Transcript MENOPAUSE - Northeast Ohio Nurse Practitioners | NEONP

PATTI BALLER, RN, CNM, MSN
APRIL 24, 2015
OBJECTIVES
 Define perimenopause, menopause, and
postmenopause.
 Discuss updated findings of the Women’s Health
Initiative (WHI).
 Discuss management options for the treatment of
hot flashes and night sweats.
 Discuss management options for the treatment of
vulvovaginal atrophy and dyspareunia.
2
DEFINITIONS BY NAMS
 PREMENOPAUSE - The span of time from puberty to
perimenopause.
 PERIMENOPAUSE - A span of time typically lasting 6
years or more that begins with the onset of menstrual
cycle changes and other menopause-related symptoms
and extends through menopause to 1 year after
menopause. (Also called menopause transition – MT)
 MENOPAUSE - The final menstrual period, which can
be confirmed after going 12 consecutive months without
a period.
 POSTMENOPAUSE - The span of time after
menopause.
3
HORMONE THERAPY
 FDA approved RXs for HT fell by half from 17.9
million in 1995 to 8.9 million in 2003, the year
following the release of the WHI findings.
 Only 3.7 million in 2013 use some form of HT.
 In 1990’s, > 90% of women with hysterectomy used
ET, currently 30% of women use ET.
 Reasons:
 Confusion among clinicians and women regarding WHI
results.
 Concerns re: breast Ca risk, CV risk.
4
WHI STUDY
 Primary prevention RCT
 Designed to evaluate effects of estrogen in promoting
CV health and in retarding the progression of
cognitive decline.
 Not designed to:
 Evaluate impact of treatment on PM symptoms. These
women were excluded from study.
 Assess safety or efficacy of established FDA-approved
drugs.
5
WHI STUDY
 16,608 healthy postmenopausal women
 EPT arm stopped after 5.2 years
 Average age 63.4 years
 2/3 between ages 60-79 with most women
postmenopausal for more than 10 years.
 3.5% of women in HT group 50-54 y.o.
6
WHI – ESTROGEN ARM
 Stopped after 6.8 yrs in February, 2004.
 Findings published in JAMA, April 14, 2004.
 Women aged 50-59, no increase in number of
strokes in CE and placebo groups.
 Study suggests younger women who use CEE
may be at decreased risk of CVD.
7
Incidence of CVD:
Relation to Menopause Status
The Framingham Study
Incidence
(per 1000 women)
7
6
6.5
Premenopausal
Postmenopausal
5
4.0
4
3.6
3
2.2
2.0
2
1
0.6
3.6
0.6
0
<40
40–44
45–49
50–54
Age (years)
n = 2873.
Kannel WB, et al. Ann Intern Med. 1976;85:447-52.
8
Effect of Hormone Therapy on Atherosclerosis Varies
With Stage of Reproductive Life
Premenopause
~5%
~15%
15-25 yrs
25-35 yrs
Benefits of Endogenous E2
Perimenopause
35-45 yrs
45-55 yrs
Primary Benefits of HT
Postmenopause
55-65 yrs
65 yrs
No Benefits of HT
Mikkola TS, et al. Ann Med. 2004;36:402-13.
9
Hypothetical Pathogenetic Sequence
No HT
MMP-9
Adventitia
Media
Internal
Elastic
Lamina
Fibrous
Cap
Fatty Streak/Plaque
Plaque
Fibrous
Cap
Fibrous
Cap
Plaque
Plaque
Necrotic Core
Necrotic Core
Early and Continued HT
HT
Mural Thrombus
Late HT
HT
Age
35–45 years
45–55 years
55–65 years
>65 years
10
RISK OF BREAST CANCER
 For every 100 women who do not take HT or ET,
2.8 will develop breast cancer after 10 years.
 WHI results indicate a hazard risk for breast
cancer of 1.26 after 5 yrs of HT use
 For every 100 women who take HT, 3.5 will
develop breast cancer after 10 yrs.
 Rate of breast cancer in obesity – 10% wt
gain is associated with 2.5 times the breast
cancer risk found in WHI.
