The effect of various regimens of hormone replacement therapy on mammographic breast density

OBJECTIVES: To evaluate the effect of three distinct hormone replacement therapy regimens on mammography. METHODS: 121 postmenopausal women who had never received or were past users of hormone replacement therapy were studied prospectively. Women with an intact uterus were randomly allocated either to conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 5 mg (CEE/MPA, n=34) or to 17beta-estradiol 2 mg plus norethisterone acetate 1 mg (E(2)/NETA, n=35). Hysterectomized women received CEE 0.625 mg (CEE, n=25). Women who either declined or did not qualify for treatment served as controls (n=27). Treatment was continuous and the study period lasted 12 months. Main outcome measures were the changes according to Wolfe classification between baseline and 12-month-mammograms. RESULTS: No increase in breast density was identified in any of the women in the control group. Two women (8%) in the CEE group showed an increase in breast density. Four women (11.8%) in the CEE/MPA and 11 women (31.4%) in the E(2)/NETA group revealed an increase in breast density. No woman in the therapy groups showed an involution of fibroglandular tissue while seven women (25.9%) in the control group exhibited involution of breast parenchyma. CONCLUSIONS: Our study suggests that hormone replacement therapy may suspend breast involution but does not increase breast density in the majority of patients. In the minority of patients who show a density increase, the magnitude of this increase varies according to the regimen employed.     

Nitric oxide in postmenopausal women taking three different HRT regimens

OBJECTIVE: To search and compare the effects of three different HRT regimens on nitric oxide levels of postmenopausal women. METHODS: Four groups of postmenopausal women were included in this prospective, randomised, placebo controlled study. 34 women used 0.625 mg conjugated estrogen continuously combined with 5 mg medroxyprogesterone acetate, 32 women used 2.5 mg tibolone, 26 women used 50 mcg transdermal estrogen alone continuously and 32 women used placebo for 12 months. Before the treatment and after 1 year, serum NO (nitrate/nitrite) and some other biochemical parameters were evaluated. RESULTS: All HRT using groups had increased serum nitric oxide levels significantly compared to placebo group and also there was not any difference among three HRT using groups concerning to increases in nitric oxide levels. CONCLUSION: Both conjugated estrogen combined with continuous progestin and transdermal estrogen alone and also tibolone increases serum nitric oxide levels of postmenopausal women equally for 12-months of treatment.     

Modification of serum IGF-I,IGFBPs and SHBG levels by different HRT regimens

During the menopause, levels of SHBG, IGF-I and IGFBPs are significantly modified by the use of different HRT regimens. Objective: The aim of this study is to evaluate the influence of three different HRT regimens on serum levels of SHBG, IGF-I, IGFBP-1 and IGFBP-3 in postmenopausal women. Methods: 41 postmenopausal women requesting HRT were enrolled in the study. Subjects were divided in three groups according to the therapy assigned; Group A: estradiol 2 mg/day+cyproterone acetate 1 mg/day in a cyclic sequential regimen; Group B: estradiol hemihydrate 2 mg/day plus norethisterone acetate (NETA) 1 mg/day in a continuous combined regimen; Group C: estradiol hemihydrate 1 mg/day plus NETA 0.5 mg/day in a continuous combined regimen. Blood samples were drawn before the start of hormonal treatment and after 6 months of HRT. Levels of SHBG, IGF-I, IGFBP-1 and IGFBP-3 in the serum were measured by means of a specific immunoassay. Results: In group A, a significant increase of SHBG, no change of IGFBPs and a significant decrease of IGF-I were observed; in group B and in group C, no significant variations for any of the parameters were recorded. Conclusions: The association of cyproterone acetate to oral estradiol determines a significant reduction of IGF-I levels and an increase of SHBG; nevertheless, it does not seem to influence the serum levels of the IGF-I binding proteins. The treatment with oral continuous combined estrogens plus androgenic progestins, at low doses, produces minor, not significant, changes in the circulating levels of IGF-I, SHBG and IGFBPs.     

Effects of different types of hormone replacement therapy on mammographic density.

