PB#141: Management of Menopausal Symptoms Flashcards by Gordon Skeoch

Clinical definition of menopause

1 year since LMP, representing permanent cessation of menstruation that occurs after loss of ovarian activity

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Median age of menopause

51 y/o

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Terms referring to years preceding FMP associated w/ physiologic changes and clinical sxs (3)

Perimenopause, climacteric, menopausal transition

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Physiologic process of menopausal transition

Fluctuations in hormone levels as ovarian function begins to slow down > serum levels of estradiol and progesterone decreasing and FSH increasing > physiologic changes/clinical sxs

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Definition of hot flush

Sudden sensation of extreme heat in upper body (particularly face/neck/chest), typically lasting 1-5 mins

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Associated characteristics of a hot flush (6)

Perspiration, flushing, chills, clamminess, anxiety, (occasionally) heart palpitations

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Possible association of vasomotor sxs on sleep

Chronic sleep disruption

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Percentage of pts who experience hot flushes on daily basis; percentage of pts who experience >10 episodes per day

87%; ~33%

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Reported median duration of hot flush sxs

4-10.2 years

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Why do hot flushes occur in perimenopause?

Thermoregulatory zone is narrowed and becomes more sensitive to subtle changes in core body temp > small increases in temp trigger themoregulatory mechanisms > sensation of hot flush (vasodilation, sweating, decreased skin resistance)

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Central physiologic mechanisms that play a role in vasomotor sxs (5)

Serotonergic, noradrenergic, opioid, adrenal, autonomic

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Has a genetic predisposition to vasomotor sxs been identified?

Yes, based on several polymorphisms related to sex steroid metabolism

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General frequency of reported vasomotor sxs by race

Black pts reported most vasomotor sxs, Asian pts reported fewest vasomotor sxs

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Theories for racial variations in vasomotor sx reporting (4)

Genetic factors, physiologic differences, diets varying in soy products, cultural perceptions/reporting differences

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Do vasomotor sx frequency vary by BMI?

Yes, more common in obese pts

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Environmental factors related to vasomotor sxs (3)

Mood sxs (ie depression/anxiety), low SES, smoking

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General cause of vaginal atrophy

Direct consequence of hypoestrogenic state associated w/ menopause > anatomic/physiologic changes in genitourinary tract

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Percentage of pts who will experience at least 1 sx of vaginal atrophy

10-40%

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Sxs associated w/ vaginal atrophy (4)

Vaginal/vulvar dryness, discharge, itching, dyspareunia

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Histologic/Physiologic changes that lead to vaginal atrophy (4)

Loss of superficial epithelial cells in genitourinary tract (causing thinning of tissue), loss of vaginal rugae and elasticity (causing narrowing/shortening of vagina), increased fragility of epithelial tissue (which may cause tearing/bleeding/fissures), loss of subQ fat in labia major

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Anatomic changes that occur w/ vaginal atrophy (3)

Narrowing of introitus, fusion of labia minora, shrinking of clitoral prepuce/urethra

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Changes to vaginal pH associated w/ menopause; clinical result

Vaginal pH becomes more alkaline, altered vaginal flora and increased risk of urogenital infection

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What happens to vaginal secretions during menopause?

Secretions (largely transudate from vaginal vasculature) may decrease

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Effects of vaginal atrophy on sexual function

Measures of sexual dysfunction seen at higher rates in pts w/ vaginal atrophy

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Most effective tx for vasomotor sxs related to menopause

Systemic HRT (w/ estrogen alone or in combo w/ progesterone)

Standard dose of conjugated estrogen (+/- progestin), is evidence of benefit demonstrated, is it FDA approved; low dose of conjugated estrogen (+/- progestin), is evidence of benefit demonstrated, is it FDA approved?

0.625mg daily, evidence of benefit demonstrated, FDA approved; 0.3-0.45mg daily, evidence of benefit demonstrated, FDA approved

Standard dose of micronized estradiol-17beta (+/- progestin), is evidence of benefit demonstrated, is it FDA approved; low dose of micronized estradiol-17beta (+/- progestin), is evidence of benefit demonstrated, is it FDA approved; ultra-low dose of micronized estradiol-17beta (+/- progestin), is evidence of benefit demonstrated, is it FDA approved?

1mg daily, evidence of benefit demonstrated, FDA approved; 0.5mg daily, evidence of benefit demonstrated, FDA approved; 0.25mg daily, evidence of benefit mixed, not FDA approved

Standard dose of transdermal estradiol-17beta (+/- progestin), is evidence of benefit demonstrated, is it FDA approved; low dose of transdermal estradiol-17beta (+/- progestin), is evidence of benefit demonstrated, is it FDA approved; ultra-low dose of transdermal estradiol-17beta (+/- progestin), is evidence of benefit demonstrated, is it FDA approved?

