John Eden, MD.

Sydney, Australia

Key words: Progestins, breast cancer, estrogen replacement therapy, hormone replacement therapy, estrogen.

I thank Karen D. Mittleman, PhD, and Stephen M. Parker, ELS, for their editorial assistance.

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From the Royal Hospital for Women, University of New South Wales. Received for publication July 9, 2002; revised September 20, 2002; accepted December 3, 2002. Reprints not available from the authors.© 2003, Mosby, Inc. All rights reserved. 0002-9378/2003 $30.00 + 0 doi:10.1067/mob.2003.201

The relationship between the use of menopausal hormone therapy (ERT, unopposed estrogen therapy; HRT, combined estrogen and progestin therapy) and the development of breast cancer remains controversial. Mechanistic studies examining progestins in human breast cancer cell lines have demonstrated a biphasic cellular response to progesterone; initial exposure to hormone results in a proliferative burst with sustained exposure resulting in growth inhibition. To date, there is no definitive evidence that progestins act in the pathogenesis of breast cancer. Epidemiologic studies have produced inconsistent results, and data from randomized, placebo-controlled trials are limited. Although recent results from the continuous combined therapy arm of the Women's Health Initiative trial showed a small increase in the risk of invasive breast cancer in women on therapy for 5 years or more, a clear consensus regarding the relationship between HRT and breast cancer risk cannot yet be drawn from existing data. Studies have consistently documented that HRT use is associated with improved mortality and survival rates for women with breast cancer. Large-scale, randomized studies on different progestin regimens are needed to critically assess the effect of progestin on breast cancer. (Am J Obstet Gynecol 2003;188:1123-31.)

Other than skin cancer, breast cancer is the prevailing cancer in women and the second leading cause of cancerrelated deaths among women in the United States.[1] Approximately 15% to 25% of all breast cancers occur in women with a positive family history of breast cancer in a first-degree relative (mother, sister, or daughter).[2] Two breast cancer genes (BRCA1 and BRCA2) have been identified[3-4] and account for approximately 5% of cancers. To date, however, the etiology of most human breast cancers is still unknown. Established risk factors include early age at menarche, nulliparity, late age at first birth, and late age at menopause. The relationship between these risk factors and normal ovarian function have led some to hypothesize that exposure to ovarian hormones may increase a woman’s risk for breast cancer, but a specific role for estrogen and/or progesterone is unclear.

The use of unopposed estrogen replacement therapy (ERT) for the relief of menopausal symptoms in postmenopausal women has been widespread for several decades. In the 1970s, hormone replacement therapy (HRT, combined estrogen and progestin therapy) was recommended for protection from endometrial cancer. In postmenopausal women, ERT/HRT is effective in alleviating clinical manifestations of estrogen deficiency, including vasomotor and urogenital symptoms,[5] bone loss,[6-9] cardiovascular risk factors,[10] and acute cognitive decline.[11,12]

Because of the influence of ovarian function on breast cancer, there has been extensive examination of a possible correlation between menopausal hormone therapy and breast cancer risk. Some researchers have proposed that unopposed ERT modestly increases the risk of breast cancer, and the addition of progestin further increases this risk[13-15]; however, a broad review of the literature does not uphold these suppositions. Despite reports to the contrary,[14,15] any association of progesterone with breast cancer risk remains controversial. This article reviews the current understanding of the role of progesterone in breast cancer, with special attention paid to its association with breast cancer risk, survival, and underlying cellular processes.

Cellular response to progesterone

The requirement for progesterone in normal mammary gland development is well established,[16,17] but its role in the precancerous and cancerous breast remains poorly defined. Studies with knockout mice have demonstrated that progesterone acts through its nuclear receptor to control normal mammary development and differentiation in preparation for lactation.[18-19] Interestingly, disruptions of mammary development are also observed in mice on deletion of a series of other cellular genes, including cell cycle regulatory proteins such as cyclin D1[20] and transcription factors.[21-22] Taken together, results from knockout studies emphasize that overall control of breast cell proliferation results from a complex balance of hormonal, growth factor, and convergent cellsignaling pathways.[23] The relative role of progesterone in this complex equilibrium is difficult to quantitate.

Research has demonstrated that progesterone can act both as a proliferative and antiproliferative agent in breast tissue. Evidence that progesterone is a proliferative hormone in breast tissue includes the in vivo observations that progesterone levels are greatest during the late luteal phase of the menstrual cycle, a period of high mitotic activity, and that the high progesterone levels during pregnancy induce breast development.[16] However, in vivo observations are inconsistent with results from several randomized clinical trials. In these trials, progesterone was administered topically to women’s breasts before lumpectomy[24] or esthetic breast surgery,[25] and epithelial cell cycles in the removed tissue were evaluated. Both studies found that percutaneous progesterone acts in normal breast as an antiproliferative agent by decreasing the number of cycling epithelial cells. In vitro studies of the cellular response to progesterone have also produced inconsistent results, with progesterone capable of acting as a proliferative[26,27] or an antiproliferative agent,[16,28-30] depending on study parameters.

There is growing evidence that the key to understanding inconsistent data regarding the cellular effects of progesterone lies in the duration of hormone exposure. Cell culture studies with human breast cancer cell lines have demonstrated that the proliferative effects of progesterone are biphasic.[31-33] A single initial pulse of progesterone results in a short-lived induction of genes associated with cell growth, with acceleration through one mitotic cycle.[34,35] However, subsequent pulses of progesterone are inhibitory and result in growth arrest in the second cell cycle.[23,31-33] The finding that the rate and duration of progesterone treatment controls the cellular response to progestin can reconcile disparate in vitro results found in the literature. These studies have led some to propose that transient or intermittent doses of progesterone are growth stimulatory in breast cells, whereas continuous or sustained progesterone is growth inhibitory.[23,32] The biphasic growth response has important implications for the timing of progestin treatments and stresses the need for careful examination of sequential versus continuous administration of progestin in postmenopausal hormone therapy with regard to breast cancer risk. The in vitro studies cited here indicate that continuous, daily administration of progestins may be advantageous.

