Menopause 1.4 Flashcards
What age is early menopause?
40 to 45 years
How is menopaused diagnosed?
After 12 months of amenorrhea
Usual age of menopause?
From 45 to 55 years
> average 50 years
Why does menopause occur?
Menopause occurs because the ovaries run out of eggs
> Each ovarian follicle contains a single oocyte
> A female infant is born with ~300 000 ovarian follicles
> By ~37 years of age ~ 25 000 ovarian follicles
> At menopause few or none remain
What are some of the hormones that change due to loss of ovarian follicles?
- Decrease ovarain hormones (oestrogen and progesterone)
- Increased FSH
- No acute change in androgens
What are some factors influencing menopause?
What does FSH and LH do?
FSH: Stimualtes follicles (contains egg) in ovaries to produce estrogen, when estrogen reaches a certain level –> brain signals pituitary to turn of FSH and produce LH
LH: LH then stimulates the ovarie to reduce egg from follicle = ovulation
> left over follicle produces progesterone and estrogen in preparation for pregnancy
> as estrogen and progesterone increase, FSH and LH drop. If pregnancy doesn’t occur, progesterone level falls and menstruation occurs.
What are some other methods in which menopause can occur?
Chemotherapy-induced & radiotherapy-induced menopause
- Sometimes periods can stop, but can return after some months, depending on a woman’s age and the type of chemotherapy received
Surgery-induced
- Removal of ovaries –> due to endometriosis or ovarian cancer ( can be prophylactic)
- Hysterectomy = uterus removed –> don’t necessarily go straight into menopause if ovaries are not removed
- Surgical menopause symptoms are liekly to be more severe
What does the arisal of menopause symptoms come from?
Many women will experience symptoms associated with a lack of oestrogen both in the perimenopausal and postmenopausal phase
What are symtpoms associated with lack of estrogen in menopause?
Vasomotor symptoms (VMS)
Psychological problems
General physical
Urogential and sexual –> occur later. Loss of estrogen causes loss of collagen and elastin.
What are some vasomotor, psychological, general physical and urgoenital + sexual symptoms that are found in menopuase?
Is there are a age limit at which menopausal symptoms cease?
No
What are some things associated with hot flushes and night sweats that 85% of women experience?
Most troublesome in the year around the final menstrual period
Feeling of heat that usually starts in the chest and spreads upwards to the neck and head
- Come and go
- Seconds to minutes
- Can be associated with sweating
- Some experience simultaneous racing or pounding heartbeats
- Many feel self conscious
Night sweats = night-time hot flushes with profuse sweating
> result in night awakenings and poor sleep
What do 50% of menopausal women experience?
Hot flushes and night sweats
Who is more likey get hot flushes?
Overweight and obese
For vasomotor symptoms, why are they often underestimated?
- Negative impact on QOL
- Length of time that they can last
What are some hot flush triggers?
- Drinking alcohol
- Consuming products with caffeine
- Eating spicy foods
- Being in a hot room
- Feeling stressed or anxious
- Wearing tight, heavy clothing
- Smoking or being exposed to cigarette smoke
- Bending over
Are there cogntivie changes in menopause? What is the actual reason behind this?
Evidence inconsistent
> Gradual decline in cognitive function expected as part of normal aging
- However gradual decline in cognitive function expected as part of normal aging
Cognitive changes related to estrogen withdrawal include:
- Deficits in verbal and working memory
- Almost 75% of women having a subjective sense of memory loss
- More likely associated with perceived stress or depressive symptoms than perimenopausal stage
Why does depression and anxiety occur in depression?
Employment status may have changed, children may have left home, gain weight and higher BMI
- Common and many risk factors, but hormones may play a role
> Dysregulation of 5HT & NA pathways due to changing oestrogen levels
- Perimenopause -period of ↑ vulnerability
> ↑ risk with previous depressive episode
> Hot flushes not necessary to development of depression
Why does sleep disturbances occur in those with menopause?
Sleep quality deteriorates with aging
Menopause adds to issue
More women report sleep issues as they enter perimenopause
Factors include:
> hormones
> sleep hygeine
> mood disorders
–> can occur with or without night sweats
Why do urogenital problems arise in menopause?
