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Endocrinology > Obesity and Sex Hormones > Flashcards

Obesity and Sex Hormones Flashcards

1
Q

What is the best measure of viceral fat (aside from MRI)?
How is this measured

A

Waist circumference
- Narrowest point between the ribs and hips
- Measured at the end of normal inspiration

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2
Q

Is waist or hip circumference a better measurement?

A

Waist

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3
Q

Where is hip circumference measured?

A

Point of maximal extension of the buttocks when viewed from the side

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4
Q

Adiopocytes regulate appetite. What do they secrete and where does this act?

A

Leptin
- secreted proportional to the amount of adiopocytes

Acts on the brain, hypothalamus
- Acts on the arcuate nucleus in the hypothalamus

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5
Q

Who does leptin therapy work for? Why doesnt it work for the general poipulation?

A

Leptin therapy works for leptin deficient pts (ie homozygoud for leptin deactivating mutation)

Doesnt work for most because leptin resistance
- Hypothalamus becomes resistance to leptin

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6
Q

How is MCR4 related to congenital obesity?

A

Leptin acts on the arcuate nuc of hypoT. Then there is interthalamic nuc signally using MCR4 as the signalling molecule leading to reduced appetite
- If def in MCR4 then cant reduce appetite

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7
Q

What is the commonest form of congential mongenetic obesity in children?

A

MCR4 mutations

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8
Q

How is short term appetite regulated?
How is long term apetite regulated?

A

Cholecystakinin +/- ghrelin
Leptin

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9
Q

What causes cholecystokinin release?

A

Stretching of the stom as we eat
- duodenum secretes this

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10
Q

Person trying to loose weight. Initially succeeding then stops losing weight. What physiological change is resp for this?

A

Decreased basal metabolic rate when trying to loose weight

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11
Q

What is the most important factors in determine whether a diet will be successful?

A

Ability to adhere to diet
- actually diet you chose doesnt matter

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12
Q

What is one existing drug regime for weight loss?

A

Phenteramine and toperimate (off label)
- 12% reduction in weight loss over 1 year

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13
Q

WHat is currently the most successful method of weight loss? When is this considered for managment?

A

Bariatric surgery
- Most successful stratergy over the long term

Consider if BMI >35 and have co-morbidities
- T2DM
- HTN
- OSA
- Dyslipidaemia
- Non alcoholic steatohepatits
- PCOS

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14
Q

What overweight co-morbidities respond well to bariatric surgery?

A

T2DM
HTN
OSA
Dyslipidaemia
PCOS
Non etoh steatohepatitis

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15
Q

What are the 3 types of barbaric surgery in common use now?

A

Adjustable gastric band
Gastric sleve (sleeve gastrectomy)
Reux en Y bypass

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16
Q

WHat is the most efective form of bariatric surgery?

A

Reux en Y bypass

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17
Q

Pt found to have recurrent severe hypoglycaemia many years following gastric bypass operation (ie reux en Y bypass). WHat is the condition?
Brief pathophys and how is it treated?

A

Post gastric bypass hypoglycaemia syndrome
- Due to beta cell expansion post gastric bypass resulting in increased insulin production

Treated with insulin antagonist Diazoxide

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18
Q

What are GLP1 and PYY? What causes their release?

A

GLP1 is an incretin. acts at multiple lveels including GIT tract, panc and brain

PYY (peptide YY) is a molecule that acts in the arcuate nucleus of the hypothal and inhibits the release NPY thereby reducing foo intake

Reduced in response to nutrition intake from endocrine L cells in the distal Ileum

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19
Q

What is the effect on GLP1 and Peptide YY post gastric bypass?

A

Both increased

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20
Q

What is an example of a twincretin drug. WHat does it contain?

A

Tirzepatide
- this contains GLP1 receptor agonist and a GIP receptor agonist (ie twincretin = contains 2x incretins)

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21
Q

WHy are very low fat diets indicated pre surgery in bariatric cases?

A

reduce hepatic steatosis -> leads to easier access surgicaly

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22
Q

Contraindications for GLP1 agonists?