Progestins and the biosynthesis of estrogen

Although the ovary serves as the primary source of estrogen for premenopausal women, after menopause estrogen biosynthesis from circulating precursors occurs in some peripheral tissues by the action of several enzymes-17ß-hydroxysteroid dehydrogenases (17ß-HSD), aromatase, and sulfatases. In the breast, both adipose tissue and malignant tumors have been shown to be capable of synthesizing estrogen,[36-37] and estrogen production by mammary adipose tissue, specifically the stromal component,[38] has been implicated in the development of breast tumors.[39] At present, aromatase inhibitors are successfully used as second-line treatment for breast cancer in postmenopausal women,[40,41] and other compounds, including progestins, are being investigated as potential therapeutic options because of their ability to modulate enzymes involved in estrogen biosynthesis.[42]

17ß-HSD consists of a complex group of enzymes[43] that catalyze the bidirectional conversion of inactive estrone to the biologically active estrogen, estradiol. Both in normal breast tissue[44] and in hormone-independent breast cancer cell lines,[45] 17ß-HSD activity is in the oxidative direction (promoting the conversion of estradiol to estrone), whereas in hormone-dependent breast cancer cell lines, reductive 17ß-HSD activity predominates.[45,46] A series of progestins have been tested in vitro for their ability to affect the relative oxidative/reductive activities of 17ß-HSD. Although early data from human breast tumors suggest that progestins can increase oxidative 17ß-HSD activity,[47] results from cell culture studies are contradictory. For example, in the hormone-dependent breast cancer cell line T-47D, nomegestrol acetate and medrogestone were shown to significantly decrease reductive 17ß-HSD activity.[48-50] In T-47D cells, however, promegestone has no effect on the reductive activity but can increase the oxidative 17ßHSD activity.[45,46] In MCF-7 breast cancer cells, progestins have been shown to increase both reductive and oxidative 17ß-HSD activities.[51,52]

Although it has been shown that aromatase activity in breast tissue is influenced by systemic elements such as growth factors and hormonal status,[36,53] studies on the effect of progestins on aromatase are very limited. With use of human breast carcinoma cell lines, Perel et al[54] have demonstrated that promegestone can inhibit aromatase activity by as much as 30%.

Minimizing the production of estradiol with antiaromatase compounds has provided significant therapeutic benefits for women. Importantly, though, in human breast cancer cells, estrone sulfates, and not androgens, are quantitatively the most important precursor of estradiol.[42] Estrone sulfates themselves have no estrogenic effect because they do not bind to the estrogen receptor. The degree of conjugation of estrone is dependent on the balance of estrone sulfatase and estrogen sulfotransferase activities. Various progestins, including nomegestrol acetate, promegestone, and medrogestone, have been shown to inhibit estrone sulfatase activities[48,49,55] and stimulate sulfotransferase activity[55,56] in hormonedependent breast cancer cell lines, effectively increasing the formation of biologically inactive sulfate derivatives.

Essentially all the data on progestins and estrogen biosynthetic enzymes have been obtained from studies on breast cancer cell lines. Future analysis of the effect of progestins in breast cancer patients, specifically the inhibition of 17P-HSD and sulfatases and the stimulation of sulfotransferases, could provide insight into a potential role for these compounds in the treatment of the disease.

Progestins and breast cancer risk

Epidemiologic studies. The relationship of post-menopausal hormone use to breast cancer risk has been examined in many epidemiologic studies, with mixed and inconclusive results.[57-60] In the past 25 years there have been more than 50 epidemiologic studies and at least 6 meta-analyses relating to breast cancer risk and hormone therapy[57] The majority of these studies contain robust data for unopposed ERT[61]; in comparison, few studies specifically address progestins and breast cancer risk. In the large Collaborative Group on Hormonal Factors in Breast Cancer analysis of 51 published studies involving a total of 52,705 women with breast cancer, the majority of women (80%) had used estrogen-only regimens and, therefore, data for progestin and breast cancer could not be extracted.[61] Of the published studies that have assessed the association between combined estrogen and progestin regimens with breast cancer risk,[14,15,62-81] only four have demonstrated significant differences. Two studies demonstrated a significantly higher breast cancer risk with long-term use of HRT (≥6 years, relative risk [RR] = 1.7 for both studies),[64,71] but in one of those the increased risk was significant only in a subpopulation of lean women.[64] The two other observational studies with significant differences have reported a protective effect with HRT use, with reported RRs of 0.3[62] and 0.5.[63]

Two recent epidemiologic studies[14,15] have garnered extensive attention because of their reported modest increase in breast cancer risk in select subpopulations of HRT users. In a reanalysis of Breast Cancer Detection Demonstration Project data, Schairer et al[14] concluded that HRT results in a greater risk of breast cancer than ERT. This conclusion, however, was based on few data associated with progestin use and was limited to a small group of lean women who used progestins for fewer than 15 days; the RRs did not achieve statistical significance. Similarly, Ross et al15 reported results of a populationbased, case-control study that suggest a greater risk of breast cancer with HRT compared with ERT; again, the number of data available for HRT was very limited and comparisons were not statistically significant. Other recent studies that have not received as much attention have demonstrated no significant effect on breast cancer risk.[74,81] For example, a cohort study monitored 5761 postmenopausal women for up to 22 years and reported a lower incidence of breast cancer in women who had used HRT compared with women who had never used HRT (RR = 0.8, 95% CI 0.6-1.1).[81] The lack of consistency from a large number of epidemiologic studies suggests either no effect of combined hormone therapy on breast cancer risk, or at best, a modest but not significant effect with long-term use in a select population of women.

Data from randomized controlled trials examining progestins and breast cancer were very limited until recently. A small, 22-year-long, placebo-controlled clinical trial of HRT use found a significantly lower incidence of breast cancer in women receiving combined therapy (0% incidence) compared with placebo (11.5% incidence, P > .01).[82] The results of the continuous combined arm (conjugated equine estrogens [CEE], 0.625 mg/day, with medroxyprogesterone acetate [MPA], 2.5 mg/day) of the Women’s Health Initiative (WHI) study involving >16,000 postmenopausal women were published in July 2002.[83] After a mean follow-up of 5.2 years, WHI investigators reported a hazard ratio for risk of invasive breast cancer of 1.26 (95% CI, 1.00-1.59). In absolute terms, after 5.2 years they found that there were eight more breast cancers per 10,000 women per year among HRT users; the absolute increased risk of breast cancer was 0.4%. However, when the investigators performed a subgroup analysis, they found that the only group that had a significantly increased risk of breast cancer was that group of women who had been on HRT before entering the study. In other words, the results from WHI are consistent with previously published observational data[64,71] suggesting that there may be a slightly increased risk of breast cancer after 5 years’ use of combined HRT. There was no increased risk of death from breast cancer. The estrogenalone arm of the WHI is still continuing.

