotoxicity)
Interactions
• enhance the effect of other drugs by inhibiting hepatic CYP450 (e.g., sulfonylureas,
warfarin)
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Ezetimibe
Ezetimibe → reduces the absorption of cholesterol through the gut.
Mechanism of action
•
Blocks cholesterol reabsorption at small intestine brush border via inhibiting
NPC1L1 in the gut lumen → ↓ LDL
Indication
•
Monotherapy: in contraindications or statin intolerance
•
Combination therapy (statin and ezetimibe): in insufficient LDL cholesterol reduction
by statins
Side effects (especially in combination therapy, otherwise rare):
•
↑ liver enzymes,
•
angioedema,
•
diarrhea,
•
myalgia
Contraindication
•
coadministration with a statin during active liver disease
Nicotinic acid (niacin )
Mechanism of action
• Inhibits lipolysis and fatty acid release in adipose tissue → ↓ triglyceride and LDL synthesis,
↑ HDL
• Niacin lowers LDL-C and increases HDL-C by:
↓ hepatic VLDL synthesis and secretion into circulation,
↓ lipolysis in peripheral adipose tissue.
Indication
• high LDL cholesterol and lipoprotein(a) levels (> 50 mg/dL) despite statin and ezetimibe
therapy (or if statins are contraindicated)
• Nicotinic acid is highly effective at raising high density lipoprotein (HDL) cholesterol
Adverse effects
•
Flushing: NSAIDs (e.g., aspirin, ibuprofen) taken 30–60 minutes before niacin can
prevent flushing by inhibiting prostaglandin synthesis.
•
Hyperglycemia (impaired glucose tolerance) →↑ HA1c in diabetics
•
Irritates the gastric mucosa, exacerbates gastroesophageal reflux. contraindicated in
patients with active peptic ulcer disease
•
Myositis
•
Hyperuricemia → precipitates acute gout
•
↑ LFTs
Contraindications
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 1
Endocrinolog & Metabolism
• Liver failure • Gout • Hemorrhage • Gastric ulcer • Cardiovascular instability
Cholestyramine Mechanism of action • bile acid sequestrant • bind bile acids in the intestine to prevent reabsorption and recycling forces liver to consume cholesterol in the process of making more bile salts binds bile acids in the intestine → interruption of enterohepatic circulation (↓ bile acid absorption and ↑ bile acid excretion) → lowers cholesterol • The main effect on lipid profile reduce LDL cholesterol (↓ unbound LDL), causes ↑ in LDL-receptor synthesis Indications • management of hyperlipidaemia. Combination treatment with statins in hypercholesterinemia • Digitoxin overdose • Pruritus associated with elevated bile acid levels (cholestasis) • Bile acid diarrhea • Bowel obstruction • occasionally used in Crohn's disease for treatment resistant diarrhoea. Adverse effects • abdominal cramps and constipation • decreases absorption of fat-soluble vitamins (e.g: vitamin D absorption will be reduced) consider fat-soluble vitamin (vitamins A, D and K) and folic acid supplementation • cholesterol gallstones • ↑ LFTs • Myalgia • may raise level of triglycerides
Contraindications • Hypertriglyceridemia > 300–500 mg/dL • Hypertriglyceridemia-induced pancreatitis
Tangier disease
Overview
• rare autosomal recessive metabolic disorder.
• also known as familial alpha-lipoprotein deficiency or hypoalphalipoproteinemia
Features
• Decreased levels or even a complete absence of high-density lipoproteins (HDL)
• Low cholesterol levels
• cholesterol ester depositions especially in:
Tonsils → enlarged, yellow-orange tonsils.
Liver and spleen resulting in hepatosplenomegaly.
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Abetalipoproteinemia
Pathophysiology
• Rare autosomal recessive disorder
• Mutation in the microsomal triglyceride transfer protein → deficiency of apolipoprotein B48 and B-100 (both necessary for chylomicron formation and fat absorption) → deficiency
of LDL, VLDL and chylomicrons.
Features
Typically presents in early childhood with steatorrhea, abdominal distension, and failure to
thrive. During childhood or adolescence, progressive ataxia, neuropathy, and vision
impairment develop.