A

Past pancreatitis or chronic pancreatitis
- increased risk of pancreatitis
Past or current medullary thyroid cancer
- Increased calcitonin production
Gastroparesis / delay gastric emptying
- Not persistent after ceasing Rx

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23
Q

WHat are the three cells in bone? What are they derrive from and what is their basic function?

A

Osteoclasts
- Derived from mononuclear cells
- resorbs bone

Osteoblasts
- Derrived from mesenchymal cells
- Makes new bone (makes collogen that is then mineralised to form bone)

Osteocytes
- osteoblasts terminally differentiate into osteocytes that are imbeded within bone
- These act as mechanoreceptors and secree FGF23 and Sclerosin

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24
Q

WHat is the role of the osteocyte (what does it secreete)?

A

Acts as a mechanoreceptor
Secretes sclerosis and FGF23

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25
Q

Describe the microstructure of bone?

A

Tripple hellix matrix of type 1 collogen that has been mineralised with deposited hydroxyappetite crystals
- 2x alpha 1 chains + 1x alpha 2 chain

Also ALP and osteocalcin embeded in bone (+ other hormones)

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26
Q

Two different types of bone? what is the respective percentage of bone mass?

A

Cortical bone
- 80%
Trabecular bone
- 20%

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27
Q

Bone with the most cortical bone? Bone with the highest cortical bone?

A

Lumbar vertebrae
Distal radius

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28
Q

Describe the main difference between boen modeling and remodeling?

A

Bone modeling occurs during growth
- Purpose is to make the skeleton during growth
- It is uncoupled, meaning teh osteoclast and osteoblast function are not related at this time (independant)

Bone remodeling is teh process that occurs after growth has completed (ie adulthood)
- role is to repair microdamage and maintain mineral homeostasis
- It is a coupled process (osteoclasts and blasts are dependant on each other)

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29
Q

Describe teh 4 phases of bone remodeling?

A

Resting phase
- bone is resting

Resorption phase
- Steoclasts are activated and start to resorb bone

Reversal phase
- Osteoclasts are apoptotic, preosteoblasts are deposited in the bone pits

Formation phase
- osteoblasts secrete osteoid into the bone pits forming new bone
- back at resting phase

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30
Q

What is RANKL? describe the funciton in relation to osteoblasts and cytes?

What is teh negative regulatory hormone equivilent to RANK L?

A

RANK ligand is a molecule secreted from osteoblasts
It binds to prefusion osteoclasts (ie before they have become multinucleated osteoclasts) and activates them

The activated multinucleated osteoclast then starts absorbing bone

Osteoprotegrin is also secreted by osteoblasts. it binds to RANKL and inhibits it, thereby stopping it from activating osteoclasts

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31
Q

What are the 4 changes that occurs in excessive bone remodeling that are responsible for the structural weakness of remodeled bone (describe in terms of trabecular and cortical bone)?

A

Trabecular bone
- Trabecular thinning (decreased density)
- Loss of connectivity (perforation of the trabecular plates)

Cortical bone
- cortical thining
- cortical porosity (incred nuber of empty pockets in the cortical bone)

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32
Q

Explain how each class of OP drug (BP, DMAB, SERM/estrogen) work to reduce the activity of osteoclasts?

A

BP
- bind to hydroxyappetite in the bone and are toxic to osteoclasts
- therefore when osteoclast tries to reabsorb the bone it dies

DMAB
- binds to RANK L and inhibits it (like OPG does), therefore stopping the maturation of osteoclasts

SERM/Estrogen
- Changes the ratio of RANK L to OPG therefore shifiting to less bone reabsorption

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33
Q

What is an osteoporeotic fracture?

A

This is any fragility fracture after the age of 50yrs, except for those of the skull, face, fingers or toes.
- Vertebral fracture is the hallmark fracture (most common fracture, they preceed the hip fracture by about 10 years)
- ie 20yr pt fractures arm after picking up a cup is not an osteoporotic fracture. Probably a pathological fractrure

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34
Q

How are osteoporosis vertebral fractures assessed? what is the definition of mild, moderate and severe fracture?

