Menopause Flashcards
What is natural menopause?
the permanent cessation of menses of 1 years duration secondary to lack of estrogen production by the ovaries
What is perimenopause?
the time period prior to menopause which is characterized by menstrual cycle irregularity, increased frequency of anovulatory cycles, & symptoms similar to menopause
-menopause transition
Differentiate early menopause and premature menopause.
early menopause: before age 45
premature menopause: before age 40
What is early natural menopause/primary ovarian insufficiency?
loss of ovarian function at a young age
POI: before 40yo, but still can have irregular or transient menstruation
What are people with early natural menopause/primary ovarian insufficiency at risk of?
symptoms from estrogen deficiency
What is recommended for women with early natural menopause/primary ovarian insufficiency?
restoring estrogen levels until natural age of menopause to prevent complications
-may require higher doses of estrogen
-also calcium, vit D, and exercise
What are some factors that may precipitate earlier onset of menopause?
smoking
exposure to toxins
chemotherapy
hysterectomy
Describe the hormonal changes in menopause.
there is an age related decrease in # and quality of ovarian follicles
-by menopause few/none remain
as a result, ovarian secretion of estradiol ceases & ovulation does not occur, so P concentrations also remain low
the pituitary increases FSH/LH in an attempt to initiate follicle development, but the ovaries cannot respond
end result: the ovaries cease to secrete E and P
this can be a slow, progressive decline over years, or a dramatic drop at once
Describe estrogen production pre-menopause.
E is mainly produced by the ovaries
other sites produce smaller amounts of E through conversion of androgens
Describe estrogen production post-menopause.
E production decreases to ~10% of premenopausal levels
the primary E is estrone
-1/3 estrogenic potency of estradiol
-produced in adipose via conversion of androstenedione
What are the symptoms of menopause?
vasomotor symptoms
sleep pattern changes
mood and cognition changes
genitourinary changes
bleeding changes
What are vasomotor symptoms?
hot flashes and night sweats
What are hot flashes?
the classic sign & major complaint of menopause
sudden onset of intense warmth that begins in the chest and may progress to the neck and face
often accompanied by visible red flushing
may also be accompanied by anxiety, palpitations, and profuse sweating
How long do hot flashes typically last?
are typically episodic and last on avg for 4 mins
What is the significance of VMS?
sweating - embarrassment
overheating - uncomfortable
night sweats - terrible sleep, terrible next day
VMS associated with:
-diminished sleep quality
-irritability
-difficulty concentrating
-decreased QoL
What causes hot flashes?
appears to be due to narrowing of the thermoregulatory system caused by changes in E levels
-postmenopausal women are thought to have narrowing of their “thermoneutral zone” - small changes in temp can stimulate the regulatory response of sweating or shivering
What are the risk factors for hot flashes?
less physical activity
family history/genetics
age of onset
induced menopause
What are the treatment options for VMS?
CBT
menopausal hormone therapy (MHT)
-estrogen
-estrogen + progestogen
-estrogen + bazedoxifene
-tibolone
nonhormonal therapy
What is the evidence for lifestyle modifications for VMS?
limited to no evidence but reasonable to suggest
What are some lifestyle modifications that can be made for VMS?
cooling techniques
-fans/AC, cool drinks, avoid hot/humid temps
avoidance of triggers
-caffeine, alcohol, spicy foods
exercise, yoga, relaxation training
-may improve overall well-being
weight loss in those who have extra weight
smoking cessation
hypnosis: limited evidence
vegan diet
What is CBT?
structured, short-term, goal-oriented form of psychotherapy
What are the benefits of CBT for VMS?
appears beneficial in reducing frequency, severity of VMS
appears beneficial for sleep
When is estrogen therapy used alone for VMS?
ET is used alone for VMS if women have had a hysterectomy
How should estrogen be used for women with VMS if they have a uterus?
combination with progestogen (EPT)
Describe the efficacy of estrogen for VMS.
