Menopause, ageing, osteoporosis Flashcards
menopause is
iatragenic menopause definition
menopause= the permanent ceasing of menstruation, a part of ageing process for women
usually early 50s. process usually gradual, wax and wane over years
iatragenic menopause= by surgery, radiotherapy, chemo etc. Ovaries removed or stopped from working
perimenopause
menopause/ postmenopausal
premature menopause
perimenopause= from beginning of menopausal symptoms to postmenopause
menopause= no menstrual periods 12 months
premature menopause= menopause before 40
describe the hormonal changes and follicular changes in perimenopause
number and responsiveness ovarian follicles declines over 40
leads to decrease in oestrogen and inhibin secretion, so negative feedback on GnRH and FSH, LH
so FSH and LH levels increase
leftover responsive follicles increase oestrogen in response
so oestrogen production may be erratic, levels fluctuating normal high and low
hormone changes in menopause/ postmenopausal
when no more responsive follicles, negative feedback loop is disrupted. FSH and LH levels stay high, stimulate ovarian stromal cells to synthesise androgens (high FSH is therefore a sign of menopause)
in postmenopause, oestrogen derived from ovarian stroma and adipose tissue, androgens aromatised to oestrogen, but a less active form
what tissues are oestrogen dependent
ovary endometrium breast bone fat blood vessels hair colon (testes)
acute clinical sympotoms of menopause
cessation of menses
vasomotor symptoms- hot flushes, night sweats
mood swings, depression, forgetfulness
headaches
explain hot flushes in menopause
70-90% of women experience
hot flushes= vasodilation in face and neck, lasting 1 to 5 mins with profuse sweating
thought caused by narrowing of hypothalmic thermoregulatory set point
- increasing chance sensitivity to intense heat in response to int and ext environmental triggers
- activates heat loss responses ie vasodilation
medium term symptoms of menopause
urogenital atrophy-
vulval, vaginal, urethral, bladder all oestrogen dependent, loss of leads to thinning of epithelium, atrophies
vagina and vulva- dryness, itching, discomfort
bladder- changes in pH, raised vaginal pH, increased bacterial growth so recurrent UTIs
increased risk urinary incontinence/ urgency/ leakage
Sexual problems-
vaginal dryness may cause painful intercourse. loss of libido.
thinning of skin, brittle nails, generalised pains
long term impact menopause on obesity
prevalence obesity higher in post m than pre
menopause causes increase in total body fat
redistribution of fat from peripheries to trunk
if combine w loss of muscle mass and inactivty- obesity and higher risk diabetes type 2
long term impact menopause cardiovascular
oestrogen is vasoactive so promotes vascular remodelling and elasticity so is able to regulate vasodilation and local inflammation
without oestrogen have more vasoconstriction, inflammation so arterial stiffness. may cause atherosclerosis and hypertension
early menopause incr risk of coronary heart diseas, stroke, death
impact menopause on mood
menopause causes decline in synthesis of NTs eg acetylcholine, serotonin, dopamine
results in lo mood, irritability, insomnia
how is diagnosis of menopause made in over 45s
in women over 45 on clinical symptoms alone,
perimenopause- vasomotor symptoms, irregular periods
menopause- no period 12 months AND not on hormonal contraception
if without uterus, based on vasomotor symptoms
how is diagnosis made in under 45s
other conditions need to be excluded, incl PCOS, hypothalmic. pituitary problems so FSH test (u40s do 2 bloods spaced)