A

They are assessed with a lateral spine radiograph. Definition is loss of >20% of vertebral height

Mild - 20-25% loss of height
Moderate - 25-40% loss of height
Severe - >40% loss of height

They can be anterior body loss of height (most common), middle or posterior body
- Anterior body loss of height is also called a wedge compression fracture

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35
Q

What is the T score? What is the definition of osteopenia and osteoporosis?

A

T score is a measure of teh number of standard dieviations away from the normal health adult you are
- for example T score -2 means that the pt has a bone density that is 2 SD less than the average bone density for a 25yo adult of the same gender

T score >-1 is normal
T score -1 to -2.5 is osteopenia
T score < -2.5 is OP

36
Q

What regions are measured by the DEXA scan?

A

Lumbar spine
Femoral neck
Total femour (total femoral head)

37
Q

What is a Z score and why is it useful?

A

A Z score compares teh BMD to that of the average BMD for a person of the same age

It is useful for ID those with an accelerated cause of OP (ie secondary cause)
- ie pt with Z score <-2 = secondary cause of OP

38
Q

What are some common causes of secondary causes of OP?

A
  • Hypogondaism (ie same mechanism of post menopausal)
  • Vitamin D deficiency
  • Hyperparathyroidism
  • Hyperthyroidism
  • Coeliac disease
  • MM
  • Drugs: steroids
  • Chronic disease: RA and many others
39
Q

Should asymptomatic vertebral fractures in pts >50 be treated?

A

Yes
- this is an OP fracture

40
Q

Should you treat osteoporosis BMD without prior fracture (inc nil vertebral fracture)?

A

This is by definition OP
However you should not treat

The risk of having a future fracture is mainly determined by past fracture, much less so by the BMD
- Fopr example pt with osteopenia with prior fracture is more likely to have a future fracture than OP without prior fracture

41
Q

Should you treat pt with osteoporotic fracture (ie colles fracture >50yrs) with a normal BMD

A

Nil evidence in this space, unclear

42
Q

Should you treat post menopausal women <50yrs with past fragility fracture if
- T score > -1
- T scor -1 to -2.5
- T score < -2.5

A
  1. unclear. Does not have OP by BMD or OP fracture definition. However post meno and past fragility fracture are significant RF therefore may treat
  2. Treat. Does not have OP by BMD or OP fracture definition, however has osteopenia. The risk of future fracture in pts with osteopenia with past fracture is > risk in pt with OP but nil past fracture
  3. Defs treat
43
Q

Does definition of OP mean you treat? How can u decide who to treat?

A

Not necessarily
- Online tools such as FRAX tool can be used to decide fracture risk and therefore how to treat

44
Q

What are common classes of mecications that lead to bone loss / OP?

A

Steroids
Aromatase inhibitors (ie for breast cancer)
- Treat is T score < -2 OR #
Androgen deprivation therapy (ie for prostate cancer)
- Treat if T score < -2.5 OR #
Antiepileptics

45
Q

How is OP treated?

A

Non pharm
- Falls prevention strategies
- Weight resistance training (loading skeleton improves bone mass)

Pharm
- Antiresorptive
-> calcium and vitamin D
-> BP
-> DMAB
-> SERM / oestrogen
- Anabolic agents
-> teriparatide

46
Q

What is def of Vit D def (mild moderate and severe)?

A

25-OH vitamin D level (not active level)
- 30-49 - mild
- 12.5-30 - moderate
- <12.5 - severe

47
Q

Vitamin D replacement for mild, mod and severe Deficiency?

A

Mild
- 1000-2000IU daily ongoing

Moderate
- 3000-5000IU daily for 6-12 weeks followed by maintenance 1000-2000IU daily

Severe
- 3000-5000IU daily for 6-12 weeks followed by 1000-2000IU daily

48
Q

Explain the risks and benefits of routine use of combined E+P HRT for post menopausal women?

