Conjugated Estrogens (Premarin): Drug Whys

Of great interest to EMS are numerous studies, many demonstrating remarkable outcomes using intravenous doses of conjugated estrogens during resuscitation

Treatment Uses — Conjugated estrogens are used primarily for hormone replacement therapy (HRT) in women after menopause. HRT is prescribed most frequently to treat moderate to severe vasomotor symptoms (hot flashes). Atrophy of the vagina and urinary tract may also require HRT to relieve pain caused by dryness and sores, although topical estrogen creams have far fewer side effects.

Conjugated estrogens have been used to prevent osteoporosis when other drug classes are contraindicated or ineffective. They also are used for treatment of breast cancer in postmenopausal women (and some men) as well as for relief of end stage prostate cancer symptoms. HRT replaces hormones after surgical removal or failure of the ovaries. Some success has been reported using conjugated estrogens to treat uterine bleeding resulting from atrophy of the uterine wall. HRT is also used in male-to-female transsexuals.

While previously used quite commonly for prevention and treatment of osteoporosis, conjugated estrogens should only be prescribed for this purpose in women at significant risk in whom non-estrogen medications are inappropriate. The standard of care for management of postmenopausal osteoporosis includes weight-bearing exercise, adequate calcium (1500 milligrams daily) and vitamin D consumption, and when diet and exercise are inadequate, pharmacologic therapy.

Of great interest to EMS are numerous studies, many demonstrating remarkable outcomes using intravenous doses of conjugated estrogens during resuscitation. Thus far, cardiac arrest and critically ill trauma patients, especially males and post-menopausal females, seem to benefit the most from these experimental interventions. It would not be at all surprising to see conjugated estrogens incorporated into prehospital resuscitation protocols in the future.

Dosing and Administration — Dosing is heavily dependent on the indication for therapy. For treatment of vasomotor symptoms and atrophic (atrophy) problems, daily oral dose ranges of 0.3 to 1.25 milligrams are used, titrated to effect. When absolutely needed for prevention of osteoporosis, a daily oral dose of 0.625 milligrams is used; cyclic administration is suggested, with three weeks on estrogen followed by one week off.

For women who have not had their uterus surgically removed, the addition of progestin during the last 10 to 14 days of estrogen therapy is recommended to reduce tissue overgrowth in the uterus that can lead to cancer. Women without a uterus do not need progestin. Highest doses are used for treatment of breast cancer, recommended at 10 milligrams orally three times daily for at least three months. Intermediate doses ranging from 1.25 milligrams daily to 2.5 milligrams taken two or three times daily are used for HRT following removal or failure of the ovaries.

Conjugated estrogens can be taken without regard to meals.

As most conjugated estrogen therapy is started in the geriatric population, dose adjustment is not needed in older patients. Doses should be reduced by 50 percent in patients with end stage renal disease (i.e. patients on hemodialysis). Because estrogens are processed in the liver, extreme caution should be used in patients with impaired liver function. There are few pediatric dosing recommendations for conjugated estrogens, but at least one study safely used smaller doses in children, titrated to effect.

Intravenous (IV) and intramuscular (IM) formulations of conjugated estrogens are available, as are topical creams, vaginal creams, vaginal suppositories, vaginal rings (that slowly release medication over three months), and transdermal patches (replaced weekly or twice weekly). Oral therapy (tablets) is the most popular form of conjugated estrogens used today.

In overdoses, serious ill effects have not been reported. Overdoses have resulted in nausea, vomiting, breast tenderness, abdominal pain, drowsiness or fatigue and menstrual bleeding in women. Treatment should be supportive.

Pharmacology/Pharmacokinetics/Stability — Following oral administration, conjugated estrogens reach peak concentrations in the bloodstream within eight hours. No differences in concentrations were found comparing once daily dosing to divided three times daily dosing. The liver transforms conjugated estrogens into three separate and distinct metabolites, each with different actions in the body.

The average half life (time required for half the active drug to be eliminated from the body) of these metabolites ranges from 11.4 to 26.5 hours. Conjugated estrogens take between two and four weeks to significantly improve menopausal symptoms. Estrogens are processed by the liver and excreted from the body in urine and bile. There is no reason to use conjugated estrogens during pregnancy; any patient taking them who becomes pregnant should discontinue use.

There is an increase in congenital defects of fetal reproductive organ associated with conjugated estrogen use during pregnancy. Small quantities are excreted in breast milk and have not been associated with any adverse effects in nursing infants although evidence suggests that this drug may decrease both quantity and quality of breast milk.

The role of estrogens in the body is to develop and maintain the female reproductive system and female sexual characteristics. The ovaries of menstruating women produce estrogen. After menopause, circulating estrogen comes from conversion of an adrenal hormone. Conjugated estrogens work like estrogen, exhibiting their effects by binding to receptors on estrogen responsive tissues.