0.0375-0.05mg daily, evidence of benefit demonstrated, FDA approved; 0.025mg daily, evidence of benefit demonstrated, FDA approved; 0.014mg daily, evidence of benefit mixed, not FDA approved

Dose of conjugated estrogen + bazedoxefine, is evidence of benefit demonstrated, is it FDA approved?

Conjugated estrogen 0.45mg daily + bazedoxefine 20mg daily, evidence of benefit demonstrated, FDA approved

Percent reduction in frequency of weekly hot flushes associated w/ PO estrogen +/- progestin; OR reduction in severity of hot flushes associated w/ PO estrogen +/- progestin

75%; OR = 0.13

OR reduction in severity of self-reported vasomotor sxs associated w/ estrogen alone; OR reduction in severity of self-reported vasomotor sxs associated w/ estrogen + progestin

OR = 0.42; OR = 0.38

Routes that estrogen +/- progestin can be administered (2)

PO, transdermally (via patch/gel/spray)

Potential adverse effects associated w/ standard doses of HRT (4)

Breast tenderness, VB, bloating, HAs

General HRT regimens associated w/ better adverse effect profiles

Low dose and ultra-low dose regimens

Lowest dosage of PO estradiol found to be effective in treating hot flushes

0.5mg daily

General principle for treating vasomotor sxs w/ HRT

Lowest effective dose for shortest duration needed to relieve sxs

Longterm risks of systemic combo HRT (2)

VTE, breast cancer

Adverse outcomes w/ slightly increased risks associated w/ 5 years of combined HRT, per WHI (4)

Breast cancer, coronary heart disease, stroke, VTE

Improved outcomes associated w/ 5 years of combined HRT, per WHI (2)

Decreased risk of fractures, decreased risk of colon cancer

Adverse outcome w/ increased risk associated w/ 5 years of estrogen only, per WHI

VTE (no increased risk of CV events or breast cancer seen)

Poss improved outcome associated w/ HRT in pts <60 y/o and within 10 years of menopause, per WHI reanalysis

Cardioprotective effects (though HRT should not be used for primary/secondary heart disease prevention)

Route of estrogen that has lower risk of VTE

Transdermal

Percentage of pts who experience sx recurrence following discontinuation of HRT

50% (regardless of age and duration of use)

Is routine discontinuation of HRT at 65 y/o recommended?

Is abrupt discontinuation or tapered discontinuation recommended for HRT?

No evidence available to recommend one over the other

Pts in whom PO conjugated estrogen + bazedoxefine should be considered

For pts requiring tx of vasomotor sxs and to prevent osteoporosis in postmenopausal pts w/ a uterus

Progestin-only regimen that may help w/ vasomotor sxs, is evidence of benefit demonstrated, is it FDA approved?

Depo Provera, evidence of benefit demonstrated, not FDA approved

Is there evidence of benefit demonstrated, and is there FDA approval for testosterone?

Evidence of benefit not demonstrated, not FDA approved

Potential adverse effects associated w/ testosterone tx (4)

Lipid derangements, clitoromegaly, hirsutism, acne

Clinical benefits to adding testosterone to HRT (2)

Improved sexual function scores, increased number of satisfying sexual episodes

Tibolone med class

Synthetic steroid w/ tissue-specific estrogenic and progestogenic effects

Benefits of tibolone (3)

Improved bone density, vasomotor sxs, vaginal sxs (w/o estrogenic effects on uterus/breasts)

Tibolone dosing, is evidence of benefit demonstrated, is it FDA approved?

2.5mg daily, evidence of benefit demonstrated, not FDA approved (and not available in US)

What are bioidenticals?

Plant-derived hormones that are chemically similar or structurally identical to those produced by the body

Concerns re bioidenticals

Do not undergo clinical testing > purity/potency/ quality are not verified > both underdosage and overdosage are possible 2/2 variable bioavailability/bioactivity

Dosing, evidence for desvenlafaxine in tx of vasomotor sxs

100mg daily, showed significant reduction in mod-to-severe hot flushes per day

Reported adverse effects associated w/ desvenlafaxine (8)

Nausea, dizziness, dry mouth, nervousness, constipation, somnolence, sweating, sexual dysfunction (side effects typically resolve w/ time and/or dose adjustment)

Paroxetine dosing, is evidence of benefit demonstrated, is it FDA approved?

7.5mg daily, evidence of benefit demonstrated, FDA approved (only nonhormonal therapy approved by FDA for tx of vasomotor sxs)

Clonidine med class

Central acting alpha2-agonist antihypertensive agent

Clonidine dosing, is evidence of benefit demonstrated, is it FDA approved?

0.1mg daily, evidence of benefit demonstrated (though not as much as HRT), not FDA approved

Common adverse effects associated w/ clonidine (3)

Dry mouth, insomnia, drowsiness (BP not adversely affected)

Gabapentin med class

Gamma-aminobutyric acid analog

Gabapentin dosing, is evidence of benefit demonstrated, is it FDA approved?