A

Decreased fracture risk significantly, however increased risk of breast cancer, PE, stroke, IHD
- nil net benefit for post menopausal women, therefore not routinely recommended. Usually used in pts with premature menopause until age of normal meno, or post meno with very troubling symptoms

49
Q

What are 2x examples of SERMs? which one is more bone specific? How do they work?

A

Tamoxifen
Raloxifene is more bone specific

These bind estrogen receptors. Have estrogen effects in some tissues and blocks estrogen effect in other trissues (hence modulator)
- Raloxifene has estrogen effects in bone, but blocks estrogen in breast cancer therefore reduced risk of estrogen positive breast cancer and fracture risk

50
Q

When would you use Raloxifene to treat OP?

A

Younger women with OP (ie who are at increased risk of vertebral fractures)

51
Q

Regarding fracture risk, raloxifene only decreases risk of…?

A

vertebral fractrure risk

52
Q

Are bisphosphonates associated with reduced hip fracture, vertebral fracture or both?

A

Both
- unlike raloxifene which is just reduced vertebral fracture

53
Q

What is the target of DMAB?

A

MAB to RANK L (inhibits it)

54
Q

How is the trend in DMB on DMAB different from BP?

A

BP appear to increased BMD up to about 5 years then plateaus

DMAB appears to just keep increasing BMD (ie beyod 5 years)

55
Q

What is the main side effect of DMAB?

A

Once started, cannot be stopped (at least without exit strategy)
- therefore have to tell pt cant miss even 1 dose

56
Q

Who would u typically put on DMAB (compared to BP)?

A

Older women that will be on the drug for life
- Not women from south east asia because can have a drug holiday therefore cant mitigate risk of AFF

57
Q

What is risk of Stop DMAB? How long is the window for it to be taken (ie if taken outside this window there is increased frfacture risk)?

A

Rebound fracture risk
- 6 week window (so if moss a dose by several weeks, nil harm done. If miss a does by 3 months then at increased fracture risk)

58
Q

How does the rapid bone loss post ceasing DMAB compare to BPs?

A

If cease BP then bone mass will return to set point but over a period of 5 years instead of a few months like DMAB
- therefore drug holiday should not be more than 5 years

59
Q

Main risk of continue antiresorptive treatment?

A

ONJ
AFF

60
Q

What is ONJ? When does it usually occur?

A

Exposure of alveolar bonebone in the jaw
Usually occurs after dental extraction because this iatrogenically exposes alveolar bone
- If this persists for > 8 weeks post extraction = ONJ
- If persists for <8 weeks then suspected ONJ

61
Q

How is ONJ managed?

A

DAily antimicrobial rinses
If infected appearing then abs
If unsresolvign then surgical debridement

Most usually get better self spont

62
Q

Can AFF occur post DMAB?

A

Yes
- Any antiresorptive

63
Q

Typical prodrome for AFF?

A

Thigh pain when weight bearing for few weeks

64
Q

How does teriparatide (PTH anologue) promote bone formation?

A

Chronic exposure to high PTH leads to bone re-absorption
- however PTH first affects osteoblasts then start to affect the osteoclasts. This delay leads to an abaloic window in which bone formation is promoted and is unopposed by bone resorption
- In other words, short courses of PTH (ie teriparatide) lead to bone formation

65
Q

What is the theoretical risk of teriparatide?

A

Osteosarcoma has been demonstrated in animal studies but not in humans

66
Q

When is teriparatide usually used?

A

Pts with recurrent fractures despiute antiresoprtive use
Pts with AFF (AR ceased, teriparatide started)

67
Q

What is an example of a sclerostin inhibitor? How does this pathway work?

A

Romosozumab

OB has a signalling pathway called LRP5/wnt
- LRP5 is a co-receptor for the wnt receptor
- Activation of this pathway leads to osteoblast bone formation

There are two inhibitor of teh LRP5/wnt pathway
- sclerostin and DKK
Therfore if inhibit sclerostin with MAB -> better bone mass

68
Q

What is the only OP agent that uncouples absorption and formation of bone?