Further, two forms of CIs are presented in the WHI report, nominal and adjusted. The nominal intervals describe the variability in the risk estimates that would arise from a simple trial for a single outcome; for invasive breast cancer these intervals were 1.00-1.59. The adjusted CIs accounted for a Bonferroni correction. The Bonferroni CIs for the breast cancer data were not significant (0.83-1.92).[83]

HRT in high-risk women. If HRT does increase breast cancer risk, this outcome would likely be exacerbated in women at high risk for development of the disease. However, several studies examining tumor incidence in women with a family history significant for breast cancer[78] or tumor recurrence in breast cancer patients[84-90] have failed to demonstrate an association between HRT use in high-risk women and increased incidence of breast cancer. For example, a large prospective cohort study involving >41,000 women with a family history of breast cancer found that women who were receiving HRT did not have a significantly higher breast cancer risk than women who had never used hormones.[78]

Although HRT has traditionally been withheld from women with a personal history of breast cancer,[88,89,91] a few studies in women previously diagnosed with breast cancer have suggested that HRT may have beneficial effects.[87,88,92] A nested, case-controlled study in Australia examined 1122 women with surgically proved breast cancer and found that ERT/HRT use after diagnosis resulted in a significant reduction in recurrence compared with nonuse (RR = 0.62; 95% CI, 0.43-0.87).[92] Also, all-cause mortality (RR = 0.34; 95% CI, 0.19-0.59) and death from primary tumor (RR = 0.40; 95% CI, 0.22-0.72) were both reduced for the subjects using ERT/HRT. The majority of women used continuous combined HRT; the median daily dose of progestin was 50 mg of MPA or 5 mg of norethisterone, a higher dose than commonly given with estrogen, in an attempt to elicit an antiestrogen effect on the breast. To my knowledge, this approach has not been tried previously.

Another study that examined 2755 women diagnosed with breast cancer observed a rate of breast cancer recurrence of 17 per 1000 person-years in women who used ERT/HRT after diagnosis and 30 per 1000 person-years in nonusers; it also demonstrated a significantly lower risk of recurrence for ERT/HRT users (RR = 0.50; 95% CI, 0.30-0.85).[87] In contrast to the Australian study, most patients (79%) used estrogen without a progestin. These data suggest that HRT use after breast cancer diagnosis may be protective. Although these results must be considered preliminary, the possibility that HRT can improve survival in patients with breast cancer would necessitate major re-evaluation of hormonal treatment of these patients.[93]

Effect on breast density. Many studies have demonstrated that women tend to have an increase in parenchymal breast density with HRT use.[94-104] This increase in density occurs soon after initiation of hormones[94,97,99,102] and is sustained throughout therapy[99,105] however, the effect reverses quickly with cessation of HRT,[103] typically within 2 weeks.[106] Although some data have suggested that increased breast density is associated with a greater breast cancer risk,[107-109] no studies to date have established a link between the rapidly reversible progestin-induced changes in breast density and increases in cancer risk.

Effect of progestin schedule. The controversy surround-ing progestins and breast cancer risk is compounded by the various progestin regimens currently available. Comparisons of different dosage or duration therapies are not well studied but may prove necessary to obtain an accurate assessment of any role of progestin in breast cancer risk. Because the use of continuous combined progestin is relatively recent, data for this treatment schedule are few. For example, in the reanalysis of the large Nurses’ Health Study data set, the number of women using continuous progestin was too low to evaluate any relationship to breast cancer risk.[65]

Of the in vivo studies that have examined breast cancer risk and treatment regimen, several have demonstrated an increased risk for breast cancer with cyclic progestin in comparison with continuous progestin. For example, results from an early population-based, casecontrol study in Denmark involving 1486 breast cancer patients showed an increased risk with sequential HRT therapy (RR = 1.36; 95% CI, 0.98-1.87), whereas continuous progestin therapy resulted in a nonsignificant reduction in risk (RR = 0.63; 95% CI, 0.26-1.53).[66] A reduction in risk with continuous progestin was also suggested in a cohort study involving 1150 premenopausal women with benign breast disease, where use of continuous 19-nortestosterone derivatives significantly reduced the risk for development of breast cancer (RR = 0.48; 95% CI, 0.25-0.90) over other regimens.[85] More recently, Ross et al[15] and Schairer et al[14] both reported a lower risk estimate with continuous progestins compared with sequential progestins, but the differences in risk between regimens were not statistically significant. In contrast, a large case-control study in Sweden reported that a continuous regimen of HRT was associated with a greater risk of breast cancer compared with a sequential regimen[64] however, some have argued that statistical considerations weaken this conclusion.[110]

Although no data have linked hormone-induced changes in mammographic density with breast cancer risk, some studies have demonstrated differences in density effects between progestin regimens. In contrast to reports from studies that cite a greater increase in breast density with continuous progestin over sequential progestin,[95-97-98-104-111] the large Postmenopausal Estrogen/ Progestin Interventions trial observed no difference in mamographic densities between continuous progestin regimens and sequential progestin regimens.[94]

Effect of progestin dose. The use of lower-dose progestins in HRT formulations is relatively recent; therefore, there is little information on their effects. For example, the extensive Collaborative Group on Hormonal Factors in Breast Cancer meta-analysis of epidemiologic data from 51 studies provided no information on progestin dose effects.[61] Although direct examination of lower doses of progestins has not yet been reported, some investigators have suggested that the data linking continuous combined therapy to a lower risk of breast cancer may be explained by the fact that continuous regimens typically use lower doses of progestin (MPA 2.5 mg) than sequential progestin therapy (typically MPA 5 to 10 mg).[15] Indeed, in a study of mammographic density, a 2.5-mg dose of MPA combined continuously with 0.625 mg of CEE resulted in mean density increases of approximately 50% of those observed with a 5-mg dose of MPA,[95] demonstrating that dose effects are highly probable. Given that the introduction of new progestin formulations has complicated analysis of progestin’s effects, bet-ter-designed investigations are necessary to elucidate any role of progestin dose.[112]