600-900mg daily, evidence of benefit demonstrated (though not as much as HRT), not FDA approved

Common adverse effects associated w/ gabapentin (3)

Dizziness, somnolence, peripheral edema

Which meds have better efficacy between gabapentin, SSRIs, and SNRIs in management of vasomotor sxs?

Similar efficacy

Which med did pts prefer in crossover trial between venlafaxine and gabapentin in tx of vasomotor sxs?

Venlafaxine

What are phytoestrogens (w/ two examples)?

Plant-derived substances w/ estrogenic biological activity (isoflavones genistein and daidzein)

Food products containing high amounts of isoflavones (3)

Soybeans, soy products, red clover

Has any significant difference in frequency of hot flushes been demonstrated w/ phytoestrogens?

No (though no evidence of detrimental effects seen either)

Examples of herbal txs for vasomotor sxs (6)

Dong quai (Angelica sinensis), dang gui bu xue tang, black cohosh (Actaea racemosa or Cimicifuga racemosa), ginseng, St. John's wort, ginkgo biloba

One situation in which herbal tx regimen was found to be as effective as HRT in relieving menopausal sxs

Chinese herbal medicine + acupuncture

Risk associated with/ black cohosh

Liver toxicity

Vitamin regimen associated w/ marginal reduction (one fewer hot flush per day) in vasomotor sxs

Vit E 800IU daily

Alternative technique that may be effective in pts w/ vasomotor sxs w/ contraindications to HRT

Local injection of anesthetic into stellate ganglion

Common sense lifestyle changes for managing vasomotor sxs (3)

Layering clothing, maintaining lower ambient temp, consuming cool drinks

Ingredients associated w/ increased severity/frequency of vasomotor sxs (2)

Alcohol, caffeine

Lifestyle modification that improves tolerance to vasomotor sxs indirectly

Aerobic exercise (by improving quality of life)

Recommended tx modality for pts w/ only vaginal sxs

Local estrogen

Estradiol-17beta vaginal ring dosing, is evidence of benefit demonstrated, is it FDA approved?

7.5mcg daily, evidence of benefit demonstrated, FDA approved

Estradiol vaginal tablet dosing, is evidence of benefit demonstrated, is it FDA approved?

25mcg daily, evidence of benefit demonstrated, FDA approved

Estradiol vaginal ring dosing, is evidence of benefit demonstrated?

0.05mg daily, evidence of benefit demonstrated

Estradiol-17beta vaginal cream dosing, is evidence of benefit demonstrated?

2g daily, evidence of benefit demonstrated

Conjugated estrogen vaginal cream dosing, is evidence of benefit demonstrated?

0.5-2g daily, evidence of benefit demonstrated

Typical administration for vaginal estrogen formulations

Administered daily x1-2 weeks > indefinitely at low doses for maintenance thereafter

Is local estrogen therapy associated w/ increased risk of endometrial hyperplasia?

No (so neither progestin add-on nor endometrial surveillance is needed unless PMB occurs)

First-line tx recs for vaginal atrophy in pts w/ hx of hormone-sensitive breast cancer

Nonhormonal methods (though short-term use of hormonal methods can be considered for pts w/ severe/refractory sxs when other options have failed)

Are low-dose systemic estrogen formulations appropriate for pts w/ vaginal atrophy in addition to vasomotor sxs?

Yes (all systemic formulations of conjugated estrogen, micronized estradiol-17beta, transdermal estradiol-17beta that are available for vasomotor sxs also have evidence of benefit demonstrated and are FDA approved for use in vaginal atrophy)

Lowest PO dosage of CEE shown to improve vaginal atrophy; lowest transdermal dosage of estradiol-17beta shown to improve vaginal atrophy

0.3mg daily; 12.5mcg daily

Ospemifene med class

SERM (estrogen agonist at vagina, antagonist at endometrium)

Ospemifene dosing, is evidence of benefit demonstrated, is it FDA approved?

60mg daily, evidence of benefit demonstrated, FDA approved

Common adverse effects of ospemifene (5)

Hot flushes, vaginal discharge, muscle spasms, genital discharge, excessive sweating

Other FDA-approved use for ospemifene besides vaginal atrophy

Mod-to-severe dyspareunia in postmenopausal pts

First-line nonhormonal options for tx of vaginal atrophy sxs

Water-based or silicone-based vaginal lubricants (evidence of benefit demonstrated, not FDA approved)

MoA of vaginal moisturizers

Trap moisture > provide long-term relief of vaginal dryness (evidence of benefit demonstrated, not FDA approved)

Measures shown to improve w/ use of vaginal moisturizers (4)

Vaginal dryness, pH balance, elasticity, vaginal itching/irritation/ dyspareunia sxs

Are herbal remedies/soy products recommended as tx of vaginal atrophy sxs?

Insufficient evidence