Editorial

Understanding alternatives for estrogen preparations

A 15-year-old girl with Turner syndrome presented to our hospital with a dilemma: She was on growth hormone and needed to start estrogen replacement.

The patient was refusing my prescription for conjugated estrogens tablets (Premarin, Wyeth Pharmaceuticals).

“I know I need to start estrogen, but it won’t be horse estrogen, not Premarin, no way! You know I am a vegetarian, I love animals and I’ve been on the Internet. There are other estrogens that don’t come from animals and that’s what I want,” she said.

Eileen Durham, C-PNP, MSN, RN
Eileen Durham

This experience prompted me to explore all of the alternative treatments.

Estrogen is one of the most commonly prescribed drugs used by both menopausal woman and young women with premature ovarian failure. Estrogen replacement therapy is prescribed to replace the three principal forms of estrogen found in the human female body: estrone, estradiol and estriol. From menarche to menopause, estradiol is the primary estrogen responsible for inducing puberty and maintaining feminization. In 1942, Wyeth produced the first FDA-approved estrogen replacement therapy; namely, Premarin, which is isolated from PREgnant MARes’ urINe (PMU) and is a mixture of conjugated equine estrogens.

For more than 50 years Premarin has been the most commonly prescribed estrogen supplement in the United States. However, the demand for alternative forms of estrogen replacement is growing.

Major concern about Premarin was prompted by the 2002 reports of adverse events from the Women’s Health Initiative. Results of this randomized controlled trial showed an increased risk of stroke, breast cancer and cardiovascular disease in older women assigned the drug. Investigators wondered if these adverse events would have been observed with all forms of estrogen or whether they might have been specific to the oral conjugated equine estrogen. In addition, resistance to the use of Premarin has increased in response to the reports concerning the treatment of the pregnant mares, their foals, and the methods used to collect their urine for the production of oral conjugated equine estrogen. For these reasons, some patients and practitioners may seek alternatives to oral conjugated equine estrogen for estrogen replacement therapy.

Approved treatment options

There are several FDA-approved hormone preparations that are identical in structure to human estrogens produced normally. Lack of familiarity with these formulations and potency has hampered physicians from prescribing them.

Before deciding on the type of estrogen replacement to prescribe for a patient like the one described above, I had to review the source, dosages, and the route of alternative estrogen preparations as well as additional medications she was currently taking. I shared this information with the patient to allow her to make an informed choice. This discussion served not only to increase the likelihood she would comply but also educated her about potential adverse effect. (see table 1 for a comparison of the different estrogen formulations). The patient preferred to take estradiol, a product derived from yams. Estradiol is identical to the hormone produced by the human body. It is a brand name product that is FDA-approved, has been well tested and comes in a conveniently standard dosage (see table 2).

Table 1: FDA–Approved Estrogen Comparisons

Conjugated Estrogens Source = pregnant horse urine (Premarin, Wyeth Pharmaceuticals) Esterified Estrogens Source = Yams (Estratab, Solvay Pharmaceuticals Inc.; Menest, King Pharmaceuticals Inc.) Estradiol Source = Soy/Yams (Estrace, Bristol-Myers Squibb; Vivelle and Estraderm, Novartis Pharmaceuticals; Climara, Berlex Laboratories)
Sodium estrone sulfate Sodium estrone sulfate 17-beta Estradiol (E2)
Sodium equilin sulfate Sodium equilin sulfate -
Sodium sulfate conjugates - -
17 alpha-dihydroequilin - -
17-alpha estradiol - -
17 beta-dihydroequilin - -
Source: Equipotent dosing: Handbook of Clinical Drug Data, 10th Edition McGraw-Hill 2002.

The next decision related to what route of the hormone she would take. The patient was on GH therapy and some research involving oral estrogen in any form in girls with Turner syndrome has shown that it interferes with the positive effects of GH therapy. Most of these studies have been done with oral estrogen. Oral conjugated equine estrogen and oral beta estradiol have been associated with decreases in levels of IGF-1 of up to 30%, which may potentially reduce the benefits of GH; however, transdermal estradiol has not. This is thought to be due to first pass metabolism of oral estrogens in the liver.