• Neurologic: caused by deficiency of vitamin E)
cognitive decline
Clumsiness may be the first neurologic manifestation
• Low visual acuity, caused by:
Retinitis pigmentosa → do fundoscopy
Vitamin A deficiency
Treatment
• high-dose vitamin E
• other fat-soluble vitamins (A, K, and D) should also be supplemented
• restriction of long-chain fatty acids
Causes of hypocholesteraemia
• Acquired:
Malignancy
Malabsorption (Short-bowel syndrome, blind loop syndrome, celiac disease,
pancreatic exocrine insufficiency, giardiasis)
Anaemia (Thalassemia, pernicious anaemia)
Chronic infection and infestations
Severe illness in hospitalised patients
• Genetic:
Hypobetalipoproteinemia (most common genetic cause),
Abetalipoproteinemia
Treatment of abetalipoproteinemia involves dietary restriction of fats, and high-dose vitamin E therapy Disease associations with low LDL-C include malignancy and malabsorption
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 1
Endocrinolog & Metabolism
Gynaecomastia
Definition
• Gynaecomastia describes an abnormal amount of breast tissue in males and is usually
caused by an increased oestrogen: androgen ratio.
Causes
• It is important to differentiate the causes of galactorrhoea (due to the actions of prolactin on
breast tissue) from those of gynaecomastia
Causes of gynaecomastia
•
physiological: normal in puberty
•
syndromes with androgen deficiency:
Kallman's, Klinefelter's (47, XXY
karyotype)
•
testicular failure: e.g. mumps
•
liver disease
•
testicular cancer e.g. seminoma
secreting hCG
•
ectopic tumour secretion
•
hyperthyroidism
•
haemodialysis
•
starvation/refeeding
•
drugs: see below
Drug causes of gynaecomastia (10-25% of cases) Relatively Common causes • spironolactone (most common drug cause) • cimetidine • digoxin • cannabis • diamorphine • cyproterone • finasteride • gonadorelin analogues e.g. Goserelin, buserelin • oestrogens, anabolic steroids Very rare drug causes of gynaecomastia • tricyclics • isoniazid • calcium channel blockers • heroin • busulfan • methyldopa
September 2010 exam: H/O developed excessive amounts of breast tissue bilaterally. Which one of the following drugs is most likely to be responsible? Goserelin (Zoladex)
Physiological changes during pregnancy – endocrine
pregnancy → ↑ oestradiol & prolactin + ↓ LH/FSH.
Progesterone • Responsible for pregnancy maintenance • Produced by the corpus luteum until the 10–12 weeks of gestation, after which it is produced by the fetoplacental unit
Human placental lactogen: a hormone synthesized by syncytiotrophoblasts of the placenta, which promotes the production of insulin-like growth factors. • Increases insulin levels • Causes insulin resistance
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
• Increases serum glucose levels and lipolysis to ensure sufficient glucose supply for the fetus • Maternal insulin resistance begins in the second trimester and peaks in the third trimester.
Pituitary gland
•
Hyperplasia of lactotroph cells in the anterior pituitary → physiological enlargement of the
pituitary gland (up to 40% increase from pregestational volume)
Thyroid gland • Thyroid gland hypertrophy The thyroid gland needs to produce 50% more thyroid hormone during pregnancy to maintain an euthyroid state. A 10–20% increase in thyroid mass occurs. • Increase in thyroid-binding globulin and albumin due to increased hepatic synthesis. Pregnancy → ↑↑ thyroxine-binding globulin (TBG) → ↑↑ total thyroxine but does not affect the free thyroxine level • Increase in total T3 and T4 in normal pregnancy (T3) and T4 levels show a slight increase with suppressed (TSH) in the first trimester due to the partial thyroid-stimulating action of human chorionic gonadotrophin (beta-HCG). Free T3 and T4 remains within normal ranges • β-hCG-mediated hyperthyroidism (↓TSH) β-hCG molecule has a similar structure to that of the TSH molecule. β-hCG binds to TSH receptors of the thyroid gland → thyroid stimulation → hyperthyroidism
• Factors influence thyroid function tests in the pregnant patient.
thyroid stimulatory effects of hCG.
HCG → activation of the TSH receptor → transient gestational
hyperthyroidism.
