MANAGING THE MENOPAUSE AFTER THE WHI
Michael S. Policar, MD, MPH, Associate Clinical Professor of Obstetrics/Gynecology and Reproductive Sciences,
University of California, San Francisco, School of Medicine, and Medical Director, UCSF Program Support, Family
PACT Program, San Francisco, CA
| Hormone replacement therapy (HRT) from 1960 to 1980s: menopause seen as endocrinopathy requiring HRT; in
1960s—oral contraceptives (OCs) first introduced in United States; HRT initially used to treat hot flushes and vaginal
symptoms; later, HRT used for protection of heart and bone
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| Impact of Heart and Estrogen-Progestin Replacement Study (HERS) and Women’s Health Initiative (WHI):
profound shift from “pro-hormone therapy (HT)” to “anti-HT” attitude; resulted in clinicians being confused because results
of randomized controlled trials (RCTs) opposite to those of 30 yr of analytic studies showing HT protected heart;
perception of HT risks and benefits varies greatly by specialty; contradictory recommendations of Food and Drug Administration
(FDA); patients confused and skeptical
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| Nonmedicinal therapies: healthy diet—low in total and saturated fat; phytoestrogens to reduce hot flushes; exercise—
prevents osteoporosis and controls hot flushes; combination of aerobic exercise and strength training; adequate elemental
calcium—calcium and vitamin D supplementation important for bone health; phytoestrogens—actually phyto selective
estrogen receptor modulators (phytoSERMS); true estrogens made only by mammals; food sources primarily tofu, soy
flour, and soy milk; relatively high in calories and fat; bloating, intestinal cramps, and gas main reasons for discontinuation;
in RCTs, shown to reduce hot flushes; isoflavone concentrates—used orally; found in soy extract capsules and red
clover (Promensil); soy isoflavones, red clover isoflavones, and black cohosh have slightly better response than placebo;
evening primrose oil, chasteberry, dong quai, ginseng, and vitamin E no better than placebo; majority of impact due to
placebo effect; relatively safe with few adverse effects; reasonable first-line choice for women with fairly mild hot
flushes, who feel strongly about avoiding HT, and willing to use medications not proven effective by evidence-based
medicine (EBM) and not regulated by FDA
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| Choice of HT regimen: if no uterus, estrogen only; if uterus still present, give estrogen and progestin to prevent endometrial
hyperplasia and avoid bleeding entirely (or make it predictable); endometrial activity predicts bleeding pattern; if recent
spontaneous or induced bleeding, continuous sequential regimen used; if no bleeding for 2 to 3 mo, use continuous combined
regimen (daily estrogen and progestin); continuous sequential—includes daily estrogen with on-and-off progestin cycle for
14 days; withdrawal bleeding occurs after taking estrogen and progestin together; continuous pulsed—daily estrogen and
off-and-on progestin cycle every 3 days (Prefest); avoid regimen of daily estrogen for 25 days, progestin for last 10 days, then
1 wk off (no reason to give respite from estrogen); transdernal estrogen (patches)—6 choices; changed once weekly or
twice weekly; patches containing estrogen and progestin also available
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| Bioequivalent HRT (b-HRT): advantages—allows for individualized treatment of menopausal changes (saliva or serum
used to evaluate hormone levels); components titrated based on hormone levels and response; often combination of
estrogen, progesterone, testosterone, and dehydroepiandrosterone (DHEA); claim that only “natural” hormones used (no
synthetic hormones); systemically administered (no first-pass effect through liver); delivery by gel, sublingual, or buccal-
oral routes, or vaginal suppository; disadvantages—production not well regulated and may be inconsistent; variability
of hormone combinations; estrone and estriol have 1/80th potency of estradiol; skin absorption of progesterone virtually
nonexistent; more expensive than commercial HT; no data about safety; no data about value of saliva or serum hormone
level testing; North American Menopause Society (NAMS) reports lack of EBM to support use
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| Choice of estrogens: start with low-dose transdermal or oral estrogen; if response suboptimal, modify by increasing estrogen
dose; if ineffective, change estrogen preparation; if that ineffective, change delivery system; if that ineffective, consider
estrogen-androgen combination; injectable estrogen not recommended (not standardized and cannot be
discontinued easily); when estrogen patch first-line choice—high triglyceride levels; gallbladder disease; migraine headaches;
daily mood swings; history of deep venous thrombosis (DVT) or pulmonary embolism (PE); stomach upset due to
oral estrogen intake; poor compliance with taking daily pill
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| Progestin component: 3 choices; most commonly used medroxyprogesterone acetate (MPA; eg, Provera); others include
norethindrone (in OCs) and micronized progesterone (eg, Prometrium; more natural type); when combined estrogen and