not used in UK but
AMH and antral follicle count on ultrasound indicates
types of oestrogen and progesterone drugs delivered in HRT
oestrogen:
oestradiol
conjugated equine oestrogen
Progesterone:
norethisterone
progesterone
what type of HRT is most likely to cause cancer
oestrogen only has 45% incr risk endometrial cancer
if take prog and oestrgen then reduced to 15%
HRT regimens
oestrogen continuously by itself- only if no uterus as othw 45% incr cancer
continuous combined regimen
sequential combined regimen- prog given sequentially for perimenopausal- 2 weeks on 2 weeks off or 3 months on 2 weeks off, useful to maintainperiods so know when enter menopause
HRT routes
oestrogen:
transdermal (patch/ gel) (local skin irritation)
oral (cost-effecive, acceptable)
vaginal oestrogen- cream, tablets, vaginal rings (for urogenital symptoms)
progesterone:
micronised progesterone
oral derivatives
mirena coil
if HRT not effective for sexual desire, testosterone
benefits vs risks HRT
benefits: vasomotor mood and sleep urogenital atrophy osteoporosis
risks:
breast cancer
stroke, venous thromboembolism
ovarian cancer
HRT re breast cancer
risk greater prog and oestro vs oestro alone
risk increases with duration HRT use
h/e lifestyle factors can increase risk just as much so maybe worhty risk
HRT re venous thromboembolism
increases w age and duration HRT
highest with oral oestrogen
no risk with non-oral oestrogens, or micronised progesterone
obesity, smoking also risks
HRT re cardiovascular disease
has beneficial effect at earlier age
in young postmenopausal, oestrogen alone is cardio protective, reduces risk CHD u60
incr risk CHD if start more than 10 y after menopause
h/e combined HRT increases risk CHD, stroke 2.2 times
shouldn’t be used for cardio protection
contraindications HRT
pregnancy undiagnosed vaginal bleeding active or recent VTE/ heart attack suspected/ active breast or endometrial cancer acute liver disease
alternative therapies in leieu HRT
lifestyle:
exercise, lighter clothing, stress reduction, trigger avoidance (caffeine smoking)
vaginal moisturisers, lube, herbal remedies
how common is premature ovarian insufficiency and what to do about it
in in 100 under 40
1 in 1000 under 30
1 in 10000 under 20
HRT recommended unless contraindicated, until age of natural menopause, to improve physical and psychosocial health
osteoporosis is
osteopenia is
osteoporosis is the loss of bone substance, such that fractures of non-traumatic origin are sustained
BMD 2.5 SDs or more below a normal, healthy control. osteoporosis is a disease of bone remodelling
Osteopenia is 2.5 to 1 SD below normal healthy control
how is BMD measured
bone mineral density is measured with DEXA, dual energy x ray absorptiometry, of lower spine and hips
x ray sent via 2 energy streams. 1 stream absorbed by soft tissues, other denotes total absorption. Subtract soft from total= bone results.
bmd computed over area measured
why is bone remodelling important and what is it a balance of
formation and maintenance of skeleton depends on balance between bone formation (osteoblasts) and bone resorption (osteoclasts)
bone remodelling is essential as removes defective bone and responds to mechanical pressure
define bone modelling vs bone remodelling
bone modelling: responsible for growth and shaping of bones during childhood and adolescence
bone remodelling: responsible for maintaining mechanical integrity of skeleton during adult life
why is menopause a risk factor for osteoporosis
oestrogen usually enables osteoblasts and inhibits osteoclasts.