Progestins and breast cancer survival

Although results from epidemiologic studies remain inconsistent, most of the studies that have examined breast cancer outcome in women who had used ERT/HRT have consistently documented improved mortality[78,87,113-116] and survival rates.[117-123] For example, in the Breast Cancer Detection Demonstration Project, breast cancer mortality for women who were receiving hormones at the time of cancer diagnosis was half the mortality of nonusers (RR = 0.5; 95% CI, 0.3-0.8) up until 10 years after diagnosis.[120] The increase in survival may be due in part to surveillance bias, including a greater frequency of mammography and breast examinations among HRT users,[124,125] but early detection may not be the only explanation. Improved survival has also been attributed to observed hormonal influences on tumor biology. Numerous studies have demonstrated that HRT users have smaller tumors[78,121,122,126-130] that are more well differentiated[60,126-133] and more localized[61,113,126,127,130,131,134] than tumors in nonusers of HRT. In addition, histologic studies have shown that breast tumors in HRT users have a lower proliferation rate (S-phase fraction) than do tumors in nonusers,[127,128,131] although one report demonstrated the opposite effect.[135] The favorable tumor characteristics observed with HRT use imply that exogenous hormones may promote the controlled growth of a malignant locus already in place. In general, breast cancer in HRT users is less aggressive than cancer in nonusers; therefore, prior HRT use is associated with a more favorable clinical outcome for breast cancer patients.


To date, there is conflicting epidemiologic evidence about the role of progestins in breast cancer. The majority of observational studies have examined estrogen-only regimens and those that were able to deduce progestin effects have differing results. Although two recent epidemiologic studies that garnered significant attention reported slightly elevated risks with HRT, the statistical strength of these conclusions is weak, and a clear consensus on progesterone and breast cancer risk is lacking. In the large, randomized WHI trial, the relationship between the small increase in risk of breast cancer after 5.2 years seen in the HRT arm and the progestin used is not clear. Despite the commercial introduction of new progestin regimens involving varied doses or treatment schedules, there has been little examination of the different effects of these formulations on breast cancer risk.

Although a consensus regarding the relationship between HRT and breast cancer risk cannot be drawn from existing epidemiologic data, studies have clearly demonstrated that prior or current HRT use results in a paradoxically improved survival for patients with breast cancer. This improved outcome may be due in part to surveillance bias but may also be due to hormone-induced tumor characteristics that result in a more favorable prognosis.

Progesterone action in a normal and neoplastic breast cell is not isolated; a series of important regulatory proteins work in concert to decide cell fate. Results from mechanistic studies with breast cancer cell lines have demonstrated both proliferative and antiproliferative effects of progestins. This disparity in response is thought to result in part from a biphasic cellular response to progestin that depends on duration of treatment. Progestins are proliferative when administered in a transient or sequential mannerm but sustained treatment results in growth arrest. The timing and dose of progesterone treatment, therefore, is likely to influence any biologic response. The implication that sustained progestin may be inhibitory to malignancies already in place corroborates the favorable tumor biology observed in breast cancer patients who use HRT. The cellular effects of progestins on modulating enzymes involved in the localized biosynthesis of estrogens may also prove advantageous for women at risk for breast cancer or as a treatment option.

Despite in vivo consonance between progesterone levels and high mitotic activity in the breast, results from epi-demiologic studies are inconsistent and mechanistic studies have not provided a physiologic foundation to implicate progestin in the pathogenesis of breast cancer. It is clear that rigorous, large-scale, double-blind, randomized trials are necessary to clarify the role of progestins and breast cancer risk. Given the variety of formulations available today, differences between progestin doses or treatment schedule must also be carefully examined. Because progestins are now widely used in postmenopausal hormone therapy, it is becoming critically important that their specific effect on breast cancer be clearly understood.


American Cancer Society. Cancer facts and figures-1998. Atlanta (GA): American Cancer Society; 1998. 

Schneider HP. HRT and cancer risk: separating fact from fiction. Maturitas 1999;33(1 Suppl):S65-72. 

Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994;266:66-71. 

Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, Collins N, et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 1994;265:2088-90. 

Johnson SR. Menopause and hormone replacement therapy. Med Clin North Am 1998;82:297-320. 

Cauley JA, Seeley DG, Ensrud K, Ettinger B, Black D, Cummings SR, et al. Estrogen replacement therapy and fractures in older women. Ann Intern Med 1995;122:9-16. 

Notelovitz M. Estrogen therapy and osteoporosis: principles and practice. Am J Med Sci 1997;313:2-12. 

Brunelli MP, Einhorn TA. Medical management of osteoporosis: fracture prevention. Clin Orthop 1998;348:15-21. 

Eastell R. Treatment of postmenopausal osteoporosis. N Engl J Med 1998;338:736-46. 

Mosca L. The role of hormone replacement therapy in the prevention of postmenopausal heart disease. Arch Intern Med 2000;160:2263-72. 

Paganini-Hill A, Henderson VW. Estrogen replacement therapy and risk of Alzheimer disease. Arch Intern Med 1996;156:2213-7. 

Kawas C, Resnick S, Morrison A, Brookmeyer R, Corrada M, Zonderman A, et al. A prospective study of estrogen replacement ther-apy and the risk of developing Alzheimer’s disease: the Baltimore Longitudinal Study of Aging. Neurology 1997; 48:1517-21. 

Colditz GA, Hankinson SE, Hunter DJ, Willett WC, Manson JE, Stampfer MJ, et al. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995;332:1589-93. 

Schairer C, Lubin J, Triosi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000;283:485-91. 

Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst 2000;92:328-32. 

Graham JD, Clarke CL. Physiological action of progesterone in target tissues. Endocr Rev 1997;18:502-19. 

Clarke CL, Sutherland RL. Progestin regulation of cellular pro-liferation. Endocr Rev 1990;11:266-301. 

Lydon JP, DeMayo FJ, Funk CR, Mani SK, Hughes AR, Montgomery CA Jr, et al. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev 1995;9: 2266-78. 