ET and EPT are the most effective treatment options for VMS
Cochrane Review: decreased hot flash frequency by 77% and severity by 87% vs placebo
WHI study: 77.6% decrease in night sweats
Why must estrogen be combined with progestogen in women with a uterus?
unopposed ET for 3 yrs is associated with a 5-fold increased risk of endometrial hyperplasia or cancer
-risk is related to dose and duration of ET
-systemic P decreases this risk in a dose and duration fashion
taken together, the risk of endometrial hyperplasia is no higher than in untreated women
How should P be taken with E?
use P for a minimum of 12-14 days/month & match the dose of P to the dose of E
Which dosage form of estrogen is best for VMS?
whether its oral or transdermal, or from plant, animal, or synthetic source, all are effective
-some individuals may switch between products based on response
What is the dose needed of estrogen for VMS?
use the most appropriate, often lowest effective dose
-e.g. Premarin 0.3 mg or Estrace 0.5 mg or 17B-estradiol 25 ug
titrate dose based upon symptom relief
What is the typical onset of VMS symptom control with estrogen?
as little as 2 weeks for some, up to 8 weeks for others
-dose dependent
assess for response at 4 weeks at standard dose and 6-12 weeks for lower doses
True or false: transdermal estrogen is more effective for VMS than oral estrogen and has a greater BMD protection
false
oral and transdermal appear similarly effective for VMS
appear to provide same protection on BMD
What are the benefits of transdermal estrogen?
avoids FPE so less nausea & HA and less effect on TG
increased sex drive ?
decreased risk of DVT
decreased risk of gallbladder disease
What is a side effect of micronized progesterone?
may cause drowsiness, especially when taken with food
What are the advantages of micronized progesterone vs MPA?
observational data shows it has a lower risk of VTE and breast cancer
What is a safety concern with the formulation of micronized progesterone?
Prometrium made with sunflower oil, some generics made with either peanut or sunflower oil
-watch for allergies
Which drug is a progestogen alternative?
Duavive
-0.45 mg CE and 20 mg bazedoxifene
What is bazedoxifene?
a SERM that acts as an antagonist of E receptors on endometrial and breast tissue and an agonist at receptors in bone
What kind of drug is CE + bazedoxifene?
tissue selective estrogen complex (TESC)
What are the advantages of CE + bazedoxifene?
provides endometrial protection without the need for a P
avoids bothersome AEs of P such as breast tenderness and uterine bleeding
What is Bijuva?
a bioidentical formulation of HRT in combination format
-17B-estradiol and progesterone
evidence shows decrease in moderate-severe VMS, improved QoL and sleep quality
What is tibolone?
synthetic steroid analogue of norethynodrel (a P), which is metabolized in the body to make 3 substances that act like E, P, and androgen (weak activity)
-does not contain actual hormones
What is the evidence for tibolone?
Cochrane Review:
-more effective than placebo
-slightly less effective than EPT
What are the CIs and AEs of tibolone?
same as E and P
True or false: pregnancy can still occur in perimenopause
true
if date of last menses was < 1 yr ago, contraception may be desired
What are some options to provide VMS relief and contraception?
low dose CHC (pill, patch, or ring)
estrogen + LNS-IUS
MHT + barrier
nonhormonal tx option + progestogen-only contraceptive
Are hormonal contraceptives safe to take in the perimenopausal period?
safe to use in the perimenopausal period when contraception is required
-do not use once in menopause as the daily dose of EE is 4-5x higher than the low-standard dose required for symptom relief and bone benefit
Which perimenopausal women should avoid hormonal contraceptives?
smoke
hx of estrogen-dependent cancer
heart disease
poorly controlled BP
diabetes
blood clots
What can CHCs mask the signs of?