Urogenital tissues –> sensitive to oestrogen and fluctuations in oestrogen during perimenopause
> fragile tissue and distressing symptoms
> 20-67% report moderate to severe symptoms of vaginal dryness or dyspareunia
Other symptoms: vaginal atrophy, narrowing and shortening of vagina and uterine prolapse
- Urinary tract contains oestrogen receptors in urethra and bladder
> urinary incontinence
What are the adverse metabolic and health effects that occur because of fal in oestrogen
metabolic
cardiovascular
skeletal
Metabolic
- Central abdominal fat deposition
- Insulin resistance and increased risk of type 2 diabetes
Cardiovascular
- Impaired endothelial function
- Increased cholesterol
Cardiovascular disease leading cause of morbidity and mortality in post-menopausal women
Skeletal
- Accelerated bone loss
- Increased fracture risk
What are some other midlifehealth changes that occur in menopause?
- Gain 2-5kg in menopause
- Hair loss and hair growth
- Skin changes with menopause = more wrinkling and dryness
- During menopause estrogen levels decrease in the body breaking down bones at a faster rate –> may lead to osteoporosis
QOL in menopause?
As life expectancy increases so does the time women spend in menopause n
Currently a women can expect to live about 35% of her life in a post-menopausal state n
The quality of life of women entering menopause at earlier ages is thought be more adversely affected.
How is diagnsosis of menopause done?
Measuring hormone levels is unhelpful n
Diagnosis is via history taking (symptoms & changes in menstruation) n
Perimenopause lasts on average 4 to 8 years
One year after the last menstrual period a woman is considered post-menopausal
Symptoms scores can be a useful diagnostic tool
Differential diagnosis
- Depression, anaemia and hypothyroidism are the most common conditions that mimic menopausal symptoms
- SSRIs can cause hot flushes
If a patient is taking hormonal treatments it can be difficult to know when menopause is reached
> HRT doesn’t provide contraceptive cover. If women still ovulating there is a risk of pregnancy.
What are the treatment options for menopause?
Non-pharmacological measure (lifestyle)
Menopausal Hormone Treatments (MHT)
Non hormone pharmacological treatments
Complementary & alternative medicines (CAMs)
How to cope with menopausal symptoms?
- Balanced and nutritious diet
- Exercise
- Relaxation
> women with healthy lifestyle appear to have fewer symptoms
Lifestyle changes for menopause?
- Quit smoking
- ≤ 2 standard alcohol drinks per day and two alcohol free days per week
- Reduce caffeine
- Keep cool/wearing layers
- Avoiding triggers of VMSs
How reduce the risk of osteoporosis during menopause?
Aim for 1300mg of dietary calcium
Weight bearing physical exercise
Adequate Vit D – follow sun exposure guideline
Avoid excessive alcohol
Stop smoking
Avoid excessive caffeine
What are options for menopausal hormone treatments?
oestrogens
- Conjugated oestrogens
- Estradiol
- Estriol
progestogens
- Medroxyprogesterone n
- Norethisterone n
- Levonorgestrel IUD n
- Micronised progesterone
TSECs
- Bazedoxifene + conjugated oestrogens
tibolone
testosterone
How does oestrogen help with menopause?
Relieves symptoms including VMSs and urogenital atrophy caused by ↓ endogenous oestradiol production
How does progestogen help with menopause?
Reduces risk of endometrial cancer associated with unopposed oestrogen
Outline when and for what patients the below drugs are used for in menopause (MHT)
A) oestrogen only (unopposed oestrogen)
B) combined therapy (oestrogen and progesterone or bazedoxifene)
C) tibolone
A)
- Estrogen taken continuously
- Recommended in women post-hysterectomy (no uterus therefore not at risk of uterine cancer)
B)
- Recommended in a women with uterus
- Can be cyclical or continuous
- *Bazedoxifene continuous only
> last menstrual period under 2 years or withdrawal bleeds or spontaenous bleeding. Use daily estrogen and progesterone.
C)
- Suitable for postmenopausal women and women who have had a hysterectomy
- Taken continuously
- Alternative when progestogen-containing combined MHT is not tolerated
- Also 1st line
What are the benefits and risks for the following routes for MHT?
A) Oral
B) Intrauterine
C) Vaginal
D) Transdermal
A)
Risk of VTE and stroke higher than transdermal
B)
- Levonorgestrel IUD instead of oral progestogen
- Minimises systemic adverse effects
- Can be prescribed in perimenopause → contraception; controls heavy bleeding
C)
- Creams, pessaries
- Progestogen not usually necessary
- Investigate if any irregular, heavy bleeding
> some systemic absorption can occur
> estrogen for urogenital symptoms = 1st line, lowest effective dose,
D)
- Gel or patch –> smaller doses of estrogen can be used
- Avoids 1st pass effects – less side effects (e.g. nausea)
- Breast cancer risk seems similar to oral
- Can cause skin irritation
- Risk of VTE and stroke lower
How to initiate therapy for oestrogen?