Like all females with hypogonadism, the patient is at increased risk of CVD. In patients with Turner syndrome, ischemic heart disease has been reported to be twice as common as in the general population. Since oral estrogen therapy has been linked to increased CV risk, this might not be the best route of delivery.

Table 2: Estrogen Equivalencies

Steroidal agents Equipotent dose Dosage forms Source
Conjugated estrogen (Premarin, Wyeth Pharmaceuticals) 0.625 mg Tablet: 0.3, 0.625, 0.9, 1.25, 2.5 mg
Vaginal Cream: 0.625mg/g
Urine of pregnant mares
Esterified Estrogen (Estratab, Solvay Pharmaceuticals Inc.; Menest, King Pharmaceuticals Inc.) 0.625 mg Tablet: 0.3, 0.625, 1.25, 2.5 mg Mexican yams
Estradiol 17 beta (Estrace, Bristol-Myers Squibb) 1 mg Tablet: 0.5, 1, 1.5, 2 mg Soy/Yams
Estradiol 17 patch (Vivelle, Estraderm, Novartis Pharmaceuticals; Climara, Berlex Laboratories) 50 mcg/day Transdermal Patch: 25, 37.5, 50, 75, 100 mcg/day Soy/Yams

After consumption of oral estrogen, the hormone is initially metabolized through the liver. This process may stimulate an increase in biochemical factors linked to inflammation. Elevations of C-reactive protein have been observed with oral estrogens in older women. Long-term use of oral estrogen replacement therapy has been shown to be associated with elevated levels of CRP even in apparently healthy women. Preliminary studies using transdermal 17-beta estradiol have not duplicated these findings, possibly because it is not first metabolized through the liver.

Transdermal estrogen offers other advantages over oral formulations. Some patients find it easier to comply with wearing a patch rather than swallowing a pill. Several experts in the treatment of Turner syndrome recommend transdermal estrogen formulation for their patients. Today’s science and technology has advanced hormone replacement therapy to the state of the art in which providers can prescribe medications that are molecularly identical to that produced by the human body. This technology has been used to make thyroxin and insulin rather than rely upon older methods of hormones extracted from beef and pork. It may now be the time to move away from equine sources of estrogen as well.

The optimal dose and route of estrogens remain controversial because of a lack of head-to-head comparison studies. Researchers at Stanford and elsewhere are conducting ongoing research to compare varying oral and transdermal estrogen therapies in adolescents with ovarian failure. We hope the results will provide some needed answers for our patients.

Eileen Durham, C-PNP, MSN, RN, is with the Division of Pediatric Endocrinology and Diabetes at Lucile Packard Children’s Hospital at Stanford, Palo Alto, Calif.

For more information:

  • Anderson G. JAMA. 2004;294:1701-1712.
  • Bondy C. J Clin Endocrinol Metab. 2007;1:10-25.
  • Bondy C. Arch Int Med. 2006;166:1322.
  • Brynhildsen J. Maturitas. 2005;50:344-352.
  • Cesari M. Circulation. 2003;108:2317-2322.de Krake AT. Maturitas. 2004;49:253-263.
  • Grady D. Ann Int Med. 2000;132:689-696.
  • Ichikawa J. Am J Hypertens. 2006;19:744-749.
  • Janssen Y. J Clin Endocrinol Metab. 2000;85:464-467.
  • Keiss W. Hormone Research. 2002;57:66-71.
  • Lacriox A. Amer J Med. 2005;118:79-87.
  • Lantiga G. Euro J Cancer. 2006;42:1415-1420.
  • Modena M. Maturitas. 2005;52:1-10.
  • Pedreira C. Int Med J. 2006;36:54-57.
  • Ridker PM. JAMA. 2005;294:326-333.
  • Rosenfeld R. J Clin Endocrinol Metab. 2005;90:6424-6430.
  • Scarabin P. Atherosclerosis, Thrombosis and Vascular Biology. 1997;17:3071-3078.
  • Scarabin P. Lancet. 2003;362:428-432.
  • Warren M. Growth Hormone and IGF Research. 2006;16:S98-S102.
  • Yilmazer M. Maturitas. 2003;46:245-253.