OBJECTIVES: to evaluate the effects of different types of hormone replacement therapy (HRT) on mammographic density in postmenopausal women. METHODS: In a prospective 1-year study, 121 healthy postmenopausal women were allocated to one of the following five study groups: twenty-six women were treated with continuous transdermal 17beta-estradiol 50 mcg/die plus acetate nomegestrolo 5 mg/die sequentially added for 12 days per month (Group A); 25 women were treated with continuous transdermal 17beta-estradiol 50 mcg/die plus acetate nomegestrolo 2.5 mg/die added every day (Group B); 23 women were treated with continuous transdermal 17beta-estradiol 50 mcg/die (Group C); 24 women were treated with tibolone 2.5 mg/die (Group D); and 23 women not receiving any medication represented the control group (Group E). At the time of recruitment and after 12 months a two-view mammography was performed to evaluate mammographic density according to a quantitative method: type 1 (less than 25% of mammary gland covered by dense tissue), type 2 (from 25 to 75% of total glandular area covered by dense tissue), type 3 (more than 75% of mammary parenchyma covered by dense tissue). RESULTS: After 12 months of HRT, seven out of 20 patients (35%) in group A, nine of 21 patients (42.85%) in group B, four out of 19 patients (21%) in group C and two of 20 patients (10%) in group D, showed an increase in mammographic density. No variation of density was observed at the second mammographic test in the control group. The mammographic density increase which occurred in groups A, B and C was statistically significant (P<0.05) when compared with group E; no statistically significant difference (P=0.49) was found in mammographic density increase between group D and group E. When the different treatment types were compared each other, a statistically significant difference (P=0.04) was found only between the mammographic density increase occurring in groups B and D. CONCLUSIONS: HRT may cause an increase of mammographic density. The frequency of the density increase is related to the type of HRT and a replacement therapy including a progestin, especially in continuous combination with estrogen, leads to more evident mammographic changes. Tibolone does not significantly affect mammographic density.     

Bleeding pattern and climacteric symptoms during different sequential combined HRT regimens in current use

Four sequential combined oestrogen and progestogen regimens were compared in terms of bleeding pattern and relief of climacteric symptoms. Treatment was with either 2 mg 17β-oestradiol with I mg norethisterone acetate [E₂ + NEta]; 2 mg oestradiol valerate with 75 μg levonorgestrel [E₂V + Lng]; 2 mg oestradiol valerate with 10 mg medroxyprogesterone acetate [E₂V + Mpa]; or 1.5 mg 17β-oestradiol with 150 βg desogestrel [E₂ + DG]. A placebo-controlled study lasting 12–24 months was completed by 143 healthy early postmenopausal women. Bleeding lengths were not substantially different; in all regimens the majority of women were bleeding for 3–6 days. Bleeding onset showed differences when related to the 11th day of progestogen addition; in the regimen with E₂V + LNG, 21% of the women were bleeding before the 11th day of progestogen addition 26% on, and 53% after that day. In the regimen with E₂V + MPA, 56% of the women were bleeding before the 11th day, 28% on, and 17% after that day, whereas in the regimen with E₂ + DG, 15% of the women were bleeding before the 11th day, 5% on, and 80% after that day. All regimens reduced climacteric symptoms to the same extent. Breast tenderness occurred in all the regimens, except in the E₂ + DG. Conclusively, the differences between the responses to treatment were not conspicuous. However, our data indicate that one regimen (E₂ + DG) resulted in optimal bleeding control, optimal effect on climacteric symptoms, and no production of breast tenderness.     

Influence of different hormonal regimens on endometrial microvascular density and VEGF expression in women suffering from breakthrough bleeding

BACKGROUND: The aim of this study was to quantify blood vessel density (BVD) and immunoreactive vascular endothelial growth factor (VEGF) levels in endometrial biopsies taken from women suffering breakthrough bleeding (BTB) under different exogenous hormonal regimes. METHODS: Endometrial biopsies from women in Melbourne with BTB were divided into four groups: combined-continuous hormone therapy (HT) (estrogen and progestin taken daily), cyclical HT (daily estrogen with progestin for 14 days each cycle), progestin-only, or no HT. Subjects from Barcelona were using the Mirena intrauterine levonorgestrel-releasing system for contraceptive purposes, with menstrual diaries for classification into four groups (amenorrhea, infrequent, regular and prolonged). Control biopsies from Melbourne were included in the study. Endometrial samples were immunostained for VEGF and blood vessel localization using an antibody to CD34. RESULTS: Results showed that BVD was significantly reduced in the progestin-only treated group compared with the other three treatment groups (P = 0.028). In addition, all four Mirena BTB groups had significantly reduced BVD compared with controls. Considerable heterogeneity was observed in VEGF immunostaining within and between individual samples with no major differences between HT or Mirena. CONCLUSION: These results provide strong evidence that unopposed progestins reduce endometrial BVD and that there is no link between VEGF immunostaining and BVD or BTB.     