progestin indicated, should give lowest dose possible for shortest time (same recommendation from FDA, NAMS, and
American College of Obstetricians and Gynecologists [ACOG])
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| Hot flushes: if symptoms mild, exercise, phytoestrogens and herbal products recommended; initiate low-dose HT if patient
has moderate or severe hot flushes, has failed non-HT, or has no interest in non-HT; titrate estrogen dose upward if
necessary; if unable to use estrogen, use selective serotonin reuptake inhibitors (SSRIs), eg, venlafaxine (Effexor XR),
with starting dose of 37.5 mg for 1 to 2 wk, then increase to full dose of 75 mg/day; clonidine also used but not as effective
as estrogen; treat for 1 to 2 yr, then attempt to wean off (in 80% of women hot flushes resolve in 2 yr)
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| Sleep and irritability symptoms: if problem mild, try exercise, phytoestrogens, and herbal products; if no response or
symptoms severe, start oral HT; increase dose if necessary; switch to patch if patient not responding or has mood swings;
if fairly significant depression present or patient not responding to HT, use venlafaxine or other SSRI
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| Cognition and menopause: many women experience worsening of short-term memory with onset of menopause; HT
may get these women back to baseline; studies show HT improves verbal memory, reasoning, and motor-speed tests
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| Atrophic vaginal changes: symptoms include irritation, dryness, and dyspareunia; vaginal estrogen cream or tablet recommended;
absorbed through vaginal epithelium into blood; should have improvement in symptoms by 4 to 6 wk, but
complete resolution may take several months; if patient also has hot flushes, use oral or transdermal HT (may need to
combine with vaginal therapy
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| Bladder symptoms: urethra and trigone of bladder also estrogen-sensitive; some dysuria, urgency, frequency, and urge
incontinence associated with estrogen deficiency; treatment choices include estrogen-releasing vaginal ring (eg, Estring,
Femring), vaginal estrogen cream or tablet, and oral HT or estrogen therapy in women without uterus; question— does
postmenopausal woman with uterus and using vaginal estrogen need progestin opposition? answer, no good studies available;
many clinicians perform progestin challenge once every 3 mo to test for withdrawal bleeding; if bleeding occurs,
withdraw every month or every other month; if no bleeding, withdraw 3 or 4 times annually to prevent endometrial hyperplasia
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| HT and quality of life (QOL): RCTs and retrospective studies show that HT has no effect on QOL measures; many
women who wean from HT feel worse, even 20 yr after menopause; conventional wisdom that women who feel better on
and worse off HT should continue low-dose HT if they have few or no risk factors; when and how often to reattempt
weaning uncertain
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| Atherosclerotic cardiovascular disease: coronary artery disease (CAD) number one cause of death in women; men start
getting heart attacks at 45 yr of age, women at 55 yr of age; 10-yr delay in women attributed to protective effect of endogenous
estrogen; retrospective analytic studies show women who use HT have 50% reduction in risk for death from myocardial
infarction (MI); protection less for women who smoke; protection greatest in women with most risk factors,
including those with previous MI or stroke, hypertension, or diabetes
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| HERS trial: 2800 women with heart disease randomized to combined HT or placebo; results showed—no value of estrogen
and progestin in secondary prevention of MI events or deaths; 3-fold increased risk for venous thromboembolic
events and slightly increased risk for gallbladder disease
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| Women’s Health Initiative: 17,000 women 50 to 79 yr of age; several end points; 2 treatment arms (if woman had
uterus, estrogen and progestin vs placebo; without uterus, estrogen alone vs placebo); first arm (estrogen and
progestin)—discontinued after 5.5 yr because risks greater than benefits; per 10,000 women/yr, 7 more MIs, 8 more
strokes, 8 more breast cancers, and 18 more thromboembolic events; on beneficial side, 6 fewer cases of colorectal cancer
and 5 fewer hip fractures; estrogen-only arm—continued for 7 yr; showed no difference in risk for coronary heart disease
and breast cancer, slightly increased risk for stroke, and slightly decreased risk for hip fracture
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| Reasons for differences between RCTs and analytic studies: in earlier studies, huge “well-woman” selection bias
(HT users healthier, more physically active, better educated, and more affluent); these behaviors reason for fewer MIs
(never HT in first place)
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| Avoid overinterpretation of RCTs: RCTs evaluated long-term benefits vs long-term risks; average age of women in
these studies 64 yr (most HT users in their early 50s); differentiate between combined HT and estrogen-only therapy; resolve