Choice of oestrogen dose depend upon how a woman’s symptoms respond
- Initiate therapy at a low or ultra low dose and then titrate upwards
- Aavailable as tablets, patches, gels and intravaginal
Oral dosage forms cheaper and preferred by women BUT transdermal (patches or gel) indicated for women with?
- Malabsorption
- Risk or past history of VTE or DVT, migraine, untreated hypertension, significant liver disease, smokers, overweight.
When is intravaginal oestrogen therapy used (creams or pessaries) in menopause?
Used in women who symptoms are predominantly genitourinary
> urinary frequency
> dysuria
> vaginal atrophy
- Also used in women or whom systemic oestrogen therapy is contraindicated or ineffective.
- Safety not assured when used in vaginal dryness and history of breast cancer –> use non-hormal treatment like replense
- Oestradiol > effect oestriol
How long do women with intact uterus use long term intravaginal oestrogen?
12 day course of progestine very 6 or 12 months –> minimise risk of endometrial hyperplasia
What causes most of the side effects from MHT?
Progestogens
What do cyclical and continuous regiments of progestogens aim for?
- Cyclical regimens aim for predictable bleeding pattern –> (10-14 days/month –> give women predictable monthly bleeding patterns)
- Continuous regimens aim for no bleeding –> been in meopause for 2 years
Irregular bleeding is common with all regimens particularly in the first 6 months for progestogens, true or false
True
> do ultrasound if longer than this and potentially hysterectomy
AE of progestogens?
Breast tenderness, fluid retention, headache, depression, PMS like syndrome, acne may occur during progestogen phase of cyclical MHT
How to manage adverse effects with progestogens?
- Changing the progestogen
- Reducing the dose (ensure endometrium is still protected)
- Changing the route
- Reducing the duration of progestogen to 10 days/month
- Changing to a 3-monthly cyclical regimen
- Changing to continous combined HRT if postmenopausal
What forms do progestogens come in? What is a more natural form of progestogen?
- Mostly taken orally
- Norethisterone is the only preparation reliably absorbed via skin and is available in a combined MHT patch with estrogen
- Micronised progesterone capsules are a form of “natural” or “ body identical” progesterone that is thought to be better tolerated
> more favourable breast safety profile
> neutral with CVD
> does not cause adverse mood effects
- Levonorgestrol IUD is an alternative method to deliver progestogen directly to the endometrium
What are tissue selective estrogen complexes (TSEC)? What are their effects on endometrium?
- = SERM (selective estrogen receptor modulator) + oestrogen
- E.g. bazedoxifene and conjugated equine oestrogen (Duavive®)
SERM exert different effects on different tissues
> agonists in some tissues
> antagonists in others
Effects one endometrium
- First generation SERMs (e.g. clomiphene and tamoxifen) stimulate the endometrium
- Newer SERMs (e.g. raloxifene and bazedoxifene) attenuate the proliferative effects of oestrogen on the endometrium
How does duavivie work (oestrogen and bazedoxifine)? What are the good things about it? What is the indication?
Progestogen not required as bazedoxifene protects endometrium
- Alleviates VMSs, ↓ vulvovaginal atrophy, improves BMD at hip and spine
- Neutral effects on breast and endometrium
Indication
- May be an option when progestogen MHT is not tolerated
- Short term treatment for relief of menopausal symptoms
What aare precautions for duavive?
- New drug and unreported adverse effects or interactions may occur
- Increased risk of VTE has been reported for both oestrogens and SERMs
> no additive effects observed on risk of VTE with TESC but true risk unknown
> contraindicated in a women with a history of VTE
> avoid in women at high risk of VTE
When is tibolone used? What are its effects?
not a 1st line option
A synthetic steroid used as an alternative to combined MHT
- Oestrogenic → vagina, bone and thermoregulatory centres = helps with hot flushes and bone loss
- Anti-oestrogenic and progestogenic → breast and endometrium
- Androgenic → ↓ total chol, HDL, LDL and triglycerides
> positive effects seen on mood and libido
Who is tibolone unsuitable in?
Periomenopausal women
> risk of breakthrough bleeding
What are the indications for tibolone?
Relief of menopausal symptoms – short term
2nd line for post-menopausal osteoporosis
What are the risks/precautions for tibolone?