menopause causes sudden increase in osteoclast activity and accelerates below process
in osteoporotic post menopausal, problem is with osteoBlasts
osteoblasts no longer able to catch up with activity of osteoclasts, causes deficit in BMD
action of oestrogen on osteoblasts
oestrogen has positive effect on osteoblasts
- increases collagen type 1 synthesis
- stimulates growth factor synthesis
- regulates osteoblast proliferation
- stimulates expression of osteoblast differentiation and maturation markers
action of oestrogen on osteoclasts
oestrogen has negative effect in osteoclasts
increases apoptosis of osteoclasts
suppresses osteoclast differentiation
acts on osteoclasts via osteoblasts
how is osteoclast differentiation and maturation usually stimulated
- RANK is receptor on osteoclast precursor cell, is an effector molecule, acts on DNA to stimulate maturation
- RANKL (RANK ligand) is located on osteoblast
- RANKL is stimulated to bind with RANK receptor (by IL1, TNF, Vit D, PTH, PTHrp)
- this promotes osteoclast maturation and differentiation
how does oestrogen interfere with osteoclast maturation and differentiation
- oestrogen promotes synthesis of OPG (osteoprotegerin)
- OPG is a decoy of RANK receptor so RANKL binds with OPG instead of RANK
- prevents osteoclast maturation and so formation of active osteoclasts
why don’t all women get osteoporosis
1 in 3 women do
in both m and w, bone mass deteriorates w age
after 45 starts to diminish, women at accelerated rate
if have a higher bone mass before the decline will be less impacted
peak bone mass is influenced by diet and vitamins and ethnicity- white women and asian women do worse
why can’t we take a blood test for osteoporosis
bone markers don’t appear abnormal as very diluted in blood sample
also remodelling process takes 9 months so may be too early to see
osteoporosis in men
1 in 12 men
higher morbidity and mortality
also assoc with falling oestrogen levels
may see osteoporosis when oestrogen receptor mutation or aromatase mutation
outline vitamin D and calcium regulation
vitamin d: sun on skin, vitamin D3 formation from cholesterol base, goes to liver and is hydroxylated to parent molecule then metabolised to active form of D£
calcium regulation:
1. decrease in calcium causes increase in parathyroid hormone PTH synthesis switches off
how do corticosteroids affect calcium regulation
corticosteroids cause calcium resorption to be shut off in the gut
PTH levels and vit D levels continue rising, act on bone to release calcium
may eventually be shut off but may not
only see with high, continuous corticosteroid use
how else do corticosteroids affect bone and so total effects are
act on osteoblasts to decrease activity, decreasing collagen 1 synthesis
this reduces osteoblast numbers
in all, corticosteroids cause calcium to be released from bone and reduce number and activity of osteoblasts so bmd loss
osteoporosis treatments
HRT for women with osteoporosis (no longer in favour)
Bisphosphonates, iv or oral- decrease osteoclast activity. side effect of osteonecrosis of jaw. oral incr stomach acidity so not well tolerated
SERMS- selected oestrogen receptor modulators
supplementation calcium and vit D
intermitent PTH enhances bone formation (if give continuously increases osteoclast activity)
denosumbad- monoclonal antibody for RANK protein. sits on RANKL, inhibits it binding to RANK receptor, much like OPG. therefore inhibits osteoclast activity
pharma- changes to absorption with age
not much change
some reduction in secretion of gastric acid and enzymes in GI tract
reduced total SA, but compensated for by some slowing of gastric emptying and motility
pharma- changes to distribution with age
when older- loss muscle mass, loss total body water, increase body fat, total body mass often decreased
SO
lipid soluble drugs:
- bc more fat, greater volume of distribution
- can accumulate in fat and brain tissue and have prolonged effects
water soluble drugs:
- bc less water, smaller volume of distribution
- can lead to higher conc serum levels, beware toxicity if drug has narrow therapeutic index
pharma- changes to metabolism of drug with age
not lots
reduced hepativ blood flow and volume- may cause reductionin metabolism of some drugs or increase bioavailability of others. reduced first pass metabolism
pharma- changes to excretion of drug with age
renal function reduces with age
may lead to reduced clearance of drugs which are excreted by kidney filtration so may lead to drug and metabolite accumulation an toxicity- may need dose reduction for renally cleared drugs
pharma- changes to pharmacodynamics with age
increased pharmacodynamic sensitivity to many drugs so
increased pharmacological effects
increased susceptibility to ADRs/ side effects
increased risk toxicity
often need lower doses
polypharmacy
use of multiple meds by a pt, usually 5+
v common in elderly as have an ageing pop living w more lifelong chronic conditions instead of dying
often working with specialists in isolation
how may polypharmacy be inapproporiate or appropriate`
appropriate:
medicines used are optimised
each achieves its benefit
no ADRs or interactions
problematic:
multiple prescribed inappropriately
intended benefit not achieved
ADRs/ interactions
impact of polypharmacy in older
increasing number of prescribed drugs increases risk ADRs and side effects, drug- drug interactions
older pts more susceptible to ADRS and interactions due to changes in pharmacokinetics and pharmacodynamics
ADR of a med may be misdiagnosed as an illness and prescribed more meds, etc
prescribing cascades
new drug prescribed to treat unrecognised ADR/ symptom between existing meds and diagnosed new condition, cycle goes on
how to prevent polypharmacy
only prescribe in necessary and pt agrees
consider NNT vs NNH as to whether it is worth it
consider deprescribing
review regularly
explain all clearly
use a limited formulary
start low and go slow
NNT
avg number pts who need to be treated to prevent one additional bad outcome
NNH
how many pts need to be exposed to risk factor over a specific period to cause harm in 1 pt
what is an iatrogenic illness
caused by medical trtmnt
prednisolone is?
