Editorial.Final 10/20/06 1:39 PM Page 10

Home , Antiestrogen, Fulvestrant, Raloxifene, Tamoxifen

OBG_11.06_Editorial.final 10/20/06 1:39 PM Page 10

EDITORIAL

Is Premarin actually a SERM? It acts like a SERM...

onjugated equine estrogen Effects of tamoxifen and Premarin (Premarin) has historically been Initially, tamoxifen was characterized as an C characterized as an estrogen ago- “anti-estrogen,” but it is now recognized nist. But the report from the Women’s that tamoxifen has mixed properties. It is an Health Initiative that long-term Premarin estrogen antagonist in some tissues (breast) Robert L. Barbieri, MD Editor-in-Chief treatment is associated with a reduced risk and an estrogen agonist in other tissues of breast cancer raises the possibility that (bone). To recognize these mixed estrogen Premarin may have both estrogen agonist agonist–antagonist properties, tamoxifen is and antagonist properties. Premarin may now categorized as a SERM. Premarin and actually be better categorized as a selective tamoxifen share many similarities in their estrogen receptor modulator (SERM). effects on major clinical outcomes in post- ® Dowden Healthmenopausal Media women (Table, page 13), WHI: Premarin vs placebo including their effects on breast and In the Premarin vs placebo arm, approximately endometrial cancer, deep venous thrombo- 10,800Copyright postmenopausalFor personal women with ause prior onlysis, and osteoporotic fracture. One clinical- hysterectomy who were 50 to 79 years of age ly important divergence is that tamoxifen were randomized to Premarin 0.625 mg daily or increases and Premarin decreases vasomo- an identical-appearing placebo.1 After a mean tor symptoms. FAST TRACK follow-up of 7.1 years, the risk of invasive breast Commonly used medications that inter- In any case, cancer in the women treated with Premarin was act with the estrogen receptor can be 0.80 (95% confidence interval [CI], 0.62–1.04, arranged along a continuum from a “pure” “Use the lowest P=.09). When the data were analyzed based on estrogen agonist, such as estradiol, to a effective dose adherence to the regimen, a statistically signifi- “pure” estrogen antagonist (antiestrogen), of hormone therapy cant reduction in invasive breast cancer risk was such as fulvestrant (Figure, below). Along for the shortest observed in the women who reliably took their this dimension, Premarin likely shares more Premarin, compared with placebo (hazard ratio properties with estrogen than other SERMs. period of time” 0.67; 95% CI 0.47–0.97, P=.03). In contrast, raloxifene probably shares more properties with a pure antiestrogen such as fulvestrant because, unlike tamox- * Premarin was the medication used in the trial. It is unclear whether the results would be similar with other formulations of ifen and Premarin, raloxifene does not conjugated estrogens or conjugated equine estrogens. increase the risk of endometrial cancer.

The estrogen agonist–antagonist continuum

PURE ESTROGEN Estradiol Premarin Tamoxifen Raloxifene Fulvestrant PURE AGONIST ANTIESTROGEN Biologically active compounds that functionally interact with the estradiol receptor can be conceptually classified along a dimension from “pure” estrogen agonists, such as estradiol, to “pure” estrogen antagonists, such as fulvestrant. Between these two extremes are mixed estrogen agonists–antagonists, which are sometimes classified as selective estrogen receptor modulators (SERMs).

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10 OBG MANAGEMENT • November 2006

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EDITORIAL Effects of tamoxifen and Premarin on clinical endpoints in postmenopausal women

ARE THE EFFECTS OF TAMOXIFEN AND CLINICAL ENDPOINT TAMOXIFEN PREMARIN PREMARIN IN THE SAME DIRECTION? Breast cancer Decreased risk Decreased risk Yes Endometrial cancer Increased risk Increased risk Yes Osteoporotic fracture Decreased risk Decreased risk Yes Deep venous thrombosis Increased risk Increased risk Yes Vasomotor symptoms Increase Decrease No

The complex biology of the estrogen The 17-alpha estrogens in Premarin may be receptor system and the complex pharma- SERMs because they have good affinity for cology of Premarin may explain its SERM the estradiol receptor but low gene promot- activity.2 The functional biology of the er activity in multiple model systems. estrogen receptor system has not been fully elucidated. The selective tissue effects of var- Is Premarin a SERM? ious estrogenic compounds are thought to Most likely the answer is “yes,” but we need be mediated by at least 3 factors: to know much more about the functional • the relative activity of the 2 types of biology of the estrogen receptor system and estrogen receptors (alpha and beta) in the relative estrogen agonist–antagonist each tissue3 effects of Premarin and its components. • the differential changes in estrogen Categorizing Premarin as a “SERM” rather receptor conformation and functional than an “estrogen” necessitates that clini- activity induced by different estrogen cians change their concepts about how this ligands4 commonly used hormone treatment actually • the relative activity of a large number works. Until we know more about this com- of intracellular co-activators and co- plex issue, most clinicians will individualize repressors that bind to the estrogen hormone treatment and follow the guideline: receptor and modulate the activity of “Use the lowest effective dose of hormone the ligand-bound estrogen receptor therapy for the shortest period of time.” Premarin’s complex on gene transcription5 In addition, Premarin is a complex hor- compounds mone containing many compounds, includ- may each have ing estrone sulfate, equilin sulfate, delta different estrogen [email protected] 8,9-dehydroestrone sulfate, 17-alpha estra- agonist-antagonist diol sulfate and 17-alpha dihyroequilin sul- REFERENCES fate. Each may have different estrogen ago- 1. Stefanick ML, Anderson GL, Margolis KL, et al. Effects of properties conjugated equine estrogens on breast cancer and mam- nist–antagonist properties in various tis- mography screening in postmenopausal women with hys- in various tissues sues. For example, some studies report that terectomy. JAMA. 2006;295:1647–1657. delta 8,9-dehydroestrone sulfate, one com- 2. Dey M, Lyttle CR, Pickar JH. Recent insights into the varying activity of estrogens. Maturitas. 2000;34 (Supplement 2): ponent of Premarin, is a potent estrogen S25–S33. agonist in the brain, but is a weak estrogen 3. Kuiper GGJM, Enmark E, Pelto-Huikko M, Nilsson S, 6 Gustafsson JA. Cloning of a novel estrogen receptor agonist in the liver. In contrast, estrone sul- expressed in rat prostate and ovary. Proc Natl Acad Sci fate, a major component of Premarin, is an USA. 1996;93:5925–5930. estrogen agonist in both the brain and liver. 4. McDonnell DP, Clemm DL, Hermann T,Goldman ME, Pike JW. Analysis of estrogen receptor function in vitro reveals 3 distinct The 17-alpha estradiol and 17-alpha dihy- classes of antiestrogens. Mol Endocrinol. 1995;9: 659–669. droequilin compounds contained in 5. Onate SA, Tsai SY, Tsai MJ, O’Malley BW. Sequence and characterization of a coactivator for the steroid hormone Premarin are also of interest, because receptor superfamily. Science. 1995;270:1354–1357. although they can bind to the human estro- 6. Baracat E, Haidar F, Lopez FJ, et al. Estrogen activity and gen receptor, the 17-alpha configuration novel tissue selectivity of delta 8,9-dehyroestrone sulfate in postmenopausal women. J Clin Endocrinol Metab. markedly reduces their biological activity. 1999;84:2020–2027.