11
NEW CONSENSUS STATEMENT
 Systemic hormone therapy is the most effective tx for
most menopausal sxs, including vasomotor sxs and
vaginal atrophy.
 Local estrogen therapy is effective and preferred for
women with sxs of vaginal dryness or dyspareunia
only.
 Systemic HT is acceptable option for relatively young
(up to age 59 or within 10 years of menopause) and
healthy women who are bothered by moderate-severe
menopausal sxs.
 Individualization is key. Consider quality of life, age,
time since menopause, risks of blood clots, HD, stroke
12
and breast cancer.
NEW CONSENSUS STATEMENT
 Rate of breast cancer-not statistically
significant. (Risk for an individual woman
taking HT is <1%)
 ^ risk seen with ≥ 5 yrs of continuous EPT
(Estrogen + progestin)
 Use of estrogen alone for a mean of 7 yrs did
not increase breast cancer risk.
 Risk decreases after HT is D/C.
13
NEW CONSENSUS STATEMENT
 Although HT increases risk for stroke, PE, VTE’s,
the risk is rare in the 50-59 yo age group.
 The lowest dose of HT should be used for the
shortest amount of time to manage menopausal
symptoms.
 Although fewer than 5 yrs is recommended for
EPT, duration should be individualized.
 For ET, more flexibility in duration of therapy may
be possible.
14
NEW CONSENSUS STATEMENT
 Data demonstrates HT reduces hip fractures and a
40% reduction in colon cancer.
 Conclusion- for younger women undergoing
therapy close to the time of menopause, the
benefits generally outweigh the risks.
15
ORAL PREPARATIONS
 Primarily metabolized in liver- 80-90% of E2
(estradiol) converted to less biologically active
estrone and estrone sulfate.
 Peak concentrations in 4-6 hrs
 Increases C-reactive protein and can increase
the cholesterol saturation of bile.
 Smoking decreases estrogen levels by 40-70%.
16
ESTROGENS
 Used in EPT and ET.
 1 ug. Ethinyl estradiol = biologic
potency to 0.625 mg. conjugated equine
estrogens.
 Vaginal and transdermal applications,
bypass liver and act directly on target
tissue.
17
ESTROGENS
 Estrones
 CEE (Conjugated equine estrogen) - from
pregnant mares’ urine


Potent estrogen, stored in fat, long-lasting.
Recommended starting dose 0.3 mg.
18
ESTROGENS
 Estradiols - synthetically produced natural 17Bestradiol. (Bioidentical )
 Micronized estradiol – oral (Estrace)

Recommended starting dose 0.5 mg.
 Transdermal systems - Estraderm, Vivelle,
Climara, etc.
 Vaginal Ring (Estring)
19
ESTROGENS
 Esterified estrogens - estradiol esters (Oral)
 Do not ^ plasma triglycerides
 Not linked to ^ risk of venous thrombosis
 Use in diabetic women or
hypertriglyceridemia
 Menest- no animal precursors
 Esterified estrogens + methyltestosterone
(Estratest, Estratest HS)
 Not indicated for use for osteoporosis.
20
SYNTHETIC CONJUGATED ESTROGENS
 Cenestin - Mixture of 9 estrogenic substances.
 Enjuvia – Mixture of 10 estrogenic substances.
 Synthesized from soy and yam plants.
 Estradiol principal physiologic estrogen.
 Doses - 0.3 - 1.25 mg./day.
 Not approved for osteoporosis.
21
DUAVEE
 Approved by FDA in October, 2013.
 Tissue selective estrogen complex.
 Conjugated estrogen 0.45 mg with bazedoxifene 20
mg
 Has estrogen agonist effect on bones and blocks
estrogen activity at uterus and breast.
 Does not cause change in breast density, thickness
of endometrium, or increase in breast pain.
 Provides an alternative to progestin.
22
DUAVEE (CONT)
 Indication: For prevention of osteoporosis and tx of
mod-severe vasomotor symptoms.
 Indicated only for use in women with a uterus.