HCG levels will fall in second and third trimester
Lipids
•
↑ Triglycerides and cholesterol (due to increased lipolysis and fat utilization)
↑ SHBG (Sex hormone-binding globulin) and corticosteroid-binding globulin
Beta-HCG has a degree of thyroid stimulating activity →↓↓ TSH. No intervention is needed
Physiological effects of LH, FSH, and sex hormones
• ♀: Ovaries
FSH: follicular maturation → ↑ estrogen
LH: ↑ estrogen, ovulation, and ↑ progesterone
• ♂: Testicles
FSH: production of sperm, ↑ inhibin
LH: stimulation of Leydig cells → ↑ production of testosterone
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 1
Endocrinolog & Metabolism
Dihydrotestosterone (DHT)
Composition
• Testosterone is a steroid hormone and can be converted to oestradiol.
Production
• LH stimulates testosterone production and FSH spermatogenesis
Binding
• It binds to intracellular receptors and is mostly bound to sex-hormone binding globulin
(SHBG)
Conversion
• Testosterone converted to dihydrotestosterone (DHT) in the body by the enzyme 5αreductase. DHT is a more active compound than testosterone.
• The absence of 5α-reductase or the absence of DHT receptors leads to testicular
feminisation.
Function
• During fetal development and early life: differentiation of the penis, scrotum, and prostate.
• expression of male secondary sex characteristics
• During late adulthood: prostate growth, male pattern baldness, and sebaceous gland
activity.
Deficiency
• →↓ testosterone is due to either:
↓ free level due to ↓ production (Leydig and pituitary dysfunction) (Lead to ↑
synthesis of SHBG)
increasing age: total testosterone concentrations fall slightly, and free
testosterone fall more.
↓ activity at receptor often due to androgen receptor deficiency (5α-reductase
deficiency).
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Patients with 5α-reductase deficiency will have ambiguous genitalia at birth until they
reach puberty, when the testosterone surge causes growth of external male
genitalia, however, these patients are otherwise healthy. Individuals with this
deficiency sometimes change their gender role in adolescence.
obesity (hyperinsulinaemia of obesity → ↓SHBG levels → ↓testosterone (low
SHBG and normal free testosterone)
Evaluation
• Initial evaluation: serum testosterone in the early morning, fasting.
• Testosterone levels vary according to the degree of binding to albumin and SHBG; (↑SHBG
↑total testosterone - when testosterone production is low-).
• The equilibrium dialysis method is most useful for measurement of free testosterone (not
bound to protein)
• If the testosterone is low:
measurement of LH and FSH to determine if the hypogonadism is primary or
secondary. If secondary assessment of other pituitary hormones.
If the patient has multiple pituitary hormonal deficiencies and/or if the testosterone is
less than 200 ng/dL, we suggest MRI of the sella.
Testosterone therapy
•
Indications
hypogonadal men to induce and maintain secondary sex characteristics and correct
symptoms of testosterone deficiency.
Older men (>65 years ) with age-related decline in testosterone concentration:
routinely prescribing testosterone therapy is not recommended
In symptomatic (such as low libido or unexplained anemia) and consistently
and unequivocally low morning testosterone, testosterone therapy may be
offered on an individualized basis after discussion of the potential risks and
benefits.
HIV-infected men with weight loss and low testosterone (when other causes
of weight loss have been excluded) to induce and maintain body weight and
lean mass gain.
•
Target
For patients receiving testosterone enanthate, the testosterone level should be
between 400 and 700 ng/dL at about half-way between administrations ( one week
after injection) which are generally given every two weeks.
•
Which type of testosterone therapy is most likely to result in an increase in
dihydrotestosterone level?
Dihydrotestosteone levels increase with the use of a testosterone scrotal patch due
to the high concentration of 5α-reductase in genital skin. Levels may return to normal
after discontinuation; however, they often remain elevated.
• Benefits of testosterone treatment
↑sexual interest and activity, slight improvement in walking, slight improvement in
mood, ↑ hemoglobin, and ↑ bone mineral density (BMD).
No change in energy or cognition is expected.
• Side effects
Erythrocytosis leading to elevated haematocrit
Haematocrit should be measured 3-6 months after initiating therapy and
yearly thereafter.
Guidelines suggest that if haematocrit is increased and no other underlying
cause is found, the dose should be down-titrated.
PSA
Androgen replacement therapy is contraindicated in patients with prostate
cancer and breast cancer.