a corticosteroid
bendroflumethiazide is?
a thiazide like diuretic- for hypertension
meds that increase fall risk
antihypertensives
diuretics (both lower bp, falls post hypertension)
hypoglycaemics
sedatives, hypnotics
opioda
antideps
antipsychs
sedating antihistamines
anticholinergics/ antimuscarinics
how do corticosteroids work and what are they
synthetic versions of hormones produced by adrenal glands
2 modes of action:
inhibit immune system, so useful for autoimmune conditions
suppress inflammation so useful for inflamm conditions
anti inflammatory effects of corticosteroids
inhibit vasodilation and increase vascular permeability– fluids can’t enter site, decr swelling
reuced number circulating lymphocytes, inhibits their emigration to site
inhibit cytokine expression eg IL1 and TNF, integral to mediated response
inhibit production phospholipidase, prevents formation of inflamm mediators
corticosteroid ADRs
occur with prolonged use of high doses
cushings disease
cushingid appearance oedema sleep disturbance hypertension osteoporosis diabetis mellitus cataracts
good prescribing of corticosteroids
use minimum dose that achieves desired effect for minimum duration to limit long term risks
taper dose before stopping for courses over 3 weeks to prevent withdrawal and allow adrenal glands to start secreting cortisol again to prevent relapse
if using high dose/ long term, consider bone protection (biphosphate) and gastric protection (proton pump inhibitor)
what is the disability free life expectancy gap difference poor vs rich
amount of years disability free before death is smaller in poorer
equal m and f
majority poorer will have disability before pension age
how may exercise reduce fall rate and frailty
what exercise
reduces by 20%
improves balance
strengthens muscle and bone so fewer breaks
reduces risk of symptoms of conditions
helps continue everyday activities and remain independent
improves brain function
should combine weight-bearing activity with impact and muscle strenghtening
what % UK pop is over 65
what % of those admitted to hospitals are over 65
25% UK are over 65
65% hospital admissions over 65
what are the biological, programmed theories of ageing
programmed longevity- sequential switching off of genes
endocrine theory- biological clocks
imunological theory- measurable decline in immune function as age so susceptible to deathly infection
what are the biological, damage/ error theories of ageing
hayflick limit- wear and tear
free radical theory- longer around, the more damage to cells and organs
glycation theory- glycation end products cause cell damage
somatic DNA damage theory- DNA mutations accumulate w more division
what are the evolutionary theories of aging
antagonistic pleiotrophy- genes have beneficial effects early and detrimental later on
disposable soma thoery- trade off between maintenance and repair vs reproduction
what are the cardiovascular effects of ageing
atherosclerotic change in arteries- walls thicken and elasticity reduced
baroreceptors less sensitive- postural bp control worse
heart valves thicken
apoptosis atrial pacemaker cells
decreased esponsiveness to adenoreceptor stimulation
decrease in maximal achievable HR
what are the musculoskeletal effects of ageing
skeletal muscles lose cells and weight
lose more fast twitch than slow twitch fibres so less explosive
hormone loss and denervation atrophy
exacerbated by inactivity/ hospital
decreased BMD
cartilage thins
ligaments less elastic
what are the vision and hearing effects of ageing
lens stiffens- difficulty focussing cloce lens denser- reduced night vision retina less sensitive to light pupils react slower presbyacuisis- less high pitched hearing
what are the nervous system effects of ageing
cerebral blood flow decreases
10% loss in brain weight
more susceptible to damage
some slowing of thought and reflexes from 30
what are the immune system effects of ageing
immunosenescence so everything is reduced
what are the GI system effects of ageing
taste buds lose sensitivitiy gums recede and less saliva food empties stomach slower liver loses cells and reduced blood flow so more toxins and side effects gut transit time decreases
