Progestin Users Research Articles

The Association Between Progestin Generation in Hormonal Contraceptives and Sociosexuality

Hormones are important for regulating women’s sexuality. Many women take hormonal contraceptives (HCs) which add synthetic hormones to women’s endocrine systems and disrupt the links between gonadal hormones and sexuality. Further, there are different types of HCs which may act differently. Whereas past research has combined all women using different types of HCs into a single comparison group, the present research explores how different methods of administration and different progestin generations may differentially affect women’s sociosexuality(SOI). 1024 female participants from 3 samples reported SOI using the revised sociosexuality inventory, HC status, method of administration, length of use, brand, and cycle information in an online survey. Results indicate that compared to women who were not using HCs, women who were using HCs containing 1st, 2nd, and 3rd generation progestins reported more unrestricted SOI attitudes. However only 2nd and 3rd generation progestin users had more unrestricted SOI attitudes than women not on HCs in the pre-luteal phases of their cycle (when sexual interest is naturally heightened). Lastly, evidence suggests that women return to ovulatory cycles after a year of using the hormonal IUD. We tested for time effects between pill using groups and IUD using groups and found an interaction such that longer duration of use on the IUD was associated with more unrestricted SOl attitudes, while oral contraceptive users did not differ in SOI independent of time using the method. Results highlight the need to understand the psychobiological processes affected by different variations of HCs.

Systemic Progestins and Progestin-Releasing Intrauterine Device Therapy for Premenopausal Patients With Endometrial Intraepithelial Neoplasia.

To estimate trends in use and outcomes of progestin therapy for premenopausal patients with endometrial intraepithelial neoplasia. The MarketScan Database was used to identify patients aged 18-50 years with endometrial intraepithelial neoplasia from 2008 to 2020. Primary treatment was classified as hysterectomy or progestin-based therapy. Within the progestin group, treatment was classified as systemic therapy or progestin-releasing intrauterine device (IUD). The trends in use of progestins and the pattern of progestin use were examined. A multivariable logistic regression model was fit to examine the association between baseline characteristics and the use of progestins. The cumulative incidence of hysterectomy, uterine cancer, and pregnancy since initiation of progestin therapy was analyzed. A total of 3,947 patients were identified. Hysterectomy was performed in 2,149 (54.4%); progestins were used in 1,798 (45.6%). Use of progestins increased from 44.2% in 2008 to 63.4% in 2020 ( P =.002). Among the progestin users, 1,530 (85.1%) were treated with systemic progestin, and 268 (14.9%) were treated with progestin-releasing IUD. Among progestin users, use of IUD increased from 7.7% in 2008 to 35.6% in 2020 ( P <.001). Hysterectomy was ultimately performed in 36.0% (95% CI 32.8-39.3%) of those who received systemic progestins compared with 22.9% (95% CI 16.5-30.0%) of those treated with progestin-releasing IUD ( P <.001). Subsequent uterine cancer was documented in 10.5% (95% CI 7.6-13.8%) of those who received systemic progestins compared with 8.2% (95% CI 3.1-16.6%) of those treated with progestin-releasing IUD ( P =.24). Venous thromboembolic complications occurred in 27 (1.5%) of those treated with progestins; the venous thromboembolism (VTE) rate was similar for oral progestins and progestin-releasing IUD. The rate of conservative treatment with progestins in premenopausal individuals with endometrial intraepithelial neoplasia has increased over time, and among progestin users, progestin-releasing IUD use is increasing. Progestin-releasing IUD use may be associated with a lower rate of hysterectomy and a similar rate of VTE compared with oral progestin therapy.

Serum metabolomic profiles associated with postmenopausal hormone use.

Postmenopausal hormone use is linked to several health outcomes and the risk associated with some may differ depending on whether estrogen is used alone or in combination with progestin. Metabolomic analyses of postmenopausal hormone use and differences between hormone regimes was done to identify metabolites associated with each type of hormone treatment. Untargeted metabolomics analysis was done on serum from 1336 women enrolled in the Cancer Prevention II Nutrition Cohort. Levels of 781 named metabolites were compared between 667 nonusers with 332 estrogen-only and with 337 estrogen plus progestin users using linear regression. Metabolite levels were also compared between estrogen-only and estrogen plus progestin users. Compared to nonusers, 276 metabolites were statistically significantly (P < 6.40 × 10- 5) associated with estrogen-only use and 222 were associated with estrogen plus progestin use. The metabolites associated with both types of hormones included numerous lipids, acyl carnitines, and amino acids as well as the thyroid hormone thyroxine and the oncometabolite fumarate. The 65 metabolites that differed significantly between estrogen-only and estrogen plus progestin users included 19 steroids and 12 lipids that contained the bioactive fatty acid arachidonic acid. These findings suggest that postmenopausal hormone use influences metabolic pathways linked to a variety of cellular processes, including the regulation of metabolism and stress responses, energy production, and inflammation. The differential association of numerous lipids which influence cellular signaling suggests that differences in signal transduction may contribute to the disparate risks for some diseases between estrogen-only and estrogen plus progestin users.