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 1
Endocrinolog & Metabolism
Urological consultation is recommended if:
↑PSA > 1.4 ng/mL within a 12-month period,
a PSA velocity > 0.4 ng/mL/year using the level after 6 months of
testosterone therapy as the reference
abnormality on digital rectal examination, or
an I-PSS score of greater than 19.
Polycystic ovarian syndrome (PCOS)
Incidence • affect between 5-20% of women of reproductive age. Aetiology • not fully understood • Both hyperinsulinaemia and high levels of luteinizing hormone are seen in PCOS
Features
•
Oligo/amenorrhoea 70%
•
hirsutism, acne (due to hyperandrogenism) 60%
•
obesity 35%
•
subfertility and infertility 30%.
Chronic anovulation is the mechanism for infertility
•
acanthosis nigricans (due to insulin resistance)
•
psychological symptoms
•
Clitoromegaly is seen occasionally in PCOS but is normally associated with very high
androgen levels. If clitoromegaly is found, then further investigations to exclude an
ovarian or adrenal androgen secreting tumour are required.
Investigations
•
pelvic ultrasound: multiple cysts on the ovaries
transvaginal ultrasound is said to have 91% diagnostic sensitivity
The presence of more than eight follicular cysts of less than 10 mm and increased
ovarian stroma is sufficient to make the diagnosis.
•
FSH, LH, prolactin, TSH, and testosterone are useful investigations:
FSH will be normal or low, while LH will be elevated.
Increased LH causes hyperplasia of ovarian theca cells.
Increased LH causes increased testosterone and androstenedione
Raised LH: FSH ratio is a 'classical' feature but is no longer thought to be useful
in diagnosis.
LH/FSH ratio is normally about 1:1 in premenopausal women, but with PCOS
a ratio of greater than 2:1 or 3:1 may be considered diagnostic.
Prolactin may be normal or mildly elevated.
10% of patients with PCOS have hyperprolactinaemia,
elevation in prolactin due to the low oestrogen stimulating GnRH, which in
turn stimulates the anterior pituitary hormones including prolactin.
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
However, the elevation in prolactin in PCOS rarely exceeds 1000 mU/l.
Testosterone may be normal or mildly elevated however, if markedly raised
consider other causes
The appropriate initial biochemical investigation
Normal or elevated testosterone, but with a low sexhormone-binding globulin
(SHBG) level, resulting in a high free androgen index.
Sex hormone-binding globulin (SHBG) is frequently low
(SHBG) is a transporter protein that binds to both testosterone and oestradiol;
it is reduced in insulin resistance, which is common in (PCOS).
(SHBG) is low in 50%, due primarily to hyperinsulinaemia.
The reasons include that androgens reduce the globulin production, whereas
oestrogen promotes production.
Many women with PCOS have a high-normal or even a normal total
testosterone, but a low SHBG because they have insulin resistance.
hyperestrogenism
Increased androstenedione/testosterone in PCOS can be peripherally
converted in adipose tissue to estrone by aromatase.
increased circulating levels of estrone endometrial hyperplasia which is
a precursor to endometrial carcinoma
•
Impaired glucose tolerance
hyperinsulinaemia (insulin resistance → high circulating insulin levels due to
peripheral insulin resistance).
Up to 40% of women with PCOS have impaired glucose tolerance,
up to 10% develop frank Type 2 diabetes mellitus
long term complication of PCOS:
• risks of diabetes (due to peripheral insulin resistance),
• sleep apnoea,
• endometrial cancer,
• mental health disorders.
Diagnostic criteria • According to the Rotterdam Consensus, two of the following three criteria are required for the diagnosis of the PCOS:
- oligo-/anovulation
- hyperandrogenism clinical (hirsutism or less commonly male pattern alopecia) or biochemical (raised free androgen index or free testosterone)
- polycystic ovaries on ultrasound.
Management • General Weight reduction: the gold-standard treatment for PCOS. A loss in weight of only 5% reduces hirsutism by up to 40%.
•
For associated hirsutism
o Dianette® (cyproterone acetate) combined oral contraceptive pill (COC) is the
most effective
o if doesn't respond to COC then topical eflornithine may be tried
o Spironolactone, flutamide and finasteride may be used for its antiandrogenic properties
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 1
Endocrinolog & Metabolism
• For infertility
Initial step →weight loss
First- line drug: Anti-oestrogen therapies such as clomifene → the most effective
treatment
work by occupying hypothalamic oestrogen receptors without activating them.
