aWell-documented risk or benefit supported by multiple clinicalstudies.
bPossible risk or benefit shown in limited clinical trials, additional data needed to confirm.
CVD, cardiovascular disease; DM, diabetes mellitus; DVT, deep venous thrombosis; EPT, estrogen and
infection; WHI, women’s health initiative.
The cardiovascular effects of HT are not fully elucidated. Analysis of data from the
WHI and other studies found no increased risk of coronary heart disease in women
aged 50 to 59 years who began therapy within 10 years of menopause, and a possible
reduced risk in women initiating therapy prior to age 55 and within 2 to 3 years of
menopause, whereas an increased risk of CVD was seen in women aged 60 years and
older who initiated HT more than 10 years after menopause.
such as L.K. who initiate HT for VMS soon after the onset of menopause, the risk of
CVD is not significantly increased.
Other less established benefits of HT (Table 51-1) include effects on urinary tract
infections, diabetes mellitus, and colorectal cancer.
Established Risks of Hormone Therapy
As noted above, an increased risk of CVD has been noted in women over the age of
60 years who initiated HT more than 10 years postmenopause.
Endometrial proliferation from exogenous estrogen exposure leads to hyperplasia
rates of 8% to 62% after 1 to 3 years of use.
In a woman with a uterus, use of ET
alone increases the risk of endometrial cancer by twofold to 10-fold, with higher
estrogen dose and longer duration associated with greater risk.
several years after discontinuation of ET.
27 Addition of adequate progestogen
significantly attenuates or eliminates the increased risk of endometrial cancer; a
progestogen should be added to ET in a woman with an intact uterus (see Case 51-1,
Studies demonstrate a 25% overall increased risk of invasive breast cancer with
EPT use, becoming significant 5 years after initiation, increasing with continued use,
and returning to baseline approximately 5 years after EPT is stopped.
increases this risk less than EPT.
36,37 Risk appears to be similar between oral and
transdermal therapies, and no dose–response relationship has been established. Risk
may be lower in overweight/obese women.
36 A short time frame between the onset of
menopause and initiation of HT appears to significantly increase the risk for breast
cancer compared with a longer interval.
HT use increases the overall risk for venous thromboembolic disease (TED),
including deep venous thrombosis and pulmonary embolism, twofold.
be mediated by inhibition of hepatic synthesis of anticoagulant factors, including
antithrombin, protein S, and protein C.
39 Transdermal estrogen appears to have a
significantly lower risk than oral estrogen as it avoids the first-pass metabolic effects
33,40,41 Observational data suggest that synthetic progesterone
derivatives but not bio-identical progesterone further increases risk of TED.
Women who are older, have a higher body mass index, or have a prothrombotic
mutation are at additional increased risk.
43 The risk is greatest within the first year of
treatment and decreases upon discontinuation of HT. HT should be avoided in
women with a history of or at high risk for TED.