contradiction between biologic plausibility of cardioprotection from estrogen and results of RCTs; take-home message
from HERS and WHI—HT does not protect women from MIs; everything else matter of perception of benefit and
risk; internal medicine perception—RCTs gold standard; drugs for prevention have lower threshold for risk; more likely
to see women with DVTs, pulmonary emboli, MI, and stroke; less likely to see benefits; therefore see HT as more risky
than beneficial; obstetrics and gynecology perception—RCTs do not apply to younger patients; less likely to see women
with DVT, pulmonary emboli, MI, and stroke; see benefit of treating hot flushes, urogenital tract atrophy, and short-term
memory loss; see more benefit than risk
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| Role of HT in prevention of osteoporotic fractures: pros—good data on fracture prevention (especially in women
who already have osteoporosis); treats hot flushes and short-term memory loss; relatively lower cost than bisphosphonates;
less concern in women who use estrogen only; cons—requires long-term use and surveillance; postmenopausal
bleeding troublesome; association with breast cancer and venous and arterial complications; if osteoporosis prophylaxis
sole indication for HT, use low dose and make sure calcium added; low-dose HT makes most sense for women between
menopause and 60 yr of age with menopausal symptoms, and with osteoporotic risk factors; HT given until women in
60s, then switched to bisphosphonate
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| Contemporary attitude toward HT: treatment of choice for hot flushes and urogenital tract atrophy; for prevention of
fractures, bisphosphonates better and safer; for primary and secondary cardioprevention, statins, aspirin, and lifestyle
changes more effective; concern about promotion of breast cancer with use >5 yr; confine HT to short-term use for hot
flushes, use topical estrogen for urogenital tract atrophy, and nonhormonal treatments for other conditions
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| When HT should be started: if woman menopausal and has hot flushes, sleep problems, irritability, short-term memory
problems, vaginal dryness, and painful intercourse, and does not have heart disease and high risk for breast cancer; use
lowest dose for 1 to 2 yr, then pause to determine whether symptoms still present; stop if symptoms resolved or if patient
develops heart disease or breast cancer; stop gradually (over 4-8 wk)
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| Questions and answers: benefit from HRT in premature menopause—premature menopause (<40 yr of age) not common;
most common cause premature ovarian failure; also due to ovarian insensitivity syndrome (autoimmune condition)
or genetic cause (mosaic); HRT indicated for 2 reasons; the younger the woman undergoing menopause, the more severe
hot flushes, and bone resorptive activity more likely (earlier osteoporosis); ovaries also making less testosterone (decreased
libido); if woman has uterus, use combined estrogen and progestin; woman with premature menopause needs relatively
higher estrogen dose; use conjugated estrogen 0.625 mg (or its equivalent) and progestin (2.5-5 mg of MPA)
daily; if woman wants to have regular menstrual periods, give continuous sequential regimen; another alternative standard
low-dose OCs (eg, Alesse); HRT stopped around time of normally expected menopause (early 50s); after stopping
HRT, determine whether hot flushes or signs of estrogen deficiency return; if symptoms return, resume HRT; bone protection
depends on osteoporosis risk profile; if patient has many risk factors, continue estrogen or other treatment; if patient
undergoing early menopause and on HRT or OC but complains of low libido, try different OC (low-dose) with third-
generation progestin (eg, Desogen, Ortho-Cept, Ortho-Cyclen; has relatively less effect on testosterone and sex hormone-
binding globulin [SHBG] levels); if on HT, good data that testosterone supplementation helps (eg, Estratest); estrogen in
women >35 yr of age who smoke—data linking OCs, smoking, and MIs and stroke generated in 1960s and 1970s when
high-dose OCs (50-100 µg of estrogen) used; information extrapolated and applied to low-dose OCs; relationship between
smoking and arterial events worrisome; no relationship between smoking and venous events; still absolute contraindication
to using OCs in woman ≥35 yr of age who smokes more than half pack of cigarettes daily; if woman smokes
at all, not good candidate for OCs; estrogen in HRT only one seventh that found in standard OC; 10 µg of ethinyl estradiol
equal to 1.25 mg of conjugated estrogens (Premarin); based on WHI, HRT provides no protection against heart attacks
but does not cause heart attacks either (attributable risk trivial); speaker would prescribe HRT for woman with
premature menopause who smokes, or woman 50 yr of age who smokes pack of cigarettes daily; counsel patient about
importance of cessation of smoking; estrogen and DVT—hypercoagulability from oral estrogen related to first-pass effect;
estrogen given systemically (transdermal or vaginal) does not have first-pass effect, so little impact on coagulation
factors; theoretically, transdermal delivery system safer, relative to DVT; European study reported that oral user has 3.5-