 Side effects: muscle spasms, nausea, diarrhea,
dyspepsia, upper abdominal pain, oropharyngeal pain,
dizziness and neck pain.
 Drug interactions: concomitant use with CYP3A4
inhibitors such as erythromycin, clarithromycin,
ketoconazole, itraconazole, and ritonavir and
grapefruit juice. (Increases estrogen exposure)
 Contraindications: Women with or H/O blood clots,
liver problems, breast cancer or uterine cancer.
23
PROGESTINS
 Medroxyprogesterone acetate (MPA) -
most common.
 Less androgenic activity, negates
estrogen’s benefits to lipid profiles.
 Found in Prempro and Premphase.
24
PROGESTINS
 Norethindrone or NETA
 Developed from testosterone molecule.
 Greater binding affinity for
endometrium and myometrium.
 Less side effects of depression and
mood changes.
 Found in FemHRT, Activella and
Combipatch.
25
PROGESTERONE
 Prometrium – FDA approved bio-identical
hormone, micronized oral progesterone.
 Synthesized from yam plant sources.
 Contains peanut oil.
 Recommended for women at risk for CVD and
those intolerant to synthetic progestins.
 Dose: 200 mg every evening for 12 days every 28
days with food
 Side effects: Somnolence, breast tenderness,
constipation, H/A, dizziness, abdominal pain,
joint pain.
26
OTHER PROGESTINS USED IN HRT
 Drospirenone – in Angeliq
 Norgestimate – in Prefest
 Levonorgestrel – in Climara Pro
27
ANDROGENS
 Methyltestosterone (Estratest, estratest HS)
 Primarily used in women who undergo
surgical menopause for sxs of decreased
libido, fatigue and changes in cognition or
memory, moodiness.
 Continue use only if sxs. alleviated
28
HT REGIMENS
 Numerous options available.
 Indications:
 Tx of moderate-severe menopausal sxs. (6-8 hot
flashes/day)

Symptoms are bothersome, disrupt sleep, or
adversely affect quality of life. (NAMS)
 Tx of vulvar and vaginal atrophy.
 Prevent osteoporosis in women at high risk for
fracture.
29
HT REGIMENS - CONTINUOUS ESTROGEN
ONLY (ET)
 Continuous estrogen
 Indications - Hx. of hysterectomy with
or without oophorectomy.
 Risks - Increased risk of endometrial
hyperplasia and cancer with unopposed
estrogen use in women with a uterus.
30
HT - CONTINUOUS COMBINED (EPT)
 Estrogen and progestin daily, either as 2
separate preparations or combined in 1
preparation.
 Advantages:
 Lower progestin dose
 Daily progestin causes endometrial
atrophy
 Minimal spotting first 6 mos, then
amenorrhea within 1 year.
31
HT - CONTINUOUS COMBINED (CONT)
 Advantages:
 Decrease in PMS symptoms
 Uterine atrophy leads to asymptomatic
fibroids.
 Convenience, better compliance.
32
HT: CYCLIC – COMBINED (EPT)
 Estrogen daily + Progestin for 14 days of cycle.
(Premphase)
 Estrogen daily for 28 days each month, with a
progestin for last 10-14 days of estrogen tx.
 Disadvantages:
 80-90% experience withdrawal bleeding
 Inconvenient
33
CHOICE OF HT REGIMEN
 If no uterus: estrogen only
 If uterus present:
 Goal is to avoid vaginal bleeding entirely or at
least to make it predictable.
 Current endometrial activity predicts bleeding
pattern
 Recent spontaneous or induced bleeding
 Cyclic combined or OCP’s if no
contraindications.
 No bleeding for > 2-3 cycles
 Continuous combined
34
TRANSDERMAL PREPARATIONS PATCHES
 Uses 17B-estradiol.
 Avoids first pass- globulins, lipoproteins, and
clotting factors less likely to change.
 Peaks in serum concentration less likely.
 Insulin sensitivity improved.
 Does not increase C-reactive protein or
triglycerides.