Differential effects of androgenic and anti-androgenic progestins on fusiform and frontal gray matter volume and face recognition performance

Effects of oral hormonal contraceptives (OC) on human brain structure and behavior have only recently become a focus of research. Two explorative reports observed larger regional gray matter (GM) volumes in OC users within the prefrontal cortex, ACC and fusiform gyri, as well as parahippocampal gyri, hippocampus and cerebellum. These studies did however not control for the androgenicity of the progestin compound of OC, did not take into consideration how long OC users had been on their OC, and did not control for age differences between the OC group and the naturally cycling group. We compared 20 naturally cycling women during their early follicular cycle phase to 18 users of OC containing androgenic progestins and 22 users of OC containing anti-androgenic progestins. When controlling for age, we found that in users of anti-androgenic progestins relative GM volumes within the bilateral fusiform gyri, fusiform face area (FFA), parahippocampal place area (PPA) and cerebellum, were significantly larger than in naturally cycling women, while in users of androgenic progestins, relative as well as absolute volumes within the bilateral middle and superior frontal gyri were significantly smaller compared to naturally cycling women. These morphological changes were related to performance in a face recognition task. Face recognition performance was significantly better in users of anti-androgenic progestins compared to the other groups and significantly related to absolute as well as relative GM volumes in the FFA and PPA. Total GM volume, as well as absolute GM volumes within the bilateral fusiform gyri, FFA, hippocampus, parahippocampus, PPA, middle frontal gyri and ACC were significantly larger, the longer the duration of OC use, particularly in users of androgenic progestins. Morphological differences between active and inactive pill phase were observed in users of androgenic progestins. These findings suggest differential effects of androgenic and anti-androgenic progestins on human brain structure.

Estrogen Plus Progestin and Breast Cancer Incidence and Mortality in the Women’s Health Initiative Observational Study

In the Women's Health Initiative (WHI) randomized trial, estrogen plus progestin increased both breast cancer incidence and mortality. In contrast, most observational studies associate estrogen plus progestin with favorable prognosis breast cancers. To address differences, a cohort of WHI observational study participants with characteristics similar to the WHI clinical trial was studied. We identified 41 449 postmenopausal women with no prior hysterectomy and mammogram negative within 2 years who were either not hormone users (n = 25 328) or estrogen and progestin users (n = 16 121). Multivariable-adjusted Cox proportional hazard regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CI). All statistical tests were two-sided. After a mean of 11.3 (SD = 3.1) years, with 2236 breast cancers, incidence was higher in estrogen plus progestin users than in nonusers (0.60% vs 0.42%, annualized rate, respectively; HR = 1.55, 95% CI = 1.41 to 1.70, P < .001). Women initiating hormone therapy closer to menopause had higher breast cancer risk with linear diminishing influence as time from menopause increased (P < .001). Survival after breast cancer, measured from diagnosis, was similar in combined hormone therapy users and nonusers (HR = 1.03, 95% CI = 0.79 to 1.35). On a population basis, there were somewhat more deaths from breast cancer, measured from cohort entry (HR = 1.32, 95% CI = 0.90 to 1.93, P = .15), and more all-cause deaths after breast cancer (HR = 1.65, 95% CI = 1.29 to 2.12, P < .001) in estrogen plus progestin users than in nonusers. Consistent with WHI randomized trial findings, estrogen plus progestin use is associated with increased breast cancer incidence. Because prognosis after diagnosis on combined hormone therapy is similar to that of nonusers, increased breast cancer mortality can be expected.

Abstract B71: Does hormone replacement therapy or mammography screening affect breast cancer incidence rates in Taiwan? A nationwide cohort study