fold higher relative risk for DVT than transdermal user, but absolute risk for DVT not especially high with oral or trasdermal
estrogen; if patient has only average risk for thromboembolic complications, no previous DVT or PE, no Factor V
Leiden mutation, and no family history of DVT, irrelevant whether oral or transdermal estrogen used; if patient has risk
factors, use transdermal estrogen; can argue that, for all patients, even though DVT rare event, patch safer than oral version;
micronized progesterone—Postmenopausal Estrogen/Progestin Interventions (PEPI) trial; results showed estrogen
has beneficial effect on lipoproteins; progestin has negative effect on lipoproteins; using synthetic progestin counteracts
beneficial effect of estrogen on lipoproteins; micronized progesterone has no effect on lipoproteins, allowing beneficial
effect of estrogen; clinical significance debatable; problem with MPA androgenic side effects (eg, weight gain, breast
tenderness, swelling); micronized progesterone also good choice for these women; disadvantages include cost and soporific
effect; HRT in women who have had breast cancer—all studies show recurrence rate of breast cancer same (≈5%),
as long as 5 yr after treatment, with or without HRT; if patient <5 yr from treatment, no data available, but conventional
wisdom to use nonhormonal alternatives
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Suggested Readings
Aubuchon M et al: Lessons learned from the WHI: HRT requires a cautious and individualized approach. Geriatrics
59:22, 2004; Ettinger B: Rationale for use of lower estrogen doses for postmenopausal hormone therapy. Maturitas 57:81,
2007; Epub 2007 Mar 23. Genazzani AR et al: Menopause and aging, quality of life and sexuality. Climacteric 10:88,
2007; Grady D et al: Discontinuation of postmenopausal hormone therapy. Am J Med 118 Suppl 12B:163, 2005; Grady
D et al: Postmenopausal hormone therapy. BMJ 334:860, 2007; Huang A et al: Hot flushes, bone mineral density, and
fractures in older postmenopausal women. Obstet Gynecol 109:841, 2007; Johnson BE: Herbal supplements did not relieve
vasomotor symptoms of menopause. ACP J Club 146:65, 2007; Liu JH: Evolving approaches in the treatment of
menopausal symptoms. Obstet Gynecol 108:4, 2006; McKee J et al: Integrative therapies for menopause. South Med J
98:319, 2005; Med. 2006 Dec 19;145(12):I25. Ness J et al: Use of hormone replacement therapy by postmenopausal
women after publication of the Women's Health Initiative Trial. J Gerontol A Biol Sci Med Sci 60:460, 2005; Newton KM
et al: Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo:
a randomized trial. Ann Intern Med 145:869, 2006; Petitti DB: Some surprises, some answers, and more questions
about hormone therapy: further findings from the Women's Health Initiative. JAMA 294:245, 2005; Potts RO et al: Transdermal
drug delivery: clinical considerations for the obstetrician-gynecologist. Obstet Gynecol 105:953, 2005; Richardson
MK: Commentary: What's the deal with menopause management? Why the Women's Health Initiative raises more
questions than it answers. Postgrad Med 118:21, 2005; Roberts H: Managing the menopause. BMJ 334:736, 2007; Shulman
LP: The menopausal transition: how does route of delivery affect the risk/benefit ratio of hormone therapy? J Fam
Pract Suppl:S13, 2004; Stevenson JC: HRT and the primary prevention of cardiovascular disease. Maturitas 57:31, 2007;
Warren MP: Historical perspectives in postmenopausal hormone therapy: defining the right dose and duration. Mayo Clin
Proc 82:219, 2007; Wingert P: Menopause. A flash of concern. Newsweek 149:16, 2007
Cultural and Linguistic Resources
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on its website. Please visit this site: www.audio-digest.org/ CLCresources.
Educational Objectives
| The goal of this program is to improve the management of menopausal symptoms. After hearing and assimilating this program,
the clinician will be better able to:
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 | 1. Describe nonmedicinal therapies for the management of menopausal symptoms.
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| 2. Discuss the advantages and disadvantages of bioequivalent hormone replacement therapy.
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| 3. Prescribe treatment for menopausal symptoms, eg, hot flushes, sleep and irritability symptoms, cognitive changes,
bladder symptoms, and atrophic vaginal changes.
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| 4. Explain the findings of the Women’s Health Initiative and the reasons for the difference from results of earlier studies.
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| 5. Recognize when hormone therapy should be started and when it should be stopped.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose relevant
financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts
were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial
interest. For this program, the faculty reported nothing to disclose.
Acknowledgements
Dr. Policar was recorded at 2006 Primary Update—Improving Patient Care, held November 5-8, 2006, in Newport
Beach, CA, and sponsored by the Interstate Postgraduate Medical Association of North America. The Audio-Digest
Foundation thanks Dr. Policar and the sponsor for their contribution in the production of this program.
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