Hormones and mammographic breast density

Mammographic density reveals information about the hormonal environment along with the heritability in which breast cancer develops. This is made possible by the widespread use of population screening by mammography. Increasingly this is an important observation not just for population studies, which reveal disease determinants, but also for the individual. Density reveals the effect of the intrinsic hormonal environment and its background genetics, and also the effect of pharmaceuticals--agents used for disease control and prevention and hormone replacement therapy (HRT) used for well-being around the menopause. Increasingly this focus on the individual will need methods of measurement of density that can be monitored with greater accuracy than the widely used BI-RADS 4 categories. For this purpose studies are under way to measure volume of dense tissue as a continuous variable. In due course, measurement of density will be used as a biomarker of risk, employed in risk models and to monitor interventions. Before this can happen more knowledge will be needed of the change occurring naturally through the menopause and the differences between individuals. This will need specific study backed up with detailed information about the patient on large numbers of women and their mammograms. Currently the widespread use of HRT has increased the prevalence of the dense patterns and potentially may adversely affect the effectiveness of mammographic screening programmes. There is a large literature recording this from which we see that combined continuous preparations of oestrogen progestin are more likely to cause increased density than oestrogen alone or tibolone. Breast density, measured more accurately, has the potential to be an important adjunct to risk estimation and to monitor interventions for breast cancer prevention with pharmaceuticals (such as SERMS) and by change in lifestyle behaviours.     

Mammographic density increase in women receiving different hormone replacement regimens.

OBJECTIVE: we investigated effects of different regimens of hormone replacement therapy (HRT) on mammographic density. METHODS: ninety-five postmenopausal women, who were on different HRT regimens and completed their 4-year mammographic follow-up, were included into this retrospective and comparative study. Twenty-three of these women, who had surgical menopause, received conjugated equine estrogens (CEE) (Group I) only, 26 of them received CEE and continuous medroxyprogesterone acetate (MPA) (Group II), 21 women received CEE and cyclic MPA (Group III), and the remaining 25 women received tibolone (Group IV) therapy. Before commencing on HRT, a baseline high-resolution mammography was performed, and repeated at 6-12-month intervals during the period of 4-year follow-up. All mammographies were evaluated according to the Wolfe classification. RESULTS: a diffuse increase in mammographic density was detected in five women (22%) in group I, nine women (35%) in group II, four women (19%) in group III, and two women (8%) in group IV. The increase in mammographic density was more common among women in group II than those in the other three groups. However, a statistically significant difference was found only between groups II and IV. CONCLUSIONS: different HRT regimens have different effects on breast parenchymal density on mammography. Continuous combination HRT may be more commonly associated with an increase in breast density than other forms of HRT.     

Two hormone replacement therapy (HRT) regimens for middle-eastern postmenopausal women

Most previous studies designed to evaluate the efficacy of hormone replacement therapy (HRT) have been carried out in Europe, North America and Australia, involving Caucasian women for 6 months or less. OBJECTIVES: To evaluate the 12-month effects of two different HRT regimens on postmenopausal symptoms of Middle-Eastern women. METHODS: Hundred healthy Libyan women with postmenopausal symptoms, 12 months or more since their last menstrual period, were enrolled in a 12-month prospective study. Participants were randomly prescribed one of the two formulations, 50 in each group. These regimens were a continuous regimen of tibolone 2.5 mg oral tablets and a continuous regimen of 17beta-oestradiol sequentially combined with dydrogesterone (2/10 mg) oral tablets. The presence and severity of short- and intermediate-term symptoms were reported at 0, 3, 6 and 12 months of treatment. Observed symptoms were hot flushes, night sweating, palpitations, insomnia, depression, nervousness, loss of memory, vaginal dryness, loss of libido and joint pain. RESULTS: Forty-nine women (98%) in each group completed the 12-month study period. Participants, in the two groups, experienced a significant improvement within the first 3 months of treatment. The observed symptoms were completely relived by the sixth month without any significant difference between the two groups. Improvements were sustained over the 12-month period of the study. HRT users showed their acceptance to the two regimens. CONCLUSIONS: Tibolone and 17beta-oestradiol/dydrogesterone oral tablets were effective and safe to treat short- and intermediate-term symptoms in Middle-Eastern postmenopausal women, within 6 months, and with no significant differences between the groups. Thus, the use of HRT to relieve menopausal symptoms is highly recommended, at least in this region.     