 HDL increases less than oral HT
 Peak concentrations in 2-8 hrs
 Site reactions 20-40%
35
36
FIRST LINE USE OF ESTROGEN PATCH
 High triglyceride levels
 Gallbladder disease
 Diabetes
 Migraine headache
 Daily mood swings
 Smokers
 Stomach upset due to oral estrogen intake
 Problems with taking a daily pill
 Night sweats unrelieved with oral estrogen.
37
GEL FORMULATIONS
 Popular in Europe since 1975
 Uses 17B-estradiol.
 Absorbed into an intradermal reservoir, from
which physiologic plasma concentrations are
delivered for steady- state bioavailability.
 Onset of action is rapid.
 Needs to be spread over wide skin area.
 Elestrin, Divagel, Estrogel and Estrasorb.
38
GEL FORMULATIONS
 Skin irritation is uncommon, may cause
pruritus.
 Avoid skin contact with others for 1 hour after
application.
 Estrogel- 1 pump full applied to 1 arm from wrist
to shoulder.
 Estrasorb- topical emulsion. Apply 2 foil
packets to each thigh and calf and rub in for 3
minutes.
 Avoid sunscreens which increase estrogen
absorption.
39
ESTROGEN SPRAY
 Evamist –Each 90mcL spray delivers 0.021 mg
estradiol.
 Applied to inner forearm. Slow absorption thru
epidermis to dermis where it reaches circulation
thru capillaries.
 Quick drying and no residue on skin.
 Skin irritation uncommon.
 Risk of transfer to another person less than with
gel preps. No difference in estradiol levels in
males.
 May use up to 3 sprays per day.
40
FEMRING
 Transvaginal systemic estrogen.
 Avoids first pass through liver.
 FDA approved for menopausal symptoms and VVA
 Inserted in vagina for 90 days.
 2 doses: 0.05 mg/day and 0.1 mg/day
 If used in a woman with an intact uterus, must also
give a progestin.
41
CHOICE OF ESTROGENS
 Start low dose transdermal (patches, gels, spray)
vaginal (Femring) or oral estrogen.
 If suboptimal response, modify by:
 Change the estrogen dose (upward)
 Change the estrogen preparation
 Change delivery systems (oral vs transdermal vs
vaginal)
 Consider an estrogen-androgen combination
 Wait at least 12 wks before changing dose.
42
SSRI’s
BRISDELLE
 Paroxetine mesylate 7.5 mg at hs.
 Non hormonal option.
 FDA approved in June, 2013 for vasomotor
symptoms.
 1-2 fewer hot flashes/day compared to placebo.
 On average, starts working 4 weeks after starting.
43
BRISDELLE (CONT)
 Side effects:
 H/A
 Fatigue
 Nausea
 Vomiting
 Doesn’t cause wt gain or sexual dysfunction.
 Inhibits cytochrome P450 and CYP2D6 enzyme.
 Reduces effectiveness of tamoxifen, other warnings –
increased bleeding risk and serotonin syndrome.
44
SSRI’s
 Escitalopram (Lexapro) 10 mg qd, increase to 20 mg
after 4 wks.
 54% reduction in hot flashes (Ms-FLASH 3 clinical trial)
 Bleeding risk if used with ASA, NSAIDS, warfarin, or




other anticoagulants.
Use with caution if H/O recent MI or unstable heart
disease, hepatic or renal impairment.
Mild effect on CYP2D6 enzyme.
Can be given with tamoxifen.
Generic available.
45
SSRI’s
 Citalopram 10 mg, may increase to 20 mg if nec.
 49-55% reduction in hot flashes.
 $4 generic available for 20 mg.
 Few, if any side effects in studies.
 Safe for elderly
 Few CV or anticholinergic adverse events.
 Mild effect on CYP2D6 enzyme.
 Can be given with tamoxifen.
46
SSRI’s
 Considered second line therapy:
 Fluoxetine 20 mg qd

58% withdrawal rate due to ineffectiveness of tx.
 Sertraline 50 mg qd


Side effects nausea and decreased sexual function.
Poor trial data.
 Less effective for hot flashes.
 Both decrease effectiveness of Tamoxifen.
