Hormone replacement therapy

  • also known as menopausal hormone therapy or postmenopausal hormone 


  • Normal women have menopause at a mean age of 51 years, with 95 percent becoming menopausal between the ages of 45 to 55 years.
  • Menopause is associated with a marked decrease in ovarian estrogen production.
  • low estrogen levels à
    •  trigger vasomotor symptoms (hot flashes)
    • onset of symptoms of vulvovaginal atrophy à vaginal dryness and dyspareunia (genitourinary syndrome of menopause [GSM]).

Menopausal hormone therapy (MHT; estrogen alone or combined with a progestin) is currently indicated for management of menopausal symptoms.

Long-term use for prevention of disease is no longer recommended.

General principles

  • Menopausal hormone therapy (MHT) is the broad term à describe both
    • unopposed estrogen use for women who have undergone hysterectomy and
    • combined estrogen-progestin therapy (EPT) for women with an intact uterus who need a progestin to prevent estrogen-associated endometrial hyperplasia.
    • By convention, unopposed estrogen therapy is known as ET, combined estrogen-progestin therapy as EPT, and menopausal hormone therapy as MHT.

Goals of therapy — 

  • relieve menopausal symptoms à most importantly hot flashes (vasomotor symptoms).
  • Other symptoms associated with perimenopause and menopause that respond to ET include mood lability/depression, vaginal atrophy, dyspareunia, sleep disturbances (when related to hot flashes), and, in some cases, joint aches and pains.
  • Women being treated for menopausal symptoms such as hot flashes require systemic estrogen;
  • women being treated only for vulvovaginal atrophy (now referred to as “genitourinary syndrome of menopause” [GSM]) should be treated with low-dose vaginal estrogen rather than systemic estrogen.
  • MHT is no longer recommended for prevention of chronic disease (CHD or osteoporosis)
  • Mood lability/depression – MHT, alone or in combination with an antidepressant such as a selective serotonin reuptake inhibitor (SSRI),

Choosing candidates — 

  • initiation of menopausal hormone therapy (MHT) to be 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

Contraindications — 

  • history of breast cancer,
  • CHD,
  • a previous venous thromboembolic event or stroke,
  • active liver disease,
  • unexplained vaginal bleeding,
  • high-risk endometrial cancer, or
  • transient ischemic attack.

Oral estrogens should be avoided in

  • women with hypertriglyceridemia,
  • active gallbladder disease, or
  • known thrombophilias such as factor V Leiden (without a personal history of venous thromboembolism [VTE]).
  • Transdermal estrogen is also preferred for women with migraine headaches with auras.

Calculating risks — 

  • The Endocrine Society guideline suggests calculating cardiovascular and breast cancer risks before initiating MHT
  • nonhormonal therapies for symptomatic women who are at high risk (>10 percent 10-year risk) for CVD or moderate (1.67 to 5 percent five-year risk) to high risk (>5 percent) for breast cancer
  • For women at moderate risk of CVD (5 to 10 percent 10-year risk), they suggest transdermal rather than oral estrogen, with micronized progesterone for those with a uterus
  • population-based CVD risk calculator à online tool such as the National Cancer Institute Breast Cancer Risk Assessment Tool can be used to assess five-year breast cancer risk
  • Prior to initiating MHT the patient should be up-to-date on breast cancer screening tests.
  • Vaginal estrogen is not associated with an increased risk of cardiovascular events, and assessment of CVD and breast cancer risk is generally not needed when low-dose vaginal estrogen is prescribed [13].

Starting estrogen — 

  • Once a decision made to treat à with estrogen,
  • consideration à type of estrogen and
  • the route
  • need for progestin and the most appropriate progestin regimen.
  • Estrogen is available in many forms: oral, transdermal, topical gels and lotions, intravaginal creams and tablets, and vaginal rings.

Estrogen therapy (ET) remains the gold standard for relief of menopausal symptoms, in particular, hot flashes.

Route — 

  • We start many women on transdermal 17-beta estradiol à a lower risk of VTE, stroke, and hypertriglyceridemia than oral estrogens.
  • However, the baseline risk of both VTE and stroke is very low in otherwise healthy, young postmenopausal women.
  • Therefore, if a patient prefers an oral preparation over a transdermal one (cost or personal preference), we consider oral estrogen to be safe.
  • oral 17-beta estradiol 
  • All routes of estrogen administration à equally effective for symptom relief (and bone density), but their metabolic effects differ:
  • Oral estrogen à more favorable effects on lipid profiles
  • In addition to oral and transdermal estrogen preparations, estrogen is available as a vaginal ring and as a topical spray, cream, or gel.

Dose — 

  • In the past, a “one-size-fits-all” approach to estrogen dosing was used, with oral conjugated estrogen (0.625 mg/day)or its equivalent oral 17-beta estradiol (1 mg/day), or transdermal 17-beta estradiol (0.05 mg [50 mcg]), prescribed to most women.
  • However, the current approach is to start with lower doses, such as transdermal estradiol (0.025 mg) or oral estradiol (0.5 mg/day), and titrate up to relieve symptoms.
  • Lower doses are associated with less vaginal bleeding and breast tenderness
  • Lower doses are also associated with fewer effects on coagulation and inflammatory markers, and a possible lower risk of stroke and VTE than standard-dose therapy.
  • Estrogen should be administered continuously; past regimens where estrogen was administered days 1 to 25 of the calendar month are considered to be obsolete.
  • Women will often get hot flashes during the days off, and there is no known advantage to stopping for several days each month.