VMS & menstrual irregularities, this can make it difficult to know when it is safe to stop taking
- > 50 yo: stop and use nonhormonal cont. until amenorrhea x 12 mo
- > 55 yo: stop, spontaneous conception very rare
What are bioidentical hormones?
plant-derived hormones structurally identical to what is produced in the body
-compounded products may contain a mix of estradiol, estrone, estriol, DHEA, testosterone, progesterone
What are the arguments in favour of bioidentical hormones?
‘safe and natural’ (marketing)
‘custom-made’ based on salivary, serum, urine hormone tests
can compound in many different delivery routes
What are the arguments against bioidentical hormones?
individualized testing not needed as not TI drugs
desired level of hormones have not been established and may not correlate with symptoms
variable potency which could result in under/overdosing
lack safety/efficacy data
How is estrogen taken for VMS?
continuously every day
How are progestogens taken for VMS?
continuously every day or cyclically for 12-14 days/month
What is the continuous combined EPT regimen?
patient takes both E and P daily
What are the advantages of continuous combined EPT?
easy to remember
avoids the withdrawal bleeding
decreases risk the most for endometrial hyperplasia
What is a potential disadvantage of continuous combined EPT?
unpredictable bleeding may occur
-if > 6 mo: see MD
-AUB after 6 mo may indicate need for higher dose or something more serious
What is the continuous E + cyclic P regimen?
E taken daily and P is taken for 12-14 continuous days per cycle
What usually occurs after the last dose of P when P is used cyclically?
withdrawal bleeding within 1-2 days
When might continuous E + cyclic P regimen be preferred?
prefer fewer pills
recent menopausal who do not want breakthrough bleeding
What are common AEs of estrogen?
nausea
breast tenderness
headache
bloating
vaginal bleeding in 1st 3-6 mo
What are common AEs of progestins?
irritability
breast tenderness
bloating
headache
PMS-like symptoms
vaginal bleeding in 1st 3-6 mo
How are the AEs of estrogen and progestins managed?
often dose related
change products
What are the contraindications with MHT?
unexplained vaginal bleeding
active liver disease
estrogen-dependent cancer
pregnancy
active thromboembolic disease
untreated/uncontrolled CVD
What is a caution for MHT?
high cancer risk
When should we consider non-oral E?
hypertriglyceridemia
hepatobiliary disease
migraine
established CVD
past VTE
diabetes
advanced age and no previous MHT
When are SSRIs or SNRIs used for VMS?
when HT is CI or not desired
What is the efficacy of SSRIs and SNRIs for VMS?
less effective than HT but still efficacious
Which SSRIs and SNRIs can be used for VMS?
paroxetine
citalopram
escitalopram
venlafaxine
desvenlafaxine
Which doses of SSRIs and SNRIs are often effective for VMS?
low doses often effective
What is the onset of SSRIs and SNRIs for VMS?
quicker than depression
-2 to 4 weeks
What is fezolinetant used for?
moderate-severe VMS associated with menopause
What is the MOA of fezolinetant?
nonhormonal selective neurokinin 3 receptor antagonist
What are common AEs of fezolinetant?
headache
liver enzyme elevation (monitor)
abdominal pain
insomnia
nausea
Asides from SSRIs and SNRIs, what are some other nonhormonal options for VMS?
clonidine
-modestly effective: 38% decrease vs 30% placebo
oxybutynin
-can reduce hot flash frequency by up to 77%
gabapentin
-decreased hot flashes by 20-30% (meta-analysis)
pregabalin
-limited data; one study showed decreased by 65% vs 50% placebo
What is the conclusion on herbal products for VMS?
evidence points to either conflicting results or no better than placebo
-some evidence for isoflavones and black cohosh
What happens to BMD post-menopause?
estrogen deficiency causes accelerated bone loss by increasing bone turnover and resorption
What is the indication of estrogen in osteoporosis?
prevention of osteoporosis only - not treatment
-can reduce fracture risk in various sites by 24-39% in postmenopausal women
What are the dose effects of estrogen on bone?