47
SNRI’s
 Venlafaxine 37.5 mg daily or Venlafaxine XR 75 mg.
 Serotonin/Norepinephrine reuptake inhibitor.
 Side effects: nausea and constipation, higher
dose increases dry mouth.
 Use with caution in women with HTN
 May cause increase in BP
 49% reduction in hot flashes (Ms-FLASH 3
clinical trial), improvement in sleep, decrease in
insomnia, and increase in sleep quality.
 Good choice for tamoxifen users.
48
SNRI’s
 Desvenlafaxine (Pristiq) 100 mg qd- higher doses
increase risk of discontinuation.
 Desvenlafaxine has same precautions with BP as
venlafaxine.
 Applied for FDA approval and denied.
 60-66% reduction in hot flashes.
 Side effects: nausea, tends to subside after a few days,
dizziness and H/A.
 Good choice for tamoxifen users.
49
OTC BOTANICALS AND ISOFLAVONES
Some studies (slightly) better than placebo, most studies no
effect.
 Soy isoflavones
Minimal to no benefit
 Red clover isoflavones
Not better than pbo
 Black cohosh (20-40mg BID)
Inconclusive
(Remifemin)
No evidence of efficacy
 Evening primrose oil
Not better than pbo
 Chasteberry (Vitex)
No studies
 Dong quai
Not better as monotx
 Ginseng
Not better than pbo
 Vitamin E
Not better than pbo
50
CUSTOM COMPOUNDED HORMONES
 Custom made HT formulations.
 Never undergone clinical testing, safety or efficacy
studies.
 Not FDA approved.
 Same or possibly additional risks.
SALIVARY TESTING –
 Large
patient to patient variability and no
biologically meaningful relationship between
saliva and serum hormone concentrations.
 Not proven accurate or reliable.
Bioidentical hormone therapy: clarifying the
misconceptions. Cleve Clin J Med. 2011;78:829836
51
FDA APPROVED BIO-IDENTICAL
HORMONES
 Oral esterase (Estrace)
 17-beta estradiol
 Transdermal patches, gels, and spray
 Vaginal ring (Estring)
 Prometrium
52
VAGINAL PREPARATIONS
 Minimize systemic exposure.
 Limited to urogenital atrophy.
 *Exception: Femring- serum levels equivalent to
patch, used for tx of menopausal sxs and
vaginal atrophy. Caution- if patient has a
uterus, must also give a progestin.
 Improves urge incontinence symptoms.
 Reduces risk for recurrent urinary tract infections.
 1st line therapy for decreased libido, mod-severe
dyspareunia, and other vulvovaginal symptoms.
(NAMS)
53
TREATMENT OF ATROPHIC VAGINITIS
 Estrace cream 2-4 g/day for 1-2 weeks, then
1 g/d 1-3x/week.
 Premarin vaginal cream 0.5-2 g/day for 2x/week or
daily for 3 weeks, then 7 days off
 Estring 2 mg ring x 90 days
 Vagifem 10 mcg/day for 2 weeks, then 10 mcg
2x/week.
 No progestin required with above meds.
 Femring x 90 days- use only if also having
menopausal sxs. (Systemically absorbed)
 All evidence A.
54
OSPEMIFENE (OSPHENA)
 Approved by FDA for atrophic vaginitis in Feb, 2013.
 Selective estrogen receptor modulator (SERM)-
estrogen agonist/antagonist.
 Estrogen agonist on vaginal tissue and estrogen
antagonist in breast tissue.
 Makes vaginal tissue thicker and less fragile.
 Can lead to endometrial hyperplasia.
 Indication: moderate to severe dyspareunia.
 Dose: 60 mg PO daily with food.
 Should be closely monitored for abnormal uterine
bleeding.
55
OSPEMIFENE (OSPHENA) CONT.
 SE: Hot flashes (most common), vaginal D/C, muscle
spasms or leg cramps, and excessive sweating.
 Drug Interactions: Metabolized through cytochrome
P450; fluconazole, ketoconazole and omeprazole
increase levels, and rifampin decreases levels.
 Not recommended to use with other SERMs or
estrogen therapy.