Abstract Background: Breast cancer incidence in Taiwan is continuous rising to the leading cancer incidence rate in women according to cancer registry. We hypothesize hormone replacement therapy (HRT) or mammography screening affect the breast cancer incidence. Objectives: 1) To determine whether a similar decline of HRT use and breast incidence occurred in Taiwan. 2) To compare frequency and dose of use HRT with breast cancer incidence. 3) To compare change of mammography rates in different age groups and period of time with breast cancer incidence and mortality. Methods: Breast cancer incidence in most industry countries declines as HRT use drops. This study analyzed national health insurance data from 2000-2008. Women aged above 40 years who was diagnosis postmenopausal or osteopenic were extracted from database for analysis. This research looked at information from prescriptions for HRT, mammography rates and breast cancer incidence and mortality rates. Approximately 82,478 postmenopausal or osteopenic women were included in this analysis. Odd ratios were derived from nested case control estimation to compare with HRT use, total dose and total duration of HRT. Mammography rates in different age groups and different period of year were compared by using national health insurance data. Results: We found that a reduced frequency of use of HRT was reflected in the decrease in dispensed HRT prescriptions after 2002 announced be the Women Health Initiative (WHI) in Taiwan. The largest drop in use of HRT occurred between 2002 and 2003 and continuous drop is noted during our study period. Compared with never users, estrogen and progestin users were with higher risk of breast cancer (OR: 1.58, 95% CI 1.16-2.14, p&amp;lt;0.003) and higher among current users of estrogen only (OR: 1.48, 95% CI 1.13-1.93, p&amp;lt;0.004). The HRT use, total dose of HRT and duration of HRT all showed dose-response effects (OR: 2.42 for HRT use more than 30 times; OR: 3.59 for total use of HRT for more than 3 years; OR: 3.18 for duration of use HRT). They are all statistical significant (p&amp;lt;0.001). Compared with mammography rates with different period of time, the study found that nearly 40% rise in breast cancer rates coincided with the 50% increase in mammography rates between 2000 and 2008. The breast cancer incidence increased following by mammography rates inclined, particular in aged 40 to 59 years group during 2001 to 2005 and 2006 to 2010. Breast cancer incidence rates began to increase dramatically in 2006 to 2010 among women aged 40-49 years. Compared with total mortality to incidence ratio [1-(M/I)] (proxy site-specific cancer survival), the survival ratio increased from 74.7% (2000) to 81.3% (2008). Conclusion: The breast cancer risk was elevated with the use of combined HRT. In Taiwan, breast cancer incidence rates continuous increase among aged 40-59 years, which is likely explained by the promotion of mammography for government breast cancer screening programs from 2003. Mortality to incidence ratio in Taiwan did show some improvement, but still limit. Some argue that the plasticizers - DEHA, DBP, BBP, DEHP, DOP - as estrogen-like substances is the cause which was discovered widely used for food packaging and illegally add into food drink in Taiwan food industry may disturb the endocrine system. Further long-term surveillance studies of time trend and spatial patterns between breast cancer incidence rate and screening rates can help reconcile the potential population-level association of these two factors. Citation Format: Eng-Mei Tsai, Po-Huang Chiang, Yen-Chen Chang. Does hormone replacement therapy or mammography screening affect breast cancer incidence rates in Taiwan? A nationwide cohort study. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B71.

Menopausal Hormone Therapy and Coronary Heart Disease: Reconciling Divergent Findings from Observational Studies and Clinical Trials

Randomized clinical trials of menopausal hormone therapy have shown increased risks of coronary heart disease in the first few years after randomization, and neutral or increased risk over the full trial period. These results diverge substantially from the protective associations of menopausal hormone use with coronary heart disease found in observational studies. In common with many other studies, conventional analyses in the Women’s Health Initiative Observational Study cohort of estrogen plus progestin users showed an association with reduced risk of coronary heart disease even after adjustment for potential confounders. However, upon allowing risk to vary by time since initiation, the hazard ratios did not differ significantly from those observed in the clinical trial. In analyses combining clinical trial and observational data the hazard ratios were 1.58 (1.12, 2.24) within the first 2 years after initiation, 1.19 (0.87, 1.63) between 2 and 5 years, and 0.63 (0.59, 1.26) after 5 years. Similar analyses for estrogen alone also reconciled trial and observational data. These findings were confirmed in novel re-analyses of the Nurses’ Health Study when investigators for the first time included outcomes occurring in the interval between the biennial study cycles. The key towards understanding the underestimation of coronary heart disease in observational studies of menopausal hormone therapy appears to lie in the time-dependent nature of coronary heart disease risk rather than differences in study populations. Observational studies typically do not capture early events in current users and the data mostly reflect the experience of long-term users who have survived the early risk, while clinical trials by design capture early events very efficiently and mainly reflect short-term use.

Postpartum factors and natural fibroid regression

Many fibroids regress with pregnancy or postpartum involution. We sought to identify factors that might inhibit or enhance this natural regression. We used a prospective cohort of women with fibroids (n = 494) determined by ultrasound screening during the early first trimester identified from the Right from the Start study. Ultrasounds were repeated 3-6 months postpartum (n = 279). Logistic regression analyses were used to identify factors associated with fibroid regression (>50% reduction in volume). Postpartum progestin users had significantly less fibroid regression (P = .01), whereas there was no association for combined estrogen-progestin use. Cesarean delivery and fever (hypothesized to inhibit regression) and breast feeding (hypothesized to enhance regression) were not associated with fibroid regression. Progestin use in the postpartum period may limit regression of fibroids, consistent with prior literature on progesterone's role in fibroid development. Research into progestin-only treatments in critical reproductive periods is needed.

Discovery and Validation of Breast Cancer Early Detection Biomarkers in Preclinical Samples

Despite the widespread use of mammography for breast cancer screening, breast cancer remains the most common cause of cancer-related mortality among women worldwide. The identification of blood-based biomarkers useful for the early detection of breast cancer could have a major impact on reducing breast cancer disease burden by identifying cancers early when they are most treatable. We conducted a series of large-scale proteomic discovery and validation studies using preclinical samples from the Women's Health Initiative Observational Study prospective cohort. Of the 503 proteins quantified in experiments conducted on samples from ER(+) breast cancer patients and matched controls, