Estrogen can be administered by oral, parenteral, topical or transdermal routes with similar effects and there are several different formulation choices available. Continuous estrogen therapy is recommended, though doses and route of administration can be changed relative to patient preference. Oral estrogen is the most popular in the United States. Transdermal estrogen patches avoid the first pass effect on the liver and offer the convenience of less frequent administration (usually weekly). Topical estradiol gel also avoids the first pass effect; it is rubbed on the arm once daily. Finally, a slow release vaginal ring can provide sustained symptomatic relief for 3 months at a time. There are lower doses available for the patches and pills that prevent bone loss as well as hot flashes. It is important to remember that a woman with an intact uterus should receive a progestin in addition to her estrogen for endometrial protection.

Table Currently available and combined oral hormone replacement therapy preparations in the US

Medication Brand Name Available Doses
Single Agent
Conjugated equine estrogens Cenestin 0.3, 0.625, 0.9, 1.25 (mg)
Menest 0.3,0.625, 1.25,2.5 (mg)
Premarin 0.3, 0.45, 0.625, 0.9, 1.25 (mg)
Estradiol Estrace 0.5, 1,2 (mg)
Estropipate (piperazine estrone sulfate) Ogen 0.75, 1.5, 3, 6 (mg)
Ortho-Est 0.75, 1.5 (mg)
Combined Agents
Conjugated equine estrogen / medroxyprogesterone acetate Prempro 0.3/1.5; 0.45/1.5; 0.625/2.5; 0.625/5 (mg/mg)
Premphase 0.625/0x21 days, then
  0.625/5 x 7 days (mg/mg)
Conjugated equine

estrogens / methyltestosterone

Estratest 1.25/2.5 (mg/mg)
Estradiol/norgestimate Prefest 1/0x21 days, then
  1/0.09×7 days (mg/mg)
Estradiol/norethindrone Activella 1/0.5 (mg/mg)
Ethinyl estradiol/ norethindrone FemHRT 5/1 (mg/mg)

There are a number of different progestins that can be used for hormone replacement therapy including the medroxyprogesterone (MPA) and micronized progesterone, as well as 19-nor testosterone derivatives such as norethindrone. Progestins are usually given cyclically or continuously. Tables Currently available and combined oral hormone replacement therapy preparations in the US and Currently available transdermal/topical estrogen replacement therapy preparation in the US list some of the combination products.

Table Currently available transdermal/topical estrogen replacement therapy preparation in the US

Medication Brand Name Available Doses
Single Agent
Estradiol Alora 0.05, 0.075, 0.1 (mg) 2 x per wk
  Climara 0.025, 0.0375, 0.05, 0.06, 0.075, 0.1 (mg) 1 x per wk
  Estraderm 0.05,0.01 (mg) 2 x per wk
  Vivelle 0.025, 0.0375, 0.05, 0.06, 0.075, 0.1 (mg) 1 x per wk
  EstroGel 1.25g 1 x per day
Combined Agents
Estradiol/norethindrone Combipatch 0.05/0.14; 0.05/0.25 (mg/mg) 2 x per wk
Estradiol/levonorgestrel ClimaraPro 0.045/0.015 (mg/mg) 1 x per wk

Estrogens, if given orally, are usually administered daily with differences in regimens dependent on how the progestin is given. A variety of topical and transdermal agents with weekly administration are also available. Cyclic therapy usually involves the administration of the progestin agent for 10-14 days each month. Since the estrogen is given daily, it is easiest to administer the progestin agent from the 1st to the 12th of each month. This usually results in a predictable, monthly, withdrawal bleed. Quarterly therapy consists of daily administration of estrogen, with a progestin administered for 14 days every 3 months. This typically will result in a withdrawal bleed every 3 months, which is preferable to some patients. Continuous combined therapy involves the daily administration of both an estrogen and a progestin. The goal of continuous therapy is to produce amenorrhea by inhibition of endometrial growth. Tables Currently available transdermal/topical estrogen replacement therapy preparation in the US, Currently available single intravaginal estrogen replacement therapy preparations in the US list the various types and doses of estrogen and progestins that are currently available.

Table Currently available single intravaginal estrogen replacement therapy preparations in the US

Medication Brand Name Available Doses
Conjugated equine Estrogen cream Premarin cream 0.625 mg/g; 1-2 g daily x 2 wk, then 1 g daily 1-3 x wk
Estradiol cream Estrace cream 0.1 mg/g; 2-4 g daily x 2 wk, then 1 g daily 1-3 x wk
Dienestrol cream Orthodienestrol 0.01 mg/g; 1-2 app qd x 2 wk, then taper to 1 -2 x wk
Estradiol tablets Vagifem tablets 0.025 mg daily x 2 weeks, attempt to discontinue over 3 to 6 mos
Estradiol ring Estring 0.075 mg/d ring; insert ring vaginally every 90 days
  Femring 0.05 mg, 0.1 mg/d ring; insert vaginally every 90 days

Alternative Treatments for Hot Flashes

There are a number of alternative therapies for women who are symptomatic from menopausal hot flashes but cannot take estrogen therapy. Venlafaxine hydrochloride and paroxetine are serotonin reuptake inhibitors that effectively reduce hot flash frequency and severity. Other drugs in this class, including fluoxetine, may also be effective, but there are few published data. Recent studies suggest that women given neurontin have fewer hot flashes than those given placebo. Low dose progestins are effective in the treatment of menopausal symptoms to a moderate degree, but still a form of hormonal therapy and may be a source of concern in patients with a history of breast cancer. Two antihypertensives, clonidine and methyldopa, have been used to treat vasomotor symptoms, suggesting a role for adrenoreceptors in the physiology of these symptoms. Low dose clonidine, is partially effective in the relief of hot flashes, but for many women, adequate therapy requires substantial doses and severe side effects. Methyldopa, at doses of 500 to 1000 mg/d, has been shown to be twice as effective as placebo for the treatment of hot flashes. Veralipride is a dopamine antagonist that has been shown to be active in the hypothalamus, effectively inhibiting flushing at a dose of 100 mg/day However, it is associated with major side effects such as galactorrhea and mastodynia. Bellergal is a combination of belladonna alkaloids, ergotamine tartrate, and phenobarbital that has been proven to be slightly better than placebo in the treatment of hot flashes, but with significant sedating effects.

Alternative Medicine

This approach includes dietary supplements, which are not considered to be drugs by the Food and Drug Administration (FDA) and therefore are not subject to the strict regulation and safety guidelines imposed on conventional medications. As a result, significant variation can occur in the content and potency of each batch of supplement. Phytoestrogens are plant-derived compounds with estrogen effects soybeans are a particularly rich source of phytoestrogens with approximately 1 to 3 mg of phytoestrogen per gram of soy protein. Since it would be very difficult to consume sufficient soy to alleviate menopausal symptoms in a typical Western diet, some patients opt to take soy supplements. Some (but not all) studies have suggested that isoflavones in soy products reduce the frequency and severity of hot flashes, favorably effect lipid profiles and increase bone mineral density (BMD). Black cohosh or remifemin is another popular herbal medication that has been used to treat menopausal symptoms. Clinical trials show that it is superior to placebo for relief of hot flashes and short term safety data are reassuring. However, many of the efficacy studies are open label and there are no long term safety studies, particularly with respect to effects on breast and endometrium. Finally, vitamin E at a dose of 800 IU daily has been shown to be only slightly more effective than placebo in the treatment of menopausal symptoms. Further study is needed in this area to determine whether there is a definitive benefit from these forms of therapy.

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