effects on bone protection are dose-related
-standard dose HT reduces risk of osteoporotic fracture
-low dose HT beneficially increases BMD
What happens to the benefits of estrogen therapy on bone after discontinuing treatment?
benefits on fracture risk dissipate
-return to pre-treatment levels in 1-2 yrs
When is systemic HT an appropriate therapy to protect against bone loss?
in the absence of CI in women < 60 yo or within 10 yrs of menopause onset
What are the effects of estrogen and progestins on lipids?
oral estrogen:
-decrease LDL, increase HDL, increase TG
topical estrogen:
-decrease LDL, increase HDL, TG neutral
MPA daily or cyclical:
-blunt good lipid effects of estrogen
micronized progesterone daily or cyclical:
-lipid friendly
What are the effects of estrogen on the CV system?
- causes vasodilation with short-term use
- with long term use:
-decrease LDL, increase HDL
-lowers fibrinogen
-lowers plasminogen-activator inhibitor type 1 - countering this is its effects on inflammation and markers of thrombosis
What does the meta-analysis of observational studies on HT suggest regarding HT and CVD?
use of HT in younger women (<60yo) within 10 years since menopause has a beneficial effect on reducing CVD, or at very least does not increase CHD risk
What is the timing hypothesis?
in younger (<60yo) healthy women & < 10 yrs since menopause transition, there is no increased CHD risk
-if > 10 yrs post menopause or > 60yo: increased risk of CHD, VTE, and stroke vs earlier initiation
-older women starting HT and women who are further away from their final menstrual period appear to be at greater risk of a CV event vs those who are younger and those who initiate HT closer to their menopause
What is the evidence regarding stroke and MHT?
no increased risk with MHT if initiated < 10 yrs and < 60yo
higher incidence if initiated later
What is the evidence regarding VTE and MHT?
increased risk regardless of < 10 yrs or > 10 yrs
How can we address risk factors for stroke and DVT before deciding to initiate HT?
high risk: avoid HT and use non-hormonal
medium risk: lower E dose, transdermal, non-hormonal
transdermal ET may confer less stroke and DVT risk
MP may be less thrombogenic than MPA
What is the relative risk of breast cancer with MHT?
risk increases with longer duration
risk persists for those on EPT but no effect on breast cancer mortality, trend persists for those on ET
studies are lacking with regard to breast cancer risk with long term use
What is the suggestion regarding HT and women with prior breast cancer history?
systemic HT is not generally advised
-low dose vaginal therapy provides minimal systemic absorption for GSM symptoms in breast cancer survivors
What is the duration of treatment of HT?
unknown
individualize - used to say 5 yrs
now, the safest regimen at appropriate dose to control sx
re-assess yearly to see if still needed
What is the hallmark symptom of the menopause transition?
sleep disorders/insomnia
-both sleep onset and maintenance insomnia are increased during (peri)menopause
-interfere with QoL, cause daytime fatigue, irritability, and impaired cognition
What is the management for sleep disorders?
general insomnia recommendations
-CBT, valerian, hypnotics, ADs
MHT may help in those experiencing VMS
What kind of mood symptoms might women be more vulnerable to during menopause transition?
depression, anxiety, irritability
-may be due to E depletion, deficiency, or changing lvls
women with mod-severe VMS up to 3x more likely to have mod-severe depressive sxs
What are the effects of E on brain function?
+ effects on serotonergic activity
increases the activity of NA
E receptors in brain regions responsible for learning and memory
increases cerebral blood flow
What is the therapy for mood symptoms?
ET may improve depressive sx in perimenopausal women and may augment clinical response to SSRIs
use of ADs and psychotherapy remains the mainstay of tx for mood disorders and anxiety
What are the changes in cognition seen with menopause transition?
anecdotally women often report experiencing memory changes, decreased concentration
What is the use of HT for cognition and dementia?