This interferes with the binding of oestradiol and thus prevents negative
feedback inhibition of FSH secretion
Second-line drug: Metformin is also used, either combined with clomifene or alone,
particularly in patients who are obese but is not a first line treatment
Gonadotrophins: usually reserved for patients who are resistant to clomifene
MRCPUK-part-1-May 2009 exam: H/O infertility with PCOS. Apart from advising her to lose weight, which intervention is most effective in increasing her chances of conceiving? Clomifene (if clomifene – the first line - is not an option, metformin – the second line - is the right answer)
September 2009 exam: Which finding is most consistently seen in polycystic ovarian syndrome? Ovarian cysts on ultrasound
MRCPUK-part-1-January 2012 exam: What is the mechanism of action of metformin in PCOS? Increases peripheral insulin sensitivity
Hirsutism Hirsutism is often used to describe androgen-dependent hair growth in women Hypertrichosis used for androgen-independent hair growth
Definition • Excessive male pattern hair growth in women (e.g., on the chin, above the upper lip, and around the umbilicus) Causes • Idiopathic (the most common ): normal menstrual cycle, normal serum androgen, , and no identifiable cause hirsutism. • Polycystic ovarian syndrome is the most common identifiable causes of hirsutism • Excess androgen (10% of cases): hirsutism, acne, menstrual dysfunction, alopecia. Cushing's syndrome congenital adrenal hyperplasia androgen therapy obesity: due to peripheral conversion oestrogens to androgens androgen secreting ovarian tumour • Drugs
Assessment of hirsutism
• Mild hirsutism and normal menses → do not require laboratory workup and can be treated
empirically.
• Moderate or severe symptoms → early morning total testosterone level
if moderately elevated, it should be followed by a plasma free testosterone level.
A total testosterone level greater than 200 ng per dL (6.94 nmol per L) should prompt
evaluation for an androgen-secreting tumor.
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
• Testing for endocrinopathies and neoplasms, such as polycystic ovary syndrome, adrenal hyperplasia, thyroid dysfunction, Cushing syndrome, and androgen-secreting tumors.
Management
• Advise weight loss if overweight
• Hair removal (Shaving)
• Pharmacologic measures
Combined oral contraceptive pills: first-line pharmacologic treatment
Facial hirsutism: topical eflornithine - contraindicated in pregnancy and breastfeeding
Treatment response should be monitored for at least six months before making
adjustment.
Hypertrichosis
Definition
• excessive hair growth above the normal for the age, sex and race of an individual, in
contrast to hirsutism, which is excess hair growth in women following a male distribution
pattern.
Causes
• Drugs:
phenytoin
minoxidil (antihypertensive vasodilator. also used to treat androgenic alopecia
slows hair loss and promotes hair regrowth)
ciclosporin
diazoxide
• Congenital hypertrichosis lanuginosa, congenital hypertrichosis terminalis
• Metabolic disorders
thyroid dysfunction
porphyria cutanea tarda
anorexia nervosa
Treatment
• Hair removal
Amenorrhoea
Primary amenorrhoea
• Definition: failure to start menses by the age of 16 years
• Causes
Turner's syndrome
testicular feminisation
congenital adrenal hyperplasia
congenital malformations of the genital tract
Secondary amenorrhoea
• Definition
absence of menses for more than 3 months (in women with previously regular
cycles) or 6 months (in women with previously irregular cycles)
• Causes
Pregnancy → most common cause of secondary amenorrhea
hypothalamic amenorrhoea (e.g. Stress, excessive exercise) ↓ FSH
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 1
Endocrinolog & Metabolism
Primary ovarian failure means that the patient never has a normal menstrual cycle, and has the triad of
- amenorrhea,
- hypergonadotropinism,
- hypoestrogenism.
Premature ovarian failure
The history of prolonged cessation of menses with a normal weight, normal thyroid function tests and a history of coeliac disease is pointed to a diagnosis of premature ovarian failure
Criteria for diagnosis
- age under 40 years
- menopausal symptoms (including no or infrequent periods)
- and elevated FSH levels on 2 blood samples taken 4–6 weeks apart.
Epidemiology • occurs in around 1 in 100 women.