- ↑ risk of breast cancer recurring
- Doubles risk of stroke in women >60 years (those with HTN, stroke, AF and diabetes)
- History of endometriosis
- ? SLE
- Surgery (immobilization)
- Bleeding that persists >6 months
Avoid tibolone in older women esp >70 years old and those at increased risk of stroke
What are the contraindications for tibolone?
- Cerebrovascular disease n
- Coronary artery disease n
- Breast cancer n
- Severe liver disease
2nd lined drug
↑ risk of breast cancer and ↑ risk of endometrial hyperplasia –> does tibolone do this?
unclear evidence
When is testosterone used in women? What is it used with?
Used in women with low testosterone who are experiencing lack or libido, lack of energy and ongoing fatigue
- Used with oestrogen most often for lack of libido
- No proven link between testosterone levels and symptoms
What are the side effects of testosterone treatment?
Oily skin, acne, excessive facial and body hair, scalp hair loss, irritability, aggression
serious side effects: deepening of the voice, enlarged clitoris (both irreversible), ?breast cancer, ?endometrial stimulation, ?lipids
> No form of testosterone therapy for women is officially approved in Australia by the TGA
If MHT is contraindicated, not tolerated, or not desired –> what to prescribe? What to consider for these other drugs?
1st line - venlafaxine 37.5 to 75mg daily (also desvenlafaxine)
2nd line - paroxetine 10 to 20mg daily (also escitalopram) –> interacts with tamoxifen. paroxetine reduces efficacy of tamoxifen.
3rd line – gabapentin 100 to 300mg daily
4th line – clonidine 25 to 50mg twice daily
> Consider effectiveness, side effects, potential interactions
- SNRIs, SSRIs → sexual dysfunction, drug interactions
- Gabapentin → well tolerated
- Clonidine → dry mouth, drowsiness and effect on BP
What are some non-hormonal pharmacotherapeutic options for vaginal dryness? If ineffective, what to use?
- Vaginal dryness
- First line therapy is non-hormonal preparations
> moisturisers e.g. replens and sylk
- If non hormonal, topical treatments are ineffective low dose vaginal oestrogens can be prescribed.
What are bioidentical hormones? What are the concerns?
Refers to compounded products marketed as hormones identical to those produced in the body
> natural estrogen = estradiol
> natural progestin = progesterone
- Concerns about safety of MHT saw an interest in bioidentical hormones develop
- Lack of studies re safety
> Not endorsed by AMS
> Concern about lack of protection for endometrial hyperplasia and neoplasia
> Unregulated manufacturing conditions
> Salivary hormone testing unreliable
Should topical progesterone be used in menopause?
- Topical progesterone creams marketed to reduce osteoporosis
- Have inadequate absorption
- If used with oestrogen may result in serious unopposed oestrogenic side effects
Is wild yam creams helpful in treating menopause?
- Originally marketed as containing progesterone but this is not the case
- Contain diosgenin which can be used to synthesise progesterone
Is red clover (phytoestrogens) helpful in menopause?
Limited and conflicting research
- May be useful for hot flushes, ?benefits on bone health, ?lower LDL cholesterol
- May take 3 months daily use to ↓ hot flushes
What are precautions for red clover?
- Adverse effects – myalgia, headaches, prolonged menstrual cycle
- In vitro studies suggest that red clover can inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4
- May inhibit P-glycoprotein → reduces absorption of drugs
- Red clover may have oestrogenic activity
> May interfere with hormonal contraceptives
> May ↑ risk of thrombosis due to estrogenic activity
> Methorexate toxicity with red clover?
What is black cohosh used for in menopause?
Affects serotonin and dopamine
- May cause improvements in VMSs
- Unclear if helps hot flushes in breast cancer patients but no association between black cohosh and ↑ breast cancer risk
- May alter efficacy and toxicity of cancer chemotherapy
- May take 3 months of daily use to improve menopausal symptoms
Black cohosh precautions and adverse efffects
May cause liver damage (rare)
- Associated with cases of liver failure and hepatitis
- Watch for symptoms of liver damage including: nausea, vomiting, loss of appetite, abdominal pain, diarrhoea, weightloss, tiredness and yellow discolouration of the skin or eyes
- Other adverse effects: GI symptoms, rash dizziness, headache, tiredness, weight gain, breast pain, vaginal spotting, musculoskeletal complaints
> Black cohosh may harm the liver in some individuals. Use under the supervision of a healthcare professional.”
What is the mainstay treatment for menopause? Why?
Oestrogen is the most effective treatment available for the relief of menopausal symptoms
- Hot flushes
- Vaginal dryness
- Dypareunia
> need to consider patient individual risks and benefits
What to do before starting oestrogen treatment?