what are the renal effects of ageing
nephron number declines 30-40% kidneys shrink less efficient clearing waste men- prostatic hypertrophy women- urinary incontinence
what are the endocrine effects of ageing
GH levels decrease
reduction in insulin sensitivity, inc diabetes type2
reduction adrenal hormones
female menopause
frailty is
frailty results in
a state of increased vulnerability to poor resolution of homeostasis after a stressor event, which increases the risk of adverse outcomes
not all frail. but frailty increases prevalence with age
someone who is frail will take longer to recover than a fit person and may never return to previous level of functional abilities
what is the clinical frailty scale
goes 1. very fit to 9. very severely frail to 9. terminally ill
useful to know as those more frail have worse outcomes so need to consider
what is the comprehensive geriatric assessment
treatment approach. uses an MDT considers all when choosing options- medical problems mh function social circumstances environmental assessment
has reduced mortality and functional decline and reduced care home admission
ways to manage an infection
symptomatically if viral topically if superficial removing focus of infection surgically immunotherapies antimicrobials
antibiotics target?
antibiotics may also be c…. or s…..?
different classes have different targets within bacteria eg
cell wall synthesis (broad spectrum antibiotics)
nucleic acid damage
protein synthesis
folic acid metabolism
antibiotics may be cidal (kill bacteria) or static (immobilises so immune system can deal with them)
types of antibiotic therapy
empiric therapy: treat per guidelines prior to firm diagnosis
typicall broad spectrum
based on international clinical trials and local epidemiology
targeted therapy: initiate when culture report available or switch to
therapy: using antibiotics to treat the infection
pre-emptive therapy: use antibiotics to treat presumed infection
prophylaxis: prevent development of infection
infection prevention measures
prophylactic use of antibiotics is OK in certain groups but very limited
decontamination PPE sharps management waste disposal laundry
isolation of pt severe, made by infection specialist
antimicrobial stewardship
antimicrobial stewardship
aims to ensure appropriate antibiotic use
the right drug at right time adt right dose via right route for right duration for right patient
what are the signs of inflammation
redness swelling heat pain
severe- loss of function
can also be signs of infection
what are some signs of infection
signs of inflammation suppuration (pus) necrosis lymphoadenopathy fever, rigors fatigue, headache, weakness etc
staphylococci
gram positive cocci in groups
facultative anaerobes- fine in aerobic but do better anaerobic
classified acc to ability to coagulase serum
—- staph aureus is coagulase positive
coagulase negative are less pathogenic
common in medical device infections, UTIs
staph aureus
gram positive cocci in groups, coagulase positive
seen in superficial skin lesions, localised abscesses, eczema infection. Deep seated infections like pneumonia, osteomyelitis, endocarditis etc
food poisoning via toxins and toxic shock syndrome
assoc with Panton Valentin toxin (PVL)
major cause hospital acquireed infections of surgical wounds
MRSA
methycillin resistant staph a
resistant to many antibiotics (is an XDR), typically resistant to several classes, especially glycopeptides
usually treated with vancomycin, but some vancomyic resistance has been reported
antibiotic resistance may develop how
- natural resistance- an inherent trait that renders it resistant
- acquired resistance- by means of mutation of transfer of plasmids
mechanisms of antibiotic resistance
- chemically modify the antibiotic with enzymes
- activate the cells efflux pumps and physically remove antibiotic from cell
- modify target sites so not recognised by antibiotics
MDR XDR PDR antibiotic resistance
MDR multi drug resistance, 1 or more drugs in 2 classes
XDR, extensively drug resistant, 3 or more classes
PDR, pan drug resistant, all drugs and classes