A statistical methodology for mammographic density detection

A statistical methodology is presented based on a chi-square probability analysis that allows the automated discrimination of radiolucent tissue (fat) from radiographic densities (fibroglandular tissue) in digitized mammograms. The method is based on earlier work developed at this facility that shows mammograms may be considered as evolving from a linear filtering operation where a random input field is passed through a 1/f filtering process. The filtering process is reversible which allows the solution of the input field with knowledge obtained from the raw image (the output). The input field solution is analogous to a prewhitening technique or deconvolution. This field contains all the information of the raw image in a much simplified format that can be approximated and analyzed with parametric methods. In the work presented here evidence indicates that there are two random events occurring in the input field with differing variances: (1) one relating to fat tissue with the smaller variance, and (2) the second relating to all other tissue with the larger variance. A statistical comparison of the variances is made by scanning the image with a small search window. A relaxation method allows for making a reliable estimate of the smaller variance which is considered as the global reference. If a local variance deviates significantly from the reference variance, based on chi-square analysis, it is labeled as nonfat; otherwise it is labeled as fat. This statistical test procedure results in a region by region continuous labeling of fat and nonfat tissue across the image. In the work presented here, the emphasis is on the methodology development with supporting preliminary results that are very encouraging. It is widely accepted that mammographic density is a breast cancer risk factor. An important application of this work is to incorporate density-based risk analysis into the ongoing statistical-based detection work developed at this facility. Additional applications include risk analysis dependent on either percentages or total amounts of fat or dense tissue. This work may be considered as the initial step in introducing many of the known breast cancer risk factors into the actual image data analysis.     

Postmenopausal hormone therapy and mammographic breast density

OBJECTIVE: The aim of this study was to evaluate the effects of different types of hormone replacement therapy (HRT) on mammographic density. MATERIALS AND METHODS: In a prospective 1-year study, 103 postmenopausal women were randomized to receive tibolone 2.5 mg/die, continuous conjugated equine estrogens 0.625 mg/die plus medroxyprogesterone acetate (MPA) 5mg/die or placebo. Mammograms were performed at baseline and after 12 months of treatment. Mammographic density was quantified according to the Wolfe classification. RESULTS: After 12 months of HRT 16 of the 35 patients (45.1%) receiving continuous combined hormonal therapy showed an increase of breast density change in the Wolfe classification. After treatment with tibolone, an up grading in breast density, according to Wolfe's classification, was found in 2 of the 43 patients (2.3%). No changes were recorded in the 25 patients of the control group. The difference between the group treated with continuous combined hormonal therapy and the control group was highly significant (p<0.001). The difference in breast density between patients in treatment with tibolone and the control group was not statistically significant (p=0.34). DISCUSSION: Continuous combination HRT may be more commonly associated with an increase of mammography density than tibolone treatment.     

Comparison of two HRT regimens with bimonthly and monthly progestin administration in postmenopause

OBJECTIVES: Here we report the results of a study in which natural estrogens were given transdermally cyclically and continuously for 1 year, and a progestin of the latest generation, namely nomegestrol acetate, was given for 10 days every month and for 15 days every 2 months. METHODS: The patients were a group of 34 post-menopausal women (51-56 years), 18 of whom (group A) were treated with continuous transdermal estradiol (50 micrograms/day) and cyclic oral nomegestrol at a dose of 5 mg/day for 15 days every 2 months for 1 year. The other 16 women (group B) were treated with cyclic transdermal estradiol for 3 weeks with oral nomegestrol for 10 days (12-21)/month. Endometrial thickness was evaluated by transvaginal ultrasonography before and after treatment. At the end of treatment, an endometrial biopsy was performed. Serum total cholesterol, HDL, LDL and triglycerides were assessed at baseline and every 4 months. The characteristics of the cycle were deduced from the diary cards recorded by the women. RESULTS: No significant differences were found in the mean interval between the last dose of nomegestrol and the start of bleeding or in the duration of bleeding. The total number of days of bleeding per year was significantly lower in group A than group B (27 +/- 12 vs. 52 +/- 18; P < 0.01). Total serum cholesterol and LDL significantly decreased after 1 year of treatment in both groups, HDL-cholesterol and triglycerides were found increased at most of the time points studied. CONCLUSIONS: The present protocol involving continuous transdermal administration of estrogen combined with oral progestin every 2 months gave good control of the menstrual cycle, did not increase the risk of endometrial pathology and met with good patient compliance.     