The introduction of generic conjugated estrogens in the United States sparked considerable controversy regarding their effectiveness compared to brand name products. Many of the generic versions were recalled for questionable equivalence to the pioneer conjugated estrogen, Premarin. Presently, there are no generic conjugated estrogens available in the United States, and worldwide Premarin holds 80 percent of the market. As you might surmise from the name, Premarin is a conjugated estrogen product extracted from pregnant mares’ urine (PMU). It most closely resembles human estrogens. There are an estimated 500 PMU farms in North America, most under exclusive contract to provide PMU needed for manufacture of Premarin used by more than 9 million women in the United States.

Premarin brand conjugated estrogen tablets are oval shaped, come in a variety of colors and strengths depending on strength. The 0.625 milligram tablets are maroon, and the 1.25 milligram is yellow. Tablets should be stored at room temperature (77 F) but remain stable when briefly kept at extremes between 59-86 F. They should be protected from moisture (kept in a capped container).

Cautions and Warnings — Estrogens increase the risk of endometrial (uterine) cancer in postmenopausal women. In women who have had breast cancer, conjugated estrogens increase the risk of new breast cancers. In the Women's Health Initiative (WHI) trial (a study of 27,000 predominantly healthy postmenopausal women), estrogens given alone (versus with progestin) decreased the risk of hip fractures but increased the risk of stroke and showed a trend towards greater risk of dementia.

Combined with progestin, conjugated estrogens increased the risk of heart attack, stroke, breast cancer, and blood clots in the lungs and legs. Conjugated estrogens, with or without progestin, should never be used for the prevention of cardiovascular disease or dementia. Data on cardiovascular risks of estrogens are conflicting except for a clearly higher risk of heart attack in smokers who take estrogens.

Estrogens should not be used in patients with history of blood clots, pulmonary embolism, or recent (within one year) cardiovascular events such as stroke or myocardial infarction. They should also not be used in patients with a history of breast cancer (unless being used as a cancer treatment). These warnings are serious enough to require very careful consideration of risks and benefits before treatment with conjugated estrogens, especially for prevention of osteoporosis.

This is even more important given newer non-estrogen drugs targeted at prevention and treatment of osteoporosis but without the serious cardiovascular, cancer, and mental health risks of estrogens. The best remaining reason to use oral conjugated estrogens is to treat vasomotor symptoms. When the sole problem is atrophy, prescribers are encouraged to use creams or suppositories instead of oral therapy.

An FDA (US Food and Drug Administration) Black Box warning appears on Premarin. Black Box warnings are the highest level alert by the FDA to consumers and prescribers warning of potential drug dangers. Five warnings are included on the conjugated estrogen Black Box:
(1) Prescribers should test for endometrial cancer in all cases of persistent or recurrent abnormal vaginal bleeding.
(2) Estrogens with or without pregestins should not be used for prevention of cardiovascular disease of dementia.
(3) Studies have demonstrated an increased risk of stroke and DVT (deep venous thrombosis or blood clots deep veins, usually involving the legs) in postmenopausal women treated with daily conjugated estrogens.
(4) Studies have demonstrated increased risks of MI (myocardial infarction), stroke, invasive breast cancer, pulmonary emboli, and DVT in postmenopausal women treated with combination conjugated estrogens and progestins.
(5) Based on these data, the manufacturer (and the FDA) suggests prescribing conjugated estrogens with or without progestins at the lowest possible doses and the shortest durations necessary to accomplish desired treatment goals.

Important Side Effects and Interactions — Conjugated estrogen side effects profile tends to be a sort of "all or nothing" experience for most patients. Either the drug works superbly with minimal or no adverse effects or the side effects are intolerable. The most common side effect of conjugated estrogens is nausea. This is significantly reduced by taking the drug with meals and will usually disappear with continued use, regardless of when taken.
Dry eye syndrome occurs in 9 percent of people taking conjugated estrogens. There is a two to four fold increase in gallbladder disease requiring surgical intervention. Estrogens tend to produce some degree of fluid retention, so patients with conditions that might be aggravated by this such as renal failure or heart failure should be observed closely. Occasional vaginal bleeding may occur with estrogens, especially when combined with progestin. Occurrence of new (or exacerbation of existing) asthma has been reported, as well as an increased incidence of osteoarthritis of the hands and hips.

There are 161 drugs reported to interact with conjugated estrogens, most not supported by good data. Increased doses of levothyroxine are usually required when taking conjugated estrogens. Blood levels of thyroid stimulating hormone (TSH) should be used to guide dose adjustments. Conjugated estrogens prolong the clearance of caffeine from the body. Of note to EMS providers: conjugated estrogens may result in an increased response to benzodiazepines.

The seriousness of adverse reactions when using conjugated estrogens make it imperative to instruct patients to report breast lumps, vaginal bleeding, jaundice, dark urine or clay colored stools, leg or calf pain, dyspnea, chest pain, or severe headaches.