Causes • idiopathic - the most common cause • chemotherapy • autoimmune • radiation
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Features
•
secondary prolonged amenorrhoea
•
infertility
•
climacteric symptoms: hot flushes, night sweats
Investigations
•
raised FSH, LH levels
• ↓↓oestradiol
• sex hormone releasing hormones would be elevated in an attempt to drive LH and FSH
release.
Treatment
• Hormone replacement therapy (HRT) or a combined hormonal contraceptive to protect against osteoporotic fracture. HRT may have a beneficial effect on blood pressure when compared with a combined oral contraceptive both HRT and combined oral contraceptives offer bone protection HRT is not a contraceptive. • Spontaneous recovery of fertility is unlikely (occurs in only 5%).
Menopause
Definitions • Peri-menopause → aged over 45,vasomotor symptoms and irregular periods • menopause → aged over 45, no period for at least 12 months, not associated with a pathology and not using hormonal contraception.
Symptoms • Usually preceded by 4–5 years of abnormal menstrual cycles. • vasomotor symptoms (e.g. hot flushes and sweats): most common • musculoskeletal symptoms (for example, joint and muscle pain) • effects on mood (e.g. low mood) • urogenital symptoms (e.g. vaginal dryness) • Sexual difficulties (e.g. low sexual desire). • Women with obesity tend to suffer from fewer symptoms in menopause due to peripheral conversion of androgens to estrogen in adipose tissue. • Most symptoms will disappear spontaneously within 5 years after onset.
Consequences
• ↓↓ bone mineral density → osteoporotic fractures.
• ischaemic heart disease,
• ↓↓ insulin sensitivity
• ↑↑ thrombotic tendency.
• Increased possibility of developing Alzheimer's dementia
Oestrogen deficiency might play a role in the development of dementia.
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 1
Endocrinolog & Metabolism
Investigations
• ↓ estradiol, ↓ progesterone, ↓ inhibin B
• ↑ GnRH, ↑↑ FSH and ↑LH (↑↑FSH is specific for menopause)
• Vaginal pH > 4.5
• Lipid profile: ↑ total cholesterol, ↓ high-density lipoprotein (HDL)
• Testosterone and prolactin levels are within normal ranges (androstenedione is produced
by ovarian stromal cells and the adrenal glands.)
Management
• Vasomotor symptoms →hormone replacement therapy (HRT)
women with a uterus → oestrogen and progestogen
Women without a uterus →Oestrogen alone.
• Psychological symptoms → low mood or anxiety → HRT & CBT
women with low sexual desire → testosterone supplementation if HRT alone is not
effective.
• Urogenital atrophy → vaginal oestrogen (including those on systemic HRT), also in whom
systemic HRT is contraindicated.
The ovaries’ failure to produce estrogen begins in the late 30s and progresses to the degree that most women have near-complete loss of estrogen production by their mid-50s.
Whereas taking estrogen alone increases the risk of endometrial cancer, taking both estrogen and a progestogen in combination, as in most birth control pills, decreases the risk.
All postmenopausal women above the age of 65 should be screened for osteoporosis (i.e., using the DEXA scan to measure bone mineral density).
Hormone replacement therapy (HRT)
• Hormone replacement therapy (HRT) involves the use of a small dose of oestrogen, combined with a progestogen (in women with a uterus), to help alleviate menopausal symptoms.
Unopposed oestrogen therapy is most appropriate for patient who had a hysterectomy and combined hormone replacement therapy (HRT) is unnecessary.
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Indications • vasomotor symptoms such as flushing, insomnia and headaches (The main indication) • Premature menopause: should be continued until the age of 50 years. Most important reason is preventing the development of osteoporosis
Types • Estrogen therapy: for women who have had a hysterectomy • Estrogen plus progestin therapy: for women with a uterus
Advantages of hormone replacement therapy (HRT)
- improvement in menopausal symptoms
- protection against fractures of the wrist, spine, and hip secondary to osteoporosis.