Humphreys RC, Lydon JP, O’Malley BW, Rosen JM. Use of PRKO mice to study the role of progesterone in mammary gland development. J Mammary Gland Biol Neoplasia 1997;2:343-54. 

Sicinski P, Donaher JL, Parker SB, Li T, Fazeli A, Gardner H, et al. Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 1995;82:621-30. 

Liu X, Robinson GW, Wagner KU, Garrett L, Wynshaw-Boris A, Hennighausen L. Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes Dev 1997;11:179-86. 

Udy GB, Towers RP, Snell RG, Wilkins RJ, Park SH, Ram PA, et al. Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression. Proc Natl Acad Sci U S A 1997;94:7239-44. 

Lange CA, Richer JK, Horwitz KB. Hypothesis: progesterone primes breast cancer cells for cross-talk with proliferative or antiproliferative signals. Mol Endocrinol 1999;13:829-36. 

Chang K-J, Lee TTY, Linares-Cruz G, Fournier S, De Lignieres B. Influences of percutaneous administration of estradiol and pro-gesterone of human breast epithelial cell cycle in vivo. Fertil Steril 1995;63:785-91. 

Foidart J-M, Colin C, Denoo X, Desreux J, Béliard A, Fournier S, et al. Estradiol and progesterone regulate the proliferation of human breast endothelial cells. Fertil Steril 1998;69:963-9. 

Edery M, McGrath M, Larson L, Nandi S. Correlation between in vitro growth and regulation of estrogen and progesterone receptors in rat mammary epithelia cells. Endocrinology 1984; 115:1691-7. 

McGrath M, Palmer S, Nandi S. Differential response of normal rat mammary epithelial cells to mammogenic hormones and EGF. J Cell Physiol 1985;125:182-91. 

Malet C, Spritzer P, Guillaumin D, Kuttenn F. Progesterone effect on cell growth, ultrastructural aspect and estradiol receptors of normal human breast epithelial (HBE) cells in culture. J Steroid Biochem Mol Biol 2000;73:171-81. 

Clark JH, Peck EJ Jr. Female sex steroids: receptors and function. New York: Springer-Verlag; 1979. 

McManus MJ, Welsch CW. The effect of estrogen, progesterone, thyroxine, and human placental lactogen on DNA synthesis of human breast ductal epithelium maintained in athymic nudemice. Cancer 1984;54:1920-7. 

Sutherland RL, Prall OW, Watts CK, Musgrove EA. Estrogen and progestin regulation of cell cycle progression. J Mammary Gland Biol Neoplasia 1998;3:63-72. 

Groshong SD, Owen GI, Grimison B, Schauer IE, Todd MC, Langan TA, et al. Biphasic regulation of breast cancer cell growth by progesterone: role of the cyclin-dependent kinase inhibitors, p21 and p27Kip1. Mol Endocrinol 1997;11:1593-607. 

Musgrove EA, Lee CS, Cornish AL, Swarbrick A, Sutherland RL. Antiprogestin inhibition of cell cycle progression in T-47D breast cancer cells is accompanied by induction of the cyclin-dependent kinase inhibitor p21. Mol Endocrinol 1997;11:54-66. 

Hissom JR, Moore MR. Progestin effects on growth in the human breast cancer cell line T-47D-possible therapeutic implications. Biochem Biophys Res Commun 1987;145:706-11. 

Musgrove EA, Lee CSL, Sutherland RL. Progestins both stimulate and inhibit breast cancer cell cycle progression while increasing expression of transforming growth factor , epidermal growth factor receptor, c-fos, and c-myc genes. Mol Cell Biol 1991;11:5032-43. 

James VHT, McNeill JM, Lai LC, Newton CJ, Ghilchik MW, Reed MJ. Aromatase activity in normal breast and breast tumor tissues: in vivo and in vitro studies. Steroids 1987;50:269-79. 

Blankenstein MA, Van DV, Maitimu-Smeele I, Donker GH, de Jong PC, Daroszewski J, et al. Intratumoral levels of estrogens in breast cancer. J Steroid Biochem Mol Biol 1999;69:293-7. 

Bulun SE, Price TM, Aitken J, Mahendroo MS, Simpson ER. A link between breast cancer and local estrogen biosynthesis suggested by quantification of breast adipose tissue aromatase cytochrome P450 transcripts using competitive polymerase chain reaction after reverse transcription. J Clin Endocrinol Metab 1993;77:1622-8. 

Miller WR. Aromatase activity in breast tissue. J Steroid Biochem Mol Biol 1991;39:783-90. 

Murray R. Role of anti-aromatase agents in postmenopausal advanced breast cancer. Cancer Chemother Pharmacol 2001; 48:259-65. 

Iqbal S, Miller WR. New drugs in breast cancer. Exp Opin Pharmacother 2001;2:975-85. 

Chetrite GS, Pasqualini JR. The selective estrogen enzyme modulator (SEEM) in breast cancer. J Steroid Biochem Mol Biol 2001;76:95-104. 

Andersson S, Moghrabi N. Physiology and molecular genetics of 17-hydroxysteroid dehydrogenases. Steroids 1997;62:143-7. 

Pollow K, Boquoi E, Baumann J, Schmidt-Gollwitzer M, Pollow B. Comparison of the in vitro conversion of estradiol-17 beta to estrone of normal and neoplastic human breast tissue. Mol Cell Endocrinol 1977;6:333-48. 

Nguyen B-L, Chetrite G, Pasqualini JR. Transformation of estrone and estradiol in hormone-dependent and hormone-independent human breast cancer cells: effects of the antiestrogen ICI 164,384, danazol, and promegestone (R-5020). Breast Cancer Res Treat 1995;34:139-46. 

Malet C, Vacca A, Kuttenn F, Mauvais-Jarvis P. 17-Estradiol dehy-drogenase (E2DH) activity in T47D cells. J Steroid Biochem Mol Biol 1991;39:769-75. 

Fournier S, Brihmat F, Durand JC, Sterkers N, Martin PM, Kuttenn F, et al. Estradiol 17-hydroxys te ro id dehydrogenase, a marker of breast cancer hormone dependency. Cancer Res 1985;45:2895-9. 