 Contraindications: undiagnosed vaginal bleeding,
pregnancy, estrogen dependent neoplasia, active or
prior VTE, previous stroke, HD, prior MI or severe
hepatic impairment.
56
NONHORMONAL THERAPIES
 Feminease
 Lubricants
 Water based
 K-Y jelly
 Astroglide
 Slippery Stuff
 Liquid Silk
 K-Y Silk-E
 Silicone based
 Moisturizers
 Replens
 Vagisil
 Silken Secret
 Me Again
 Luvena




Astroglide X
K-Y Intrique
Pink
ID Millennium
57
RECOMMENDATIONS AND
CONSIDERATIONS
 Do not use for primary or secondary prevention
of heart disease.
 Low risk for CHD if HT initiated within 10 yrs
of menopause or by age 59.
 Extended use of HT is acceptable in certain
circumstances, especially with ET therapy.
 Evidence suggests HT route of administration
has an impact on potential risks.
58
Questions????
59
Case Study
64 yo, Cau female presents with C/O 10 hot flashes/day
since menopause at age 52. She took HT for 1 year after
menopause then stopped because everyone told her it
caused breast cancer and heart disease. PMH: HTN,
hyperlipidemia, DM. PSH: None. Meds: Lisinopril 20
mg qd, atorvastatin 80 mg qd. Allergies: None
BP today: 130/80 No recent labs done.
She would like something for her hot flashes, what will
you give her and why?
60
Case Study
56 yo AA, female presents with c/o hot flashes all day
long, night sweats that continually wake her up and
vaginal dryness. Has tried remifemin, lubricants and
moisturizers without relief. Menopause: age 52. PMH:
HTN. PSH: Hysterectomy for adenomyosis. Meds:
HCTZ 25 mg daily. No allergies. Nonsmoker. BP today:
130/84.
What will you give her for her complaints and why?
61
Case Study
53 yo Cau, female presents with c/o >10 hot flashes daily.
She finds it embarrassing at work and everyone can tell
when she gets one. Menopause: age 50. Smoker 1 ppd.
PMH: Osteopenia, hyperlipidemia. PSH: None.
Meds: Caltrate 600 mg bid, atorvastatin 20 mg daily.
Last lipid panel normal 3 mos ago. BP 120/70
What will you give her and why?
62
References
 American College of Obstetricians and Gynecologists.
Website: www.acog.org
 North American Menopause Society. Website:
www.menopause.org
 Writing Group for the Women’s Health Initiative
Investigators. Risks and benefits of estrogen plus
progestin in healthy postmenopausal women: principal
results from the Women’s Health Initiative randomized
controlled trial. JAMA. 2002; 288:321-333.
 Chlebowski, RT, Hendrix, SL, Langer, RD, et al, for the
WHI Investigators. Influence of estrogen plus progestin
on breast cancer and mammography in healthy
postmenopausal women: the Women’s Health Initiative
Randomized Trial. JAMA. 2003; 289: 3243-3253.
63
References
 Writing Group for the Women’s Health Initiative
Investigators. Effects of conjugated equine estrogen in
postmenopausal women with hysterectomy. JAMA. 2004;
291:1701-1712.
 Rossouw, JE, Prentice, Rl, Manson, JE, et al.
Postmenopausal hormone therapy and risk of
cardiovascular disease by age and years since menopause.
JAMA. 2007; 297: 1465-1477.
64
References
 LaCroix, AZ, Chlebowski, RT, Manson, JE, et al, for the
WHI Investigators. Health outcomes after stopping
conjugated equine estrogens among postmenopausal
women with prior hysterectomy: a randomized controlled
trial. JAMA. 2011; 305: 1305-1314.
 Stuenkel, CA, Gass, MLS, Manson, JE, et al. A decade after
the Women’s Health Initiative-the experts do agree.
Menopause. 2012; 19(8): 1-2.
 North American Menopause Society. Management of
symptomatic vulvovaginal atrophy: 2013 position statement
of The North American Menopause Society. Menopause
2013; 20(9): 888-899.
65