- reduce incidence of colorectal cancer
- reduce incidence of Alzheimer's
• Hormone replacement therapy and effects on bone mass Reduction in total-body bone mass begins in women in their late twenties This loss is accelerated at the menopause Both trabecular bone loss at the level of the vertebrae and cortical bone loss at the radius are prevented by oestrogen therapy The risk of osteoporotic fractures is reduced, but not eliminated, by oestrogen therapy If the uterus has been removed in a patient, there is no need for additional progesterone therapy The effect of oestrogens on bone loss may be reduced after 10 years of oestrogen therapy
Adverse effects • Cancer Unopposed estrogen can result in endometrial hyperplasia → increased risk of endometrial cancer Estrogen plus progestin therapy → increased risk of breast cancer • Thromboembolism: Cardiovascular disease: coronary heart disease, deep vein thrombosis, pulmonary embolism, stroke
Selective Estrogen Receptor Modulators (SERMs)
Raloxifene
•
Mechanism of action
estrogen antagonist in breast and endometrium
agonist in bone to increase mineralisation
•
Clinical use
osteoporosis in menopausal women
breast cancer prevention in women high risk for breast cancer
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 1
Endocrinolog & Metabolism • Toxicity ↑ risk of venous thromboembolism induces menopause →hot flashes
Tamoxifen
•
Mechanism of action
mixed oestrogen-receptor antagonist and partial agonist depending on the
target tissue
estrogen antagonist in breast
estrogen agonist in endometrium and bone
•
Clinical use
estrogen and progesterone receptor positive breast cancer
breast cancer prevention in women high risk for breast cancer
•
Toxicity
↑ risk of venous thromboembolism
↑ risk of endometrial cancer secondary to agonist activity
induces menopause →hot flashes
Androgen insensitivity syndrome
The testosterone which is in the male range, the history of hernias as a baby and absence of acne or secondary sexual hair are all pointers towards androgen insensitivity syndrome.
The presence of breast development in the absence of secondary sexual hair, with a history of hernias as a child is suggestive of a diagnosis of androgen insensitivity syndrome. It is likely that the hernias were related to undescended testes. The vagina is blind ended, and there are no ovaries.
Pathophysiology
• X-linked recessive mutation of the gene encoding the androgen receptor (AR gene) →
Defects in the androgen receptor → end organ insensitivity to androgens. end-organ
resistance to testosterone causing genotypically male children (46XY) to have a female
phenotype.
• Complete androgen insensitivity syndrome is the new term for testicular feminisation
syndrome
Features
•
Primary amenorrhoea
•
Undescended testes causing groin swellings, Cryptorchidism (absence of one or both
testes from the scrotum)
•
External genitalia ranges from normal female to female with clitoromegaly, to underdeveloped male (hypospadias) → Associated with abdominal hernias.
•
Breast development may occur as a result of conversion of testosterone to oestradiol
•
Blind-ended vaginal pouch, uterine and fallopian tube agenesis (due to testicular antiMullerian hormone secretion)
•
Scant or no pubic hair
Diagnosis
•
High level of LH
•
↑ Oestrogen
•
Normal/↑ testosterone levels (no virilization)
•
Buccal smear or chromosomal analysis to reveal 46XY genotype
Management • Counselling - raise child as female • Bilateral orchidectomy (increased risk of testicular cancer due to undescended testes) • Oestrogen therapy
Disorders of sex hormones The table below summarises the findings in patients who have disorders of sex hormones: Disorder LH Testosterone Primary hypogonadism (Klinefelter's syndrome) High Low Hypogonadotrophic hypogonadism (Kallman's syndrome) Low Low Androgen insensitivity syndrome High Normal/high Testosterone-secreting tumour Low High
Menstrual cycle
The menstrual cycle may be divided into the following phases:
Follicular phase (proliferative phase)
(from day 1 until day 14)
Ovarian
histology
• A number of follicles develop.
• One follicle will become dominant
around the mid-follicular phase
Endometrial
histology
• Proliferation of endometrium
• Endometrium changes to
Hormones
• A rise in FSH results in the development
of follicles which in turn secrete
oestradiol
• When the egg has matured, it secretes
enough oestradiol to trigger the acute
release of LH. This in turn leads to
ovulation
• Graafian follicle is a large
mature tertiary follicle containing
an oocyte that is ready to be ovulated.
• Ovulation occurs 14 days before
menses, regardless of cycle length.
• estradiol stimulates the growth of
the endometrium.
• Progesterone levels are low
• FSH activates aromatase within
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Luteal phase (secretory phase)
(From day 15 until day 28)
• Corpus luteum
secretory lining under influence
of progesterone
• corpus luteum produces (3
hormones) estrogen, inhibin,
and progesterone.