Pasqualini JR, Chetrite G, Nguyen B-L, Maloche C, Delalonde L, Talbi M, et al. Estrone sulfate-sulfatase and 17-hydroxysteroid de-hydrogenase activities: a hypothesis for their role in the evolution of human breast cancer from hormone-dependence to hormone-independence. J Steroid Biochem Mol Biol 1995; 53:407-12. 

Chetrite G, Paris J, Botella J, Pasqualini JR. Effect of nomegestrol acetate on estrone-sulfatase and 17-hydroxysteroid dehydrogenase activities in human breast cancer cells. J Steroid Biochem Mol Biol 1996;58:525-31. 

Chetrite GS, Ebert C, Wright F, Philippe J-C, Pasqualini JR. Effect of Medrogestone on 17-hydroxysteroid dehydrogenase activity in the hormone-dependent MCF-7 and T-47D human breast cancer cell lines. J Steroid Biochem Mol Biol 1999;68:51-6. 

Adams EF, Coldham NG, James VHT. Steroidal regulation of oestradiol-17 dehydrogenase activity of the human breast cancer cell line MCF-7. J Endocrinol 1988;118:149-54. 

Coldham NG, James VHT. A possible mechanism for increased breast cell proliferation by progestins through increased reductive 17 beta-hydroxysteroid dehydrogenase activity. Int J Cancer 1990;45:174-8. 

Miller WR, Mullen P. Factors influencing aromatase activity in the breast. J Steroid Biochem Mol Biol 1993;44:597-604. 

Perel E, Daniilescu D, Kharlip L, Blackstein M, Killinger DW. Steroid modulation of aromatase activity in human cultured breast carcinoma cells. J Steroid Biochem 1988;29:393-9. 

Chetrite GS, Ebert C, Wright F, Philippe A-C, Pasqualini JR. Control of sulfatase and sulfotransferase activities by medrogestone in the hormone-dependent MCF-7 and T-47D human breast cancer cell lines. J Steroid Biochem Mol Biol 1999;70:39-45. 

Chetrite G, Le Nestour E, Pasqualini JR. Human estrogen sulfotransferase (hEST1) activities and its mRNA in various breast cancer cell lines: effect of the progestin, promegestone (R5020). J Steroid Biochem Mol Biol 1998;66:295-302. 

Bush TL, Whiteman M, Flaws J. Hormone replacement therapy and breast cancer: a qualitative review. Obstet Gynecol 2001; 98:498-508. 

Campagnoli C, Biglia N, Cantamessa C, Lesca L, Sismondi P. HRT and breast cancer risk: a clue for interpreting the available data. Maturitas 1999;33:185-90. 

Santen RJ, Pinkerton J, McCartney C, Petroni GR. Risk of breast cancer with progestins in combination with estrogen as hormone replacement therapy. J Clin Endocrinol Metab 2001; 86:16-23. 

Beral V, Banks E, Reeves G, Appleby P. Use of HRT and the sub-sequent risk of cancer. J Epidemiol Biostat 1999;4:191-210. 

Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer. Lancet 1997;350:1047-59. 

Gambrell RD Jr, Maier RC, Sanders BI. Decreased incidence of breast cancer in postmenopausal estrogen-progestogen users. Obstet Gynecol 1983;62:435-43. 

Ng E-H, Gao F, Ji C-Y, Ho G-H, Soo K-C. Risk factors for breast carcinoma in Singaporean Chinese women: the role of central obesity. Cancer 1997;80:725-31. 

Magnusson C, Baron JA, Correia N, Bergstrom R, Adami H-O, Persson I. Breast-cancer risk following long-term oestrogenand oestrogen-progestin-replacement therapy. Int J Cancer 1999; 81:339-44. 

Colditz GA, Rosner B. Cumulative risk of breast cancer to age 70 years according to risk factor status: data from the Nurses’ Health Study. Am J Epidemiol 2000;152:950-64. 

Ewertz M. Influence of non-contraceptive exogenous and endogenous sex hormones on breast cancer risk in Denmark. Int J Cancer 1988;42:832-8. 

Kaufman DW, Palmer JR, de Mouzon J, Rosenberg L, Stolley PD, Warshauer ME, et al. Estrogen replacement therapy and the risk of breast cancer: results from the Case-Control Surveillance Study. Am J Epidemiol 1991;134:1375-85. 

Palmer JR, Rosenberg L, Clarke EA, Miller DR, Shapiro S. Breast cancer risk after estrogen replacement therapy: results from the Toronto Breast Cancer Study. Am J Epidemiol 1991;134:1386-95. 

Yang CP, Daling JR, Band PR, Gallagher RP, White E, Weiss NS. Noncontraceptive hormone use and risk of breast cancer. Cancer Causes Control 1992;3:475-9. 

La Vecchia C, Negri E, Franceschi S, Favero A, Nanni O, Filiberti R, et al. Hormone replacement treatment and breast cancer risk: cooperative Italian study. Br J Cancer 1995;72:244-8. 

Persson I, Weiderpass E, Bergkvist L, Bergstrom R, Schairer C. Risks of breast and endometrial cancer after estrogen and estrogen-progestin replacement. Cancer Causes Control 1999;10: 253-60. 

Stanford JL, Weiss NS, Voigt LF, Daling JR, Habel LA, Rossing MA. Combined estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in middle-aged women. JAMA 1995;274:137-42. 

Newcomb PA, Longnecker MP, Storer BE, Mittendorf R, Baron J, Clapp RW, et al. Long-term hormone replacement therapy and risk of breast cancer in postmenopausal women. Am J Epidemiol 1995;142:788-95. 

Moorman PG, Kuwabara H, Millikan RC, Newman B. Menopausal hormones and breast cancer in a biracial population. Am J Public Health 2000;90:966-71. 

Schuurman AG, van den Brandt PA, Goldbohm RA. Exogenous hormone use and the risk of postmenopausal breast cancer: results from the Netherlands Cohort Study. Cancer Causes Control 1995;6:416-24. 

Levi F, Lucchini F, Pasche C, La Vecchia C. Oral contraceptives, menopausal hormone replacement therapy and breast cancer risk. Eur J Cancer Prev 1996;5:259-66. 