A 15-year-old girl with Turner syndrome presented to our hospital with a dilemma: She was on growth hormone and needed to start estrogen replacement.

The patient was refusing my prescription for conjugated estrogens tablets (Premarin, Wyeth Pharmaceuticals).

“I know I need to start estrogen, but it won’t be horse estrogen, not Premarin, no way! You know I am a vegetarian, I love animals and I’ve been on the Internet. There are other estrogens that don’t come from animals and that’s what I want,” she said.

Eileen Durham, C-PNP, MSN, RN
Eileen Durham

This experience prompted me to explore all of the alternative treatments.

Estrogen is one of the most commonly prescribed drugs used by both menopausal woman and young women with premature ovarian failure. Estrogen replacement therapy is prescribed to replace the three principal forms of estrogen found in the human female body: estrone, estradiol and estriol. From menarche to menopause, estradiol is the primary estrogen responsible for inducing puberty and maintaining feminization. In 1942, Wyeth produced the first FDA-approved estrogen replacement therapy; namely, Premarin, which is isolated from PREgnant MARes’ urINe (PMU) and is a mixture of conjugated equine estrogens.

For more than 50 years Premarin has been the most commonly prescribed estrogen supplement in the United States. However, the demand for alternative forms of estrogen replacement is growing.

Major concern about Premarin was prompted by the 2002 reports of adverse events from the Women’s Health Initiative. Results of this randomized controlled trial showed an increased risk of stroke, breast cancer and cardiovascular disease in older women assigned the drug. Investigators wondered if these adverse events would have been observed with all forms of estrogen or whether they might have been specific to the oral conjugated equine estrogen. In addition, resistance to the use of Premarin has increased in response to the reports concerning the treatment of the pregnant mares, their foals, and the methods used to collect their urine for the production of oral conjugated equine estrogen. For these reasons, some patients and practitioners may seek alternatives to oral conjugated equine estrogen for estrogen replacement therapy.

Approved treatment options

There are several FDA-approved hormone preparations that are identical in structure to human estrogens produced normally. Lack of familiarity with these formulations and potency has hampered physicians from prescribing them.

Before deciding on the type of estrogen replacement to prescribe for a patient like the one described above, I had to review the source, dosages, and the route of alternative estrogen preparations as well as additional medications she was currently taking. I shared this information with the patient to allow her to make an informed choice. This discussion served not only to increase the likelihood she would comply but also educated her about potential adverse effect. (see table 1 for a comparison of the different estrogen formulations). The patient preferred to take estradiol, a product derived from yams. Estradiol is identical to the hormone produced by the human body. It is a brand name product that is FDA-approved, has been well tested and comes in a conveniently standard dosage (see table 2).

Table 1: FDA–Approved Estrogen Comparisons

Conjugated Estrogens Source = pregnant horse urine (Premarin, Wyeth Pharmaceuticals) Esterified Estrogens Source = Yams (Estratab, Solvay Pharmaceuticals Inc.; Menest, King Pharmaceuticals Inc.) Estradiol Source = Soy/Yams (Estrace, Bristol-Myers Squibb; Vivelle and Estraderm, Novartis Pharmaceuticals; Climara, Berlex Laboratories)
Sodium estrone sulfate Sodium estrone sulfate 17-beta Estradiol (E2)
Sodium equilin sulfate Sodium equilin sulfate -
Sodium sulfate conjugates - -
17 alpha-dihydroequilin - -
17-alpha estradiol - -
17 beta-dihydroequilin - -
Source: Equipotent dosing: Handbook of Clinical Drug Data, 10th Edition McGraw-Hill 2002.

The next decision related to what route of the hormone she would take. The patient was on GH therapy and some research involving oral estrogen in any form in girls with Turner syndrome has shown that it interferes with the positive effects of GH therapy. Most of these studies have been done with oral estrogen. Oral conjugated equine estrogen and oral beta estradiol have been associated with decreases in levels of IGF-1 of up to 30%, which may potentially reduce the benefits of GH; however, transdermal estradiol has not. This is thought to be due to first pass metabolism of oral estrogens in the liver.