• progesterone is significantly
higher than in other phases of
the menstrual cycle.
• If fertilisation does not occur the
corpus luteum will degenerate
and progesterone levels fall
Chapter 1
Endocrinolog & Metabolism
Follicular phase (proliferative phase)
(from day 1 until day 14)
granulosa cells, increasing estradiol
production.
• The main hormone controlling
the follicular phase is estradiol, secreted
by Granulosa cells.
Cervical
mucus
• Following menstruation the mucus is
thick and forms a plug across the
external os
• Just prior to ovulation the mucus
becomes clear, acellular, low viscosity.
It also becomes 'stretchy' - a quality
termed spinnbarkeit
Basal body
temperature
• Falls prior to ovulation due to the
influence of oestradiol
Which hormone levels would be most likely to indicate the occurrence of ovulation? Luteinising hormone
At which point in the menstrual cycle do progesterone levels peak? Luteal phase Progesterone is secreted by the corpus luteum following ovulation.
Which mechanism is most likely responsible for the missed period in early pregnancy? Syncytiotrophoblast produces human chorionic gonadotropin (hCG), which stimulates progesterone production by the corpus luteum.
Hypogonadism
Primary hypogonadism (Hypergonadotropic hypogonadism)
if LH and FSH are not elevated a primary hypogonadism is excluded.
• Pathophysiology
gonadal insufficiency (↓ testosterone, ↓ estrogen) → ↑ gonadotropin secretion (↑
FSH and ↑ LH) from the anterior pituitary (lack of negative feedback from the
impaired gonads)
• Causes
Congenital abnormalities: (Primary gonadal insufficiency):
Turner syndrome (females)
Klinefelter syndrome (males)
androgen insensitivity syndrome
Acquired diseases: (Secondary gonadal insufficiency) →(damage to leydig cells or
ovarian tissue):
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Luteal phase (secretory phase)
(From day 15 until day 28)
• Under the influence of
progesterone it becomes thick,
scant, and tacky
• Rises following ovulation in
response to higher
progesterone levels
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Medications (Radiation, chemotherapy, Ketoconazole, Glucocorticoids, toxins)
Autoimmune disease
Infections (mumps, tuberculosis)
Tumour, infiltration (Testicular tumour)
Chronic systemic illnesses (eg: Hepatic cirrhosis, Chronic renal failure)
Ageing: Andropause (↓ testosterone with age ˃50).
Primary testicular failure (idiopathic failure).
• Investigations
↑LH & FSH + ↓ testosterone + ↓ sperm count
Testicular ultrasound (the most important investigation after blood hormones)
Secondary hypogonadism (hypogonadotrophic hypogonadism)
• Pathophysiology
↓ pituitary gonadotropins (↓ FSH and ↓ LH) → ↓ testosterone and ↓ estrogen
• Causes
Genetic defects: (e.g., Kallmann syndrome, Prader-Willi syndrome, Gaucher
disease)
Hypothalamic and/or pituitary lesions due to: Neoplasm (e.g. prolactinoma,
craniopharyngioma, astrocytoma)
Malnutrition (e.g., anorexia nervosa)
Chronic diseases (e.g., inflammatory bowel disease, hypothyroidism, cystic fibrosis,
diabetes and obesity.)
• Investigations
serum testosterone and sperm count are subnormal + normal or reduced LH
and FSH
Prolactin level (↑Prolactin reduces LH and FSH)
measure of free testosterone (as total testosterone can be low due to SHBG being
decreased in obesity and with ageing).
Pituitary MRI : the best image to exclude other pituitary pathology.
Clinical features • Delayed puberty • Developmental abnormalities with genitalia (undescended testes, hypospadias) • Infertility (↓ sperm count), impotence, and/or ↓ libido • Secondary amenorrhea
Treatment
• Treat underlying cause: e.g., surgical excision of tumors, pharmacotherapy for
prolactinomas
• Hormone replacement therapy
Poor ability to concentrate is most consistent with post-pubertal loss of testicular function, whereas (High-pitched voice, Gynecomastia, Disproportionately long arms and legs, Scant pubic and axillary hair) are most consistent with hypogonadism that develops before puberty. In male patients with low libido have been found to have a low testosterone first line investigation should include prolactin and LH to assess for a central cause
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