HT is not recommended to preserve cognitive function or prevent/tx dementia
-initiation > 65 yo may increase the risk
How does menopause contribute to urogenital aging?
there are many E receptors in vagina, vulva, urethra, and bladder
decrease in E levels may cause changes such as
-tissue atrophy
-reduced secretions
-reduced blood flow
-vaginal pH increase to 6-8
a decrease in E can result in vaginal sx (in addition to tissue aging)
What do GSM refer to?
signs/sx resulting from E deficiency to GU tract
What are the common GSM symptoms?
vaginal dryness
vaginal itching/irritation
burning
painful intercourse
lower urinary tract sxs
nocturia, dysuria
onset varies
What is 1st line line for GSM?
non-hormonal lubricants
-for dryness and dyspareunia
-can use pre-intercourse or continuously
Differentiate when to use a lubricant vs a moisturizer.
lubricants: use with intercourse
moisturizers: use regularly (2-3x/week)
-goal is to reduce daily sxs and make intercourse comfortable
How effective are vaginal estrogens preparations for GSM?
reduce GSM symptoms by 60-80%
Describe the safety of vaginal estrogen preparations.
minimal systemic absorption, hence less concerns with use
-risk of VTE, CVD does not seem to be increased
-rates of endometrial cancer appear to be consistent with general population
-does not appear to be associated with increased breast cancer risk
Are progestogens needed alongside vaginal estrogens?
at recommended doses (low), an accompanying progestogen is not needed
What can be tried for GSM if OTC agents are ineffective?
vaginal estrogen
prasterone
ospemifene
What are the benefits of intravaginal estrogens?
GSMs symptoms such as dryness and dyspareunia
preventing recurrent UTI and managing incontinence
Do vaginal estrogen tablets have systemic absorption?
minimal
What are the common side effects of local vaginal products?
local burning/irritation
leakage (hs dose)
Which local vaginal product has the greatest efficacy for GSM?
efficacy is similar for all
When should improvement of GSM be seen with local vaginal products?
a few weeks
-up to 12 weeks for max benefit
-assessed at 3-6 months, then yearly typically
What can be tried if someone is experiencing VMS and GMS?
oral MHT would be trialed as in addition to helping VMS sx, it will also help with the GSM sx as well
True or false: intravaginal estrogen and systemic MHT can be used together
true
What is prasterone?
synthetic form of DHEA that has no E or A activities
-when administered intravaginally, the cells of the vagina convert it into E and A where they act locally, thus avoiding exposure of other tissues to these hormones
What are the side effects of prasterone?
well tolerated
-melting of the hard fat may cause discharge
When might prasterone be tried?
an alternative for women who do not want to use or have CI to estrogen
What is ospemifene?
a nonhormonal SERM
-has a weak agonist effect in the endometrium, activates estrogenic pathways in vulvar and vaginal tissues and bone, and blocks pathways in breast (antagonist)
Is ospemifene co-administered with a progesterone?
not co-administered with a progesterone
What are the side effects of ospemifene?
hot flashes
-do not administer with E
What causes the weight gain seen in menopause?
decreased metabolic rate that occurs with aging
-not MHT
-avg weight gain of 1.5 lbs/yr
What happens to the skin with menopause?
skin collage content, thickness, and elasticity declines
What is AUB?
abnormal uterine bleeding
-common during the menopause transition period
-prolonged cycle intervals as well as variable bleeding patterns precede eventual amenorrhea and menopause
What are the potential causes of AUB?
dysfunctional uterine bleeding which results from anovulation
endometrial hyperplasia and cancer
benign lesions (endometrial polyps)
What are the therapeutic options for AUB?
treatment is aimed at regular bleeding patterns
-low dose OCPs (20 ug EE)
-progestin therapy (intermittent or continuous)
What kind of bleeding needs to be investigated in menopause?
any bleeding after 12 months of amenorrhea is considered post-menopausal bleeding and should be investigated
any unscheduled bleeding after > 6 mos of hormonal treatment should be investigated