Agents Labeled for Use in ET and EPT
Drug (Brand Name) Route, Initial Dosage
Conjugated equine estrogens (Premarin)
Synthetic conjugated estrogens (Enjuvia) PO 0.3 mg
Estropipate (piperazine estrone sulfate) (Ortho-Est)
Micronized estradiol (Estrace)
Estradiol transdermalsystem (various brand name
TD 0.014 (ultralow dose)–0.025 mg/24-hour patch
applied weekly or twice weekly
Estradiol acetate tablet (Femtrace)
Estradiol acetate vaginal ring (Femring)
c HDV 0.05 mg/24 hour ring inserted vaginally every 90
Estradiol topical emulsion/gel/solution (Divigel, Elestrin,
TD 0.0125 mg to 0.75 mg (product dependent)
Progestogens (Minimum Recommended Dose to Prevent Endometrial Hyperplasia)
Medroxyprogesterone acetate (Provera generic and
PO 5 mg for sequential regimens; 2.5 mg for
Norethindrone acetate (Aygestin generic and combo
PO 2.5 mg for sequential regimens; 1 mg for
Micronized progesterone (Prometrium)
c PO 200 mg for sequential regimens; 100 mg for
Progesterone vaginal gel (Prochieve, Crinone)
Progesterone vaginalsuppository (First Progesterone
V one full applicator of 4% gel every other day
Levonorgestrel-releasing IUD (Mirena) IU 0.02 mg/day
Examples of Estrogen and Progestogen Combination Products
a PO 0.3 mg CEE and 1.5 mg MPA
a PO 0.625 mg CEE for 28 days with 5 mg MPA for last
(estrogen) TD 0.045 mg estradiol/0.015 mg levonorgestrel/24-hour
Low-dose Vaginal Estrogens (Localized Effect Only)
Conjugated equine estrogen cream (Premarin) LDV initial: 0.5–2 g cream (0.3125–1.25 mg CEE)
Maintenance: 0.5–2 g cream (0.3125–1.25 mg CEE)
once/twice weekly based on severity
c LDV initial: 2–4 g cream (0.2–0.4 mg estradiol) daily
Maintenance: 1 g cream (0.1 mg estradiol) twice
c LDV 2-mg ring (0.0075 mg/day) every 90 days
Estradiol hemihydrate tablets (Vagifem and Vagifem
LDV one tablet (0.01 mg) daily for 2 weeks, then one
aApproved by the US Food and Drug Administration for prevention of osteoporosis.
bRequires addition of progestogen in women with a uterus.
cFDA-approved bio-identical hormone.
systemic absorption; MPA, medroxyprogesterone acetate; PO, orally; TD, transdermally; V, vaginal.
Other risks with HT include potential adverse effects on cognition and urinary tract
function, an increased risk of stroke and the development of ovarian and lung cancer
27 For women with premature ovarian failure, it is
recommended that HT be given until the typical age of natural menopause to avoid
early manifestations of estrogen deficiency.
As L.K. continues to experience severe hot flushes that are affecting her quality of
life, she is recently postmenopausal, and she has no absolute contraindications to
estrogen (such as TED, history of breast or endometrial cancer, uncontrolled
hypertension, migraine with aura, tobacco use, obesity), a trial of HT is appropriate.
CASE 51-1, QUESTION 4: What is an appropriate HT regimen for the management of L.K.’s hot flushes?
Figure 51-2 Algorithm for the management of symptomatic menopausal women. EPT, estrogen/progestogen
therapy; ET, estrogen therapy; HT, hormone therapy.
There are a number of hormonal products currently available for the management of
VMS (Table 51-2). Oral and nonoral estrogens appear to be equally efficacious in
27,45 Because it avoids first-pass metabolism, nonoral estrogen is
associated with a lower risk for TED, hypertension, and gallbladder disease than
Current recommendations are to initiate estrogen at a low dose (e.g., 0.3 mg of
conjugated equine estrogens or 0.025 mg of transdermal estradiol). Ultralow-dose
estrogen (TD estradiol 0.014 mg/day) reduces the risk of harm but may not
adequately control menopausal symptoms.
If symptoms persist after 2 to 3 weeks
of therapy, the dose of estrogen can be increased to the next available dosage strength
for the product being used (Table 51-2).
There is strong consumer interest in natural (bio-identical) HT (BHT) as a
potentially safer alternative to synthetic estrogens. BHTs are defined as having the
same chemical structure as the hormones produced by the human reproductive system
and include estradiol, estrone, progesterone, and testosterone. Studies of
commercially available BHT products demonstrate a similar efficacy to synthetic
hormones; however, clinical evidence to support claims of greater safety is
50,51 Women desiring to use bio-identical products should be advised of
commercially available products (Table 51-2); extemporaneously compounded BHT
does not carry FDA-approved warnings and may be of inadequate quality.