The effect of low dose hormone therapy on mammographic breast density

OBJECTIVES: To evaluate the effect of two standard and one low dose continuous hormone therapy regimens on mammography. METHODS: One hundred and thirty-two non-hysterectomized postmenopausal women were randomly allocated either to conjugated equine estrogens 0.625 mg plus medroxyprogesterone acetate 5 mg (CEE/MPA, n=38), 17beta-estradiol 2 mg plus norethisterone acetate 1 mg (E2/NETA, n=44) or 17beta-estradiol 1 mg plus norethisterone acetate 0.5 mg (low E2/NETA, n=50). Treatment was continuous and the study period lasted 12 months. Main outcome measures were the changes according to Wolfe classification between baseline and 12-month mammograms. RESULTS: Five (13.2%) women in the CEE/MPA group showed an increase in breast density. Fourteen (31.8%) women on E2/NETA and 6 (12.2%) on low E2/NETA treatment revealed an increase in breast density. No woman exhibited an involution of fibroglandular tissue. CONCLUSIONS: Different hormone therapy regimens have a variable impact on breast density probably depending on the steroid used. Low dose hormone therapy associates with significantly lesser increase in breast density.     

A new method for quantitative analysis of mammographic density

Women with mammographic percent density >50% have a approximately three-fold increased risk of developing breast cancer, potentially making them screening candidates for breast MRI scanning. The purpose of this work is to introduce a new method to quantify mammographic percent density (MPD), and to compare the results with the current standard of care for breast density assessment. Craniocaudal (CC) and mediolateral oblique (MLO) mammograms for 104 patients were digitized and analyzed using an interactive computer-assisted segmentation routine implemented for two purposes: (1) to segment the breast area from background and radiographic markers, and (2) to segment dense from fatty portions of the breast. Our technique was evaluated by comparing the results to qualitative estimates determined by a certified breast radiologist using the BI-RADS Categorical Assessment (1 (fatty) to 4 (dense) scale). Statistically significant correlations (two-tailed, p < 0.01) were observed between calculated MPD and BI-RADS for both CC (Spearman rho = 0.67) and MLO views (Spearman rho = 0.71). For the CC view, statistically significant differences were revealed between the mean MPD for each BI-RADS category except between fatty (BI-RADS 1) and scattered (BI-RADS 2). Finally, for the MLO views, statistically significant differences in the mean MPD between all BI-RADS categories were observed. Comparing the CC and MLO views revealed a strong positive correlation (Pearson r = 0.8) in calculated MPD. In addition, an evaluation of the reproducibility of our segmentation demonstrated the average standard deviation of MPD for a subsample of eight patients, measured five times, was 1.9% (range: 0.03%-9.9%). Eliminating one misassignment reduced the average standard deviation to 0.75% (range: 0.03%-3.16%). Further analysis of approximately 10% of the patient sample revealed strong agreement (ICC = 0.80-0.85) in the reliability of MPD estimates for both mammographic views. Overall, these results demonstrate the feasibility of utilizing our approach for quantitative breast density segmentation, which may be useful for detecting small changes in MPD introduced through chemoprevention, diet, or other interventions.     

Imaging characteristics of different mammographic screens.

A study of mammography systems with green-emitting screens was conducted to determine how the image quality parameters (apart from dose requirement), such as modulation transfer function (MTF) and Wiener spectrum (WS), depend on the dye content of the compound and coating weight of the screen. In addition, the contribution to total noise of the individual components, i.e., film, screen, and quantum noise, was studied. The quantities derived from MTF and WS, namely detective quantum efficiency (DQE) and noise equivalent quanta (NEQ), were also investigated in regard to their dose dependency. It can be demonstrated that the MTF of the screens becomes more favorable when the dye content is increased, while noise is not significantly affected. This suggests the use of a mammography screen capable of greater detail recognition, requiring at least double the dose of today's conventional systems with approximately 80 microGy system dose. On the other hand, the manufacture of a screen with about 60% of the dose of the conventional system is possible with very little loss in image quality. For the systems in common use today (80 microGy), quantum noise represents a considerable share of the total noise at low spatial frequencies, whereas in high spatial frequencies, the graininess of the film dominates quantum noise and screen structure.     