Recommended to calculate cardiovascular risk and breast cancer risk prior to commencing therapy
- Benefits outweighs risks if initiated for symptomatic women before the age of 60 years or 10 Years after menopause
What to usse for hysterectomy patients
Oestrogen alone
When to use combined oestrogen + progestin (or + bazedoxifene or + tibolone)?
In patients who have a uterus
What is the goal of treatment for MHT? What were thy used for previously?
to relieve menopausal symptoms
- In the past menopausal hormone treatments (MHT) were used to prevent
> coronary heart disease (CHD)
> osteoporosis
NO LONGER RECOMMENDED for disease prevention
> due to results of womens health initiative –> unfavourable risk/benefit profile of MHT for this use
Increased in patient CV risk in MHT?
Yes
- Need to assess patient CV risk before commencing MHT
What do guidelines say about MHT and CV disease?
- Risk not increased if MHT commenced under 60 years
- Mortality from CV disease not increased
- Presence of CV risk factors is not a contraindication to MHT
- Oestrogen alone therapy is associated with no or ↓ risk of CV disease
- Oestrogen + progestogen associated with little or no ↑ risk of CHD
- Oral (but not transdermal) oestrogen is associated with a small ↑ in stroke risk (but baseline risk under 60 years is low)
Evaluating CVD risk for MHT?
What is associated with an increased risk of VTE? What to use instead?
Oral estrogen is associated with an ↑ risk of VTE (2-4 fold)
Absolute risk is small for women < 60 years old
–> individuals have different risk factors
- Transdermal estrogen is preferred for women at increased risk of VTE, i.e. smokers, obese
> bypasses first pass metabolism
Relationship between MHT and breast cancer?
The baseline risk of breast cancer for women around menopausal age varies from one woman to another
- MHT with oestrogen alone is associated with little or no change in the risk of breast cancer
- HRT with oestrogen and progestogen can be associated with an increase in the risk of breast cancer and in women without hystrecetomy
- Any increase in the risk of breast cancer is related to treatment duration and reduces after stopping MHT.
Postmenopausal women with a history of hormone-dependent cancer, need special consideration. Why?
Menopausal symptoms can arise because
- Cancer treatments induce menopause
- MHT is stopped with the diagnosis of cancer
- Endocrine therapies commenced (eg tamoxifen, aromatase inhibitors)
> symptoms similar to natural menopause
> added psychological component of the woman’s response to her cancer diagnosis
- Non hormone therapies may be helpful however paroxetine should be avoided in patients on tamoxife
Does MHT help with osteoporosis? Which ones help?
Combination, tibolone, TSECS
MHT effective in the prevention of bone loss in postmenopausal woman
- ↓ risk of hip, vertebral and other osteoporosis-related fractures in post-menopausal women
- Only therapy to ↓ risk of fracture in women with low fracture risk (T-scores normal to osteopoenic)
- However, ↓ fracture risk is lost a few years after stopping
> this is an issue because patients >70 need it as fracture risk is higher but wont be on because sx of menopause last until 65.
When can MHT be initiated in post-menopausal women at risk of fracture or osteoporosis?
MHT can be initiated in postmenopausal women at risk of fracture or osteoporosis <60 years (or within 10 years of menopause)
Why is MHT 2nd line treatment for fracture prevention >60 years?
Benefits dont outweight their risks such as VTE, stroke and breast cancer
What is spontaneous menopause <45 years (esp<40 years) associated with?
- ↑ risk CVD
- ↑ risk of osteoporosis
- ↑ risk affective disorders and dementia
Advantages of using MHT in early menopause?
- ↓ risk of heart disease
- Longer lifespan
- May prevent Alzheimer’s disease in later life
- May improve depressive/anxiety symptoms but antidepressants 1st line
Summary: benefits and risks
- In women requiring combined MHT, the use of a neutral progestogen such as micronised progesterone or dydrogesterone may be associated with lower risks of breast cancer and VTE
- Each women’s individual risks and needs should be assessed before initiating therapy
- Initiation of menopausal hormone therapy (MHT) a safe option for healthy, symptomatic women who are within 10 years of menopause or younger than age 60 years and who do not have contraindications to MHT
CI include
- Breast cancer n
- Cerebrovascular disease (stroke) or coronary artery disease n
- History of thromboembolic disease (VTE) n
- Active liver disease n
- Unexplained vaginal bleeding
> Estrogen-progestin therapy – intact uterus
> Unopposed estrogen - post-hysterectomy
> Vaginal atrophy symptoms only - vaginal estrogen