A

Romosozumab
- leads to increased bone formation and decreased reabsorption
- thought to be useful in preventing adynamic bone diseasde that is thought to underly AFFs

69
Q

What is pagets disease? Waht are the clinical manifestations? How is it Dx?

Treatment?

A

THis is characterised by increassed bone reabsorption with increased formation of disorganised bone
- central abnormality is in the osteoclast
- Cause is unclear
- Causes disorganized bone formation that is prone to fracture

CLinical features
- bone pain
- Bone deformity (bent tibia)
Fractures, complete and incomplete

ALP raised
XR shows characteristic disorganized bone appearance
Bone scan shows what is affected

Treatment is zoledronic acid
- usually cures it for at least 5 years

70
Q

How is estrogen produced? What are the two cells involved?

A

The two cells that are involved are the theca cell and the granulosa cell
- Found in the ovary

LH binds to receptor on the theca cell
-> cholesterol in the thecca cell is converted via a number of step to androstenedione

Androstenedione then travels to the granulosa cell where it is converted to estradiol via amoramtisation under the control of FSH

71
Q

In women what cell does LH and FSH act on respectivly?

A

Thecca cell
Granulosa cell

Both in ovary

72
Q

How is testosterone produced in men?

A

1 cell involved: Leydig cell
- LH binds to receptor on Leydig cell
- Cholesterol in leydig cell is converted to testosterone via two pathways, one involving to intermidiate formation of DHEA, and the other involving the formation of andostrenedione. Both pathways can make testosterone

73
Q

What is the role of the sertoli cell in men?

A

FSH acts on the sertoli cell
- promotes spermatogenesis

74
Q

Where is the receptor for estrogen and testosterone. What happen when binds?

A

steroid hormone receptors are intracellular receptor
- found in cytoplasm

When bound, complex is transported to nucleus where it regulates transcription

75
Q

Categorization of amenorhoea?

A

Primary (never had a period)
Secondary (had a period but not having anymore)

76
Q

Approach to Dx / work up of amenorhoea (primary and secondary)?

A

Hx and Ex
Bloods:
- LH, FSH, prolactin, E2 (oestridiol) and bHCG
-> Preg: bHCG elevated
-> Hypergonadotrophic hypoogonadism: high FSH, low E2
-> Hyperprolactinaemia: increased prolactin
-> hypogonadotrophic hypogonadism: low FSH/LH/E2
-> PCOS - normal hormones

May need to consider genital tract USS depending on Hx and Ex to look for genital tract abnormalities

77
Q

Bloods in hypergonadotrophiuc hypogonadism and cause? Next test?

A

FSH increased, E2 low
Turners syndrome (45X0)
premature ovarian failure

next test would be karyotype in woman <40yrs

78
Q

Bloods in hypogonadotrophiuc hypogonadism and cause?

A

Low FSH, LH, E2
Commoest cause is too much exercise and poor nutrition (functional hypogonadotrophic hypogonadism)

other causes inc
- panhypopit
- Kallamns syndrome
- Craniopharyngioma

79
Q

Pt with coarctation / aortic dissection with amenorhoea. What condition? Other features?

A

Turners syndrome

Streak gonads
Short stature
Dysmorphic features
Renal problems

80
Q

PCOS key features?

A

Menstrual irregularity (oligo or amen)
Hyperangrogenism (clinical or biochemical)
Polycystic ovaries on USS
exclusion of other causes

81
Q

Can a woman with nil cysts on ovaries have PCOS?

A

YES, unlikely but it is not strictly nec in Dx

82
Q

What conditions are PCOS pts at risk of?

A

OSA
HTN
Dyslipidaemia
CVD (IHD)

83
Q

Treatment of PCOS?

A

Depends on symptoms / complaints

Initial therapy is weight loss
Letrozole
metformin

84
Q

Commonest cause of male factor infertility?

A

is kleinfelters syndrome

85
Q

genetics of kleinfelters? clinial phenotype?

A

XXY
- small testes, tall stature, gynacomastia

86
Q

blood tests in kleinfelters?

A

elevated LH and FSH, low/normal testosterone

Endocrinology (4 decks)

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