Prospective,randomised study with three HRT regimens in postmenopausal women with an intact uterus

Objective: To compare compliance, symptom control, bleeding patterns, lipid and biochemical changes in postmenopausal women treated with three regimens of HRT. Methods: In a prospective, randomised, group comparative study, with 165 patients, the effects on the aforementioned parameters, as well as treatment compliance and side effects were studied with oral tibolone 2.5 mg per day, with cyclic combined regimen of transdermal oestrogen and progestogen (transdermal patch of 17β-oestradiol 50 μg/day during 14 days and transdermal patch of 17β-oestradiol 50 μg/day plus 0.25 mg/day NETA during the following 14 days), and with intermittent progesterone regimen (transdermal 17β-oestradiol 50 μg/day and oral micronised natural progesterone 200 mg twice a week). Statistical analysis was carried out using the Fisher-test, analysis of the variance (ANOVA) and the Bouferoni test. Results: Ten women dropped out of the tibolone group, 11 dropped out of the intermittent dosing group and 21 dropped out of the cyclid combined group. Irregular bleeding occurred at more rates in the cyclid combined group. Similar reductions in climacteric symptoms were found in the three groups. No differences were observed with respect to biochemical analysis. Conclusions: Efficacy and safety of the three treatment regimens being comparable, but the patients in our study preferred those that did not produce bleeding episodes.     

Bleeding patterns in recent postmenopausal outpatients with uterine myomas: comparison between two regimens of HRT

Objectives: To evaluate and to compare the bleeding patterns obtained with two regimens of hormone replacement therapy given to early postmenopausal women with asymptomatic uterine leiomyomas. Methods: In this randomised prospective 1-year study 50 early postmenopausal women with one to four asymptomatic uterine leiomyomas were enrolled into two study-groups to take two regimens of hormone replacement therapy for 12 28-day cycles: (A) Tibolone, 2.5 mg/day; (B) conjugated equine estrogens (CEE), 0.625 mg/day plus medroxyprogesterone acetate (MPA), 5 mg/day. The bleeding patterns and the changes in uterine volume of the 47 outpatients who completed the study were evaluated and compared. Results: Amenorrhea incidence was higher in group A (75.0% of the cycles) than in group B (65.6% of the cycles), while irregular bleeding and irregular spotting incidences were higher in group B (29.7 and 4.7% of the cycles, respectively) compared to group A (22.6 and 2.4% of the cycles, respectively). The mean bleeding and spotting lengths were not statistically different between patients in group A and those in group B. Finally, at the end of the study period transvaginal ultrasonography showed no significant change in leiomyoma size. Conclusions: The results demonstrate that, in early postmenopausal patients with asymptomatic uterine leiomyomas, Tibolone treatment seems to be preferable compared to CEE–MPA continuous combined treatment in relation to the lesser occurrence of irregular bleeding. Furthermore, neither Tibolone nor CEE–MPA therapy, at the doses used here, promote fibroid growth.     

Hormone therapy,mammographic density,and breast cancer risk

Percent mammographic density (PMD) is a strong independent risk factor for breast cancer. The effects of age, parity and menopause on PMD are consistent with it being a marker of susceptibility to breast cancer. In this review, we describe the association of PMD with breast cancer, the biological plausibility of this association, and discuss the extent to which PMD meets the criteria for a surrogate marker for the effects of exogenous hormones on risk of breast cancer.     

Computing mammographic density from a multiple regression model constructed with image-acquisition parameters from a full-field digital mammographic unit

Breast density (the percentage of fibroglandular tissue in the breast) has been suggested to be a useful surrogate marker for breast cancer risk. It is conventionally measured using screen-film mammographic images by a labor-intensive histogram segmentation method (HSM). We have adapted and modified the HSM for measuring breast density from raw digital mammograms acquired by full-field digital mammography. Multiple regression model analyses showed that many of the instrument parameters for acquiring the screening mammograms (e.g. breast compression thickness, radiological thickness, radiation dose, compression force, etc) and image pixel intensity statistics of the imaged breasts were strong predictors of the observed threshold values (model R(2) = 0.93) and %-density (R(2) = 0.84). The intra-class correlation coefficient of the %-density for duplicate images was estimated to be 0.80, using the regression model-derived threshold values, and 0.94 if estimated directly from the parameter estimates of the %-density prediction regression model. Therefore, with additional research, these mathematical models could be used to compute breast density objectively, automatically bypassing the HSM step, and could greatly facilitate breast cancer research studies.