Persson I, Thurfjell E, Bergstrom R, Holmberg L. Hormone re-placement therapy and the risk of breast cancer: nested casecontrol study in a cohort of Swedish women attending mammography screening. Int J Cancer 1997;72:758-61. 

Sellers TA, Mink PJ, Cerhan JR, Zheng W, Anderson K, Kushi LH, et al. The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer. Ann Intern Med 1997;127:973-80. 

Brinton LA, Brogan DR, Coates RJ, Swanson CA, Potischman N, Stanford JL. Breast cancer risk among women under 55 years of age by joint effects of usage of oral contraceptives and hormone replacement therapy. Menopause 1998;5:145-51. 

Henrich JB, Kornguth PJ, Viscoli CM, Horwitz RI. Postmenopausal estrogen use and invasive versus in situ breast cancer risk. J Clin Epidemiol 1998;51:1277-83. 

Lando JF, Heck KE, Brett KM. Hormone replacement therapy and breast cancer risk in a nationally representative cohort. Am J Prev Med 1999;17:176-80. 

Nachtigall LE, Nachtigall RH, Nachtigall RD, Beckman EM. Estrogen replacement therapy II: a prospective study in the relationship to carcinoma and cardiovascular and metabolic problems. Obstet Gynecol 1979;54:74-9. 

Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-33. 

Dupont WD, Page DL, Parl FF, Plummer WD Jr, Schuyler PA, Kasami M, et al. Estrogen replacement therapy in women with a history of proliferative breast disease. Cancer 1999;85: 1277-83. 

Plu-Bureau G, Le MG, Sitruk-Ware R, Thalabard JC, MauvaisJarvis P. Progestogen use and decreased risk of breast cancer in a cohort study of premenopausal women with benign breast disease. Br J Cancer 1994;70:270-7. 

Col NF, Hirota LK, Orr RK, Erban JK, Wong JB, Lau J. Hormone replacement therapy after breast cancer: a systematic review and quantitative assessment of risk. J Clin Oncol 2001;19:2357-63. 

O’Meara ES, Rossing MA, Daling JR, Elmore JG, Barlow WE, Weiss NS. Hormone replacement therapy after a diagnosis of breast cancer in relation to recurrence and mortality. J Natl Cancer Inst 2001;93:754-61. 

Eden JA, Bush T, Nand S, Wren BG. A case-control study of combined continuous estrogen-progestin replacement therapy among women with a personal history of breast cancer. Menopause 1995;2:67-72. 

Dew J, Eden J, Beller E, Magarey C, Schwartz P, Crea P, et al. A cohort study of hormone replacement therapy given to women previously treated for breast cancer. Climacteric 1998;1:137-42. 

Eden JA, Durna EM, Wren BG, Heller G, Leader LR. HRT after breast cancer: the latest results from the Royal Hospital for Women breast cancer study [abstract]. Proceedings of the 5th 

Australasian Menopause Society Congress, Melbourne, Aus-tralia, 23-27 Oct, 2001. Melbourne: The Society; 2001. 

Cobleigh MA, Berris RF, Bush T, Davidson NE, Robert NJ, Sparano JA, et al. Estrogen replacement therapy in breast cancer survivors. JAMA 1994;272:540-5. 

Durna EM, Wren BG, Heller GZ, Leader LR, Sjoblom P, Eden JA. Hormone replacement therapy after a diagnosis of breast cancer: cancer recurrence and mortality. Med J Aust 2002;177:347-51. 

Cuzick J. Is hormone replacement therapy safe for breast cancer patients? J Natl Cancer Inst 2001;93:733-4. 

Greendale GA, Reboussin BA, Sie A, Singh HR, Olson LK, Gatewood O, et al. Effects of estrogen and estrogen-progestin on mammographic parenchymal density. Ann Intern Med 1999; 4:262-9. 

Laya MB, Gallagher JC, Schreiman JS, Larson EB, Watson P, Weinstein L. Effect of postmenopausal hormone replacement therapy on mammographic density and parenchymal pattern. Radiology 1995;196:433-7. 

McNicholas MM, Heneghan JP, Milner MH, Tunney T, Hourihane JB, MacErlaine DP. Pain and increased mammographic density in women receiving hormone replacement therapy: a prospective study. AJR Am J Roentgenol 1994;163:311-5. 

Lundström E, Wilczek B, von Palffy Z, Söderqvist G, von Schoultz B. Mammographic breast density during hormone replacement therapy: differences according to treatment. Am J Obstet Gynecol 1999;181:348-52. 

Persson I, Thurfjell E, Holmberg L. Effect of estrogen and estrogen-progestin replacement regimens on mammographic breast parenchymal density. J Clin Oncol 1997; 15:3201-7. 

Sterns EE, Zee B. Mammographic density changes in perimenopausal and postmenopausal women: is effect of hormone replacement therapy predictable? Breast Cancer Res Treat 2000;59:125-32. 

Erel CT, Seyisoglu H, Senturk ML, Akman C, Ersavasti G, Benian A, et al. Mammographic changes in women on hormonal replacement therapy. Maturitas 1996;25:51-7. 

Stomper PC, Van Voorhis BJ, Ravnikar VA, Meyer JE. Mammographic changes associated with postmenopausal hormone replacement therapy: a longitudinal study. Radiology 1990; 174:487-90. 

Ozdemir A, Konus O, Nas T, Erba G, Cosar S, Isik S. Mammographic and ultrasonographic study of changes in the breast related to HRT. Int J Gynaecol Obstet 1999;67:23-32. 

Colacurci N, Fornaro F, de Franciscis P, Mele D, Palermo M, del Vecchio W. Effects of a short-term suspension of hormone re-placement therapy on mammographic density. Fertil Steril 2001;76:451-5. 

Sendag F, Cosan Terek M, Ozsener S, Oztekin K, Bilgin O, Bilgen I, et al. Mammographic density changes during different postmenopausal hormone replacement therapies. Fertil Steril 2001;76:445-50. 

Rutter CM, Mandelson MT, Laya MB, Seger DJ, Taplin S. Changes in breast density associated with initiation, discontinuation, and continuing use of hormone replacement therapy. JAMA 2001;285:171-6. 

Harvey JA, Pinkerton JV, Herman CR. Short-term cessation of hormone replacement therapy and improvement of mammographic specificity. J Natl Cancer Inst 1997;89:1623-5. 