In women with an intact uterus, such as L.K., a progestogen must be added to the
regimen to minimize the risk of endometrial cancer (Table 51-3).
no indication for adding a progestogen to ET in women without a uterus. There does
not appear to be a difference in the endometrial protective effect between
progestogens. Combined continuous regimens may provide better endometrial
protection than sequential regimens (Table 51-3). Although not FDA-approved for
this indication, progesterone vaginal gel and progestogen-releasing intrauterine
systems protect against endometrial hyperplasia from ET.
EPT may result in resumption of uterine withdrawal bleeding. The pattern and
frequency of bleeding depend on the EPT regimen used (Table 51-3).
of estrogen are associated with a lower risk of bleeding.
regarding bleeding patterns should be considered when selecting an EPT regimen.
Progestogen monotherapy appears to be similar to estrogen in relieving the
symptoms of VMS. Effective regimens include megestrol acetate, 40 mg/day orally,
micronized progesterone 300 mg/day orally, and medroxyprogesterone acetate, 10
mg/day orally, 150 mg intramuscularly every 3 months or 400 mg intramuscularly one
59–62 Adverse effects of progestogens include vaginal bleeding, fluid retention,
increased appetite, breast tenderness, acne, hirsutism, headaches, mood swings,
fatigue, and depression. In the absence of ET, progestogens do not appear to increase
61 However, data on long-term safety, especially in regard to breast
cancer, are lacking. Progestogen monotherapy for the treatment of hot flushes is
generally reserved for women with contraindications to estrogen use.
As some risks of HT increase with longer use, use beyond 5 years has generally not
been recommended. However, as many women continue to have VMS beyond this
time frame, a thorough risk versus benefit review is needed to determine the
appropriate duration for each woman.
63 Because hot flushes are self-limiting, it can
be difficult to assess whether symptom relief is related to the treatment or natural
resolution of symptoms. Six to 12 months after L.K.’s hot flushes are fully treated,
she should attempt discontinuation of EPT. There are no specific guidelines for
withdrawing therapy; typical taper regimens involve decreasing the daily estrogen
dose to the next available dosage strength or increasing the dosing interval. If
symptoms recur during the taper, therapy can be resumed at the lowest effective dose
and another taper attempted in 6 months.
ET/EPT Regimens and Expected Vaginal Bleeding Patterns
Interval Typical Bleeding Pattern
Combined Regimens (EPT) for Patient with Intact Uterus
Estrogen (PO or TD): days 1–25 of each
Progestogen: days 10–25 or 14–25 of each
˜80% experience regular bleeding
Estrogen (PO or TD) and progestogen:
Lower incidence than cyclic regimen
Progestogen: 10–14 days every month
˜80% experience regular bleeding
Progestogen: 14 days every third month
˜70% experience regular bleeding
Estrogen (PO or TD) and progestogen:
None ˜40% have irregular bleeding for first 6–12
˜75%–89% become amenorrheic within 12
Estrogen + Progestogen PO × 3 days
˜80% are amenorrheic at the end of 12
Estrogen-only Regimens (ET) for Patients Without Uterus
Estrogen (PO or TD): daily None None
bBleeding more than 1 year after initiation of therapy requires endometrial evaluation.
requires use of a tampon or sanitary pad.
dSpotting is light bleeding that lasts <1 day.
EPT, estrogen and progestogen therapy; ET, estrogen therapy; PO, orally; TD, transdermally.
CASE 51-1, QUESTION 5: To minimize the risks of TED, L.K. is prescribed a combination
estrogen/progestogen patch. How should she be counseled about possible side effects of EPT?
In addition to being counseled about the serious risks of EPT, L.K. should be
advised regarding nuisance side effects from HT. These most commonly include
resumption of vaginal bleeding and breast tenderness.
edema, headache, premenstrual syndrome-like symptoms, and increased vaginal
discharge have also been reported. Skin irritation may occur with the use of
transdermal products. Frequently, these side effects diminish with time or may
respond to a change in dosage or product. Although ET and EPT have not been
shown to consistently induce or worsen hypertension, patients with hypertension,
such as L.K., should be monitored for increases in blood pressure.
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