Like all females with hypogonadism, the patient is at increased risk of CVD. In patients with Turner syndrome, ischemic heart disease has been reported to be twice as common as in the general population. Since oral estrogen therapy has been linked to increased CV risk, this might not be the best route of delivery.

Table 2: Estrogen Equivalencies

Steroidal agents Equipotent dose Dosage forms Source
Conjugated estrogen (Premarin, Wyeth Pharmaceuticals) 0.625 mg Tablet: 0.3, 0.625, 0.9, 1.25, 2.5 mg
Vaginal Cream: 0.625mg/g
Urine of pregnant mares
Esterified Estrogen (Estratab, Solvay Pharmaceuticals Inc.; Menest, King Pharmaceuticals Inc.) 0.625 mg Tablet: 0.3, 0.625, 1.25, 2.5 mg Mexican yams
Estradiol 17 beta (Estrace, Bristol-Myers Squibb) 1 mg Tablet: 0.5, 1, 1.5, 2 mg Soy/Yams
Estradiol 17 patch (Vivelle, Estraderm, Novartis Pharmaceuticals; Climara, Berlex Laboratories) 50 mcg/day Transdermal Patch: 25, 37.5, 50, 75, 100 mcg/day Soy/Yams

After consumption of oral estrogen, the hormone is initially metabolized through the liver. This process may stimulate an increase in biochemical factors linked to inflammation. Elevations of C-reactive protein have been observed with oral estrogens in older women. Long-term use of oral estrogen replacement therapy has been shown to be associated with elevated levels of CRP even in apparently healthy women. Preliminary studies using transdermal 17-beta estradiol have not duplicated these findings, possibly because it is not first metabolized through the liver.

Transdermal estrogen offers other advantages over oral formulations. Some patients find it easier to comply with wearing a patch rather than swallowing a pill. Several experts in the treatment of Turner syndrome recommend transdermal estrogen formulation for their patients. Today’s science and technology has advanced hormone replacement therapy to the state of the art in which providers can prescribe medications that are molecularly identical to that produced by the human body. This technology has been used to make thyroxin and insulin rather than rely upon older methods of hormones extracted from beef and pork. It may now be the time to move away from equine sources of estrogen as well.

The optimal dose and route of estrogens remain controversial because of a lack of head-to-head comparison studies. Researchers at Stanford and elsewhere are conducting ongoing research to compare varying oral and transdermal estrogen therapies in adolescents with ovarian failure. We hope the results will provide some needed answers for our patients.

Eileen Durham, C-PNP, MSN, RN, is with the Division of Pediatric Endocrinology and Diabetes at Lucile Packard Children’s Hospital at Stanford, Palo Alto, Calif.

For more information:

  • Anderson G. JAMA. 2004;294:1701-1712.
  • Bondy C. J Clin Endocrinol Metab. 2007;1:10-25.
  • Bondy C. Arch Int Med. 2006;166:1322.
  • Brynhildsen J. Maturitas. 2005;50:344-352.
  • Cesari M. Circulation. 2003;108:2317-2322.de Krake AT. Maturitas. 2004;49:253-263.
  • Grady D. Ann Int Med. 2000;132:689-696.
  • Ichikawa J. Am J Hypertens. 2006;19:744-749.
  • Janssen Y. J Clin Endocrinol Metab. 2000;85:464-467.
  • Keiss W. Hormone Research. 2002;57:66-71.
  • Lacriox A. Amer J Med. 2005;118:79-87.
  • Lantiga G. Euro J Cancer. 2006;42:1415-1420.
  • Modena M. Maturitas. 2005;52:1-10.
  • Pedreira C. Int Med J. 2006;36:54-57.
  • Ridker PM. JAMA. 2005;294:326-333.
  • Rosenfeld R. J Clin Endocrinol Metab. 2005;90:6424-6430.
  • Scarabin P. Atherosclerosis, Thrombosis and Vascular Biology. 1997;17:3071-3078.
  • Scarabin P. Lancet. 2003;362:428-432.
  • Warren M. Growth Hormone and IGF Research. 2006;16:S98-S102.
  • Yilmazer M. Maturitas. 2003;46:245-253.