Boyd NF, Byng JW, Jong RA, Fishell EK, Little LE, Miller AB, et al. Quantitative classification of mammographic densities and breast cancer risk: results from the Canadian National Breast Screening Study. J Natl Cancer Inst 1995;87:670-5. 

Kato I, Beinart C, Bleich A, Su S, Kim M, Toniolo PG. A nested case-control study of mammographic patterns, breast volume, and breast cancer (New York City). Cancer Causes Control 1995;6:431-8. 

Byrne C, Schairer C, Wolfe J, Parekh N, Salane M, Brinton LA, et al. Mammographic features and breast cancer risk: effects with time, age, and menopause status. J Natl Cancer Inst 1995; 87:1622-9. 

Speroff L. Postmenopausal estrogen-progestin therapy and breast cancer: a clinical response to an epidemiologic report. Contemp OB/GYN 2000;103-22. 

Stomper PC, D’Souza DJ, DiNitto PA, Arredondo MA. Analysis of parenchymal density on mammograms in 1353 women 25-79 years old. AJR Am J Roentgenol 1996;167:1261-5. 

112.Shoupe D. HRT dosing regimens: continuous versus cyclic- pros and cons. Int J Fertil 2001;45:7-15. 

Hunt K, Vessey M, McPherson K. Mortality in a cohort of longterm users of hormone replacement therapy: an updated analysis. Br J Obstet Gynaecol 1990;97:1080-6. 

Henderson BE, Paganini-Hill A, Ross RK. Decreased mortality in users of estrogen replacement therapy. Arch Intern Med 1991; 151:75-8. 

Grodstein F, Stampfer MJ, Colditz GA, Willett WC, Manson JE, Joffe M, et al. Postmenopausal hormone therapy and mortality. N Engl J Med 1997;336:1769-75. 

Willis DB, Calle EE, Miracle-McMahill HL, Heath CW Jr. Estrogen replacement therapy and risk of fatal breast cancer in a prospective cohort of postmenopausal women in the United States. Cancer Causes Control 1996;7:449-57. 

Bergkvist L, Adami H-O, Persson I, Bergstrom R, Krusemo UB. Prognosis after breast cancer diagnosis in women exposed to estrogen and estrogen-progestogen replacement therapy. Am J Epidemiol 1989;130:221-8. 

Bonnier P, Romain S, Giacalone PL, Laffargue F, Martin PM, Piana L. Clinical and biologic prognostic factors in breast cancer diagnosed during postmenopausal hormone replacement therapy. Obstet Gynecol 1995;85:11-7. 

Persson I, Yuen J, Bergkvist L, Schairer C. Cancer incidence and mortality in women receiving estrogen and estrogen-progestin replacement therapy-long-term follow-up of a Swedish cohort. Int J Cancer 1996;67:327-32. 

Schairer C, Gail M, Byrne C, Rosenberg PS, Sturgeon SR, Brinton LA, et al. Estrogen replacement therapy and breast cancer survival in a large screening study. J Natl Cancer Inst 1999;91:264-70. 

Fowble B, Hanlon A, Freedman G, Patchefsky A, Kessler H, Nicolaou N, et al. Postmenopausal hormone replacement therapy: effect on diagnosis and outcome in early-stage invasive breast cancer treated with conservative surgery and radiation. J Clin Oncol 1999;17:1680-8. 

Jernstrom H, Frenander J, Ferno M, Olsson H. Hormone replacement therapy before breast cancer diagnosis significantly reduces the overall death rate compared with never-use among 984 breast cancer patients. Br J Cancer 1999;80:1453-8. 

DiSaia PJ, Brewster WR, Ziogas A, Anton-Culver H. Breast cancer survival and hormone replacement therapy: a cohort analysis. Am J Clin Oncol 2000;23:541-5. 

LaCroix AZ, Burke W. Breast cancer and hormone replacement therapy. Lancet 1997;350:1042-3. 

Gajdos C, Tartter PI, Babinszki A. Breast cancer diagnosed during hormone replacement therapy. Obstet Gynecol 2000;95: 513-8. 

Bonnier P, Bessenay F, Sasco AJ, Beedassy B, Lejeune C, Romain S, et al. Impact of menopausal hormone-replacement therapy on clinical and laboratory characteristics of breast cancer. Int J Cancer 1998;79:278-82. 

Salmon RJ, Ansquer Y, Asselain B, Languille O, Lesec G, Remvikos Y. Clinical and biological characteristics of breast cancers in post-menopausal women receiving hormone replacement therapy for menopause. Oncol Rep 1999;6:699-703. 

Holli K, Isola J, Cuzick J. Low biologic aggressiveness in breast cancer in women using hormone replacement therapy. J Clin Oncol 1998;16:3115-20. 

O’Connor IF, Shembekar MV, Shousha S. Breast carcinoma de-veloping in patients on hormone replacement therapy: a histological and immu no his to logical study. J Clin Pathol 1998; 51:935-8. 

Magnusson C, Holmberg L, Norden T, Lindgren A, Persson I. Prognostic characteristics in breast cancers after hormone replacement therapy. Breast Cancer Res Treat 1996;38: 325-34. 

Squitieri R, Tartter PI, Ahmed S, Brower ST, Theise ND. Carcinoma of the breast in postmenopausal hormone user and nonuser control groups. J Am Coll Surg 1994;178:167-70.  

Harding C, Knox WF, Faragher EB, Baildam A, Bundred NJ. Hormone replacement therapy and tumour grade in breast cancer: prospective study in screening unit. BMJ 1996;312:1646-7. 

Bilimoria MM, Winchester DJ, Sener SF, Motykie G, Sehgal UL, Winchester DP. Estrogen replacement therapy and breast cancer: analysis of age of onset and tumor characteristics. Ann Surg Oncol 1999;6:200-7. 

Strickland DM, Gambrell RD Jr, Butzin CA, Strickland K. The relationship between breast cancer survival and prior postmenopausal estrogen use. Obstet Gynecol 1992;80:400-4. 

Cobleigh MA, Norlock FE, Oleske DM, Starr A. Hormone replacement therapy and high S phase in breast cancer. JAMA 1999;281:1528-30.