Side effects — 

Common side effects of estrogen à

  • breast soreness, which can often be minimized by using lower doses.
  • some women experience mood symptoms and bloating with progestin therapy.
  • Vaginal bleeding occurs in almost all women receiving cyclic estrogen-progestin regimens and is common in the early months of a continuous estrogen-progestin regimen.

Adding a progestin — 

  • oral micronized progesterone à first-line progestin.
  • All women with an intact uterus need a progestin in addition to estrogen to prevent endometrial hyperplasia, which can occur after as little as six months of unopposed ET.
  • Women who have undergone hysterectomy should not receive a progestin, as there are no other health benefits other than prevention of endometrial hyperplasia and carcinoma.
  • The most extensively-studied formulation for endometrial protection is the synthetic progestin used in the WHI, medroxyprogesterone acetate (MPA) (2.5 mg daily).
  • While MPA is endometrial protective, it was associated with an excess risk of CHD and breast cancer when administered with conjugated estrogen in the WHI. In addition, regimens using continuous versus cyclic MPA may be associated with a higher risk of breast cancer.
  • Our first choice of progestin is natural micronized progesterone (200 mg/day for 12 days/month or 100 mg daily). There are reasons to believe that natural progesterone might be safer for the cardiovascular system (no adverse lipid effects) and possibly the breast.

Side effects and bleeding — 

  • Some women are unable to tolerate cyclic progestin administration (with any type of oral progestin) because of mood side effects and bloating.
  • In addition, cyclic progestins almost always result in monthly withdrawal bleeding, which can be a lifestyle concern for many women.
  • For any of these concerns, we suggest switching to a continuous regimen. This often resolves the issue of mood symptoms and bloating. However, for women who are newly menopausal, breakthrough bleeding can be anticipated.

Women who cannot tolerate oral progestins — 

Some women are unable to tolerate any oral progestin, whether given in a cyclic or continuous regimen. In this case, we sometimes suggest off-label use of the lower dose levonorgestrel-releasing intrauterine device (IUD).

Conjugated estrogen/bazedoxifene — Another option is the combination of bazedoxifene, a selective estrogen receptor modulator (SERM), with conjugated estrogen.

  • the SERM bazedoxifene prevents estrogen-induced endometrial hyperplasia so that administering a progestin is not necessary.
  • Potential candidates include women with moderate-to-severe hot flashes who have breast tenderness with standard estrogen-progestin therapy (EPT) or women who cannot tolerate any type of progestin therapy because of side effects.
  • Like other SERMs, the risk of VTE is increased with bazedoxifene.

Duration of therapy — 

For women who choose estrogen or combined EPT, short-term use is suggested (generally not more than five years or not beyond age 60 years

However, hot flashes persist for an average of 7.4 years, and many women continue to have symptoms for more than 10 years

Monitoring with mammography — 

  • Routine mammograms and breast exams are recommended in women taking MHT, even when used short-term.

Use of oral contraceptives during the menopausal transition — 

  • A low-estrogen oral contraceptive (OC) is an option for perimenopausal women who seek relief of menopausal symptoms, who also desire contraception, and who in some instances need control of bleeding when it is heavy
  • Most of these women are between the ages of 40 and 50 years and are still candidates for OCs. For them, an OC containing 20 mcg of ethinyl estradiol provides symptomatic relief while providing better bleeding control than conventional MHT because the OC contains higher doses of both estrogen and progestin (which suppresses the hypothalamic-pituitary-ovarian axis).
  • OCs should be avoided in obese perimenopausal women because they are at greater risk for thromboembolism.

Stopping hormone therapy — 

Many women have no trouble stopping estrogen

However, abrupt withdrawal of exogenous estrogen at any age may result in the return of hot flashes and other menopausal symptoms.

Tapering — 

Although tapering MHT has not been proven to be more effective than stopping treatment abruptly, we suggest a gradual taper, particularly in women with a history of severe vasomotor symptoms.

When tapering, one approach is to decrease the estrogen by one pill per week every few weeks (ie, six pills per week for two to four weeks, then five pills per week for two to four weeks, etc) until the taper is completed. The progestin is tapered on the same schedule.

Implications of stopping — 

The implications of stopping EPT include:

●Return of estrogen deficiency symptoms is common.

For women who experience recurrent, bothersome hot flashes after stopping estrogen, we initially suggest nonhormonal options before considering resuming estrogen

●Resumption of bone loss

●Decrease in breast cancer risk

●The effect of estrogen cessation on CHD, particularly in young postmenopausal women, is unclear

Extended use of MHT — 

menopausal hormone therapy (MHT) should be individualized and not discontinued solely based upon patient age.

They suggest that extended use of MHT (beyond age 60 or even 65 years) may be reasonable when the clinician and patient agree that the benefits of symptom relief outweigh the risks

For women who choose extended use of MHT (more than five years or beyond age 60 years), we restart estrogen at the lowest dose possible and make plans for a future attempt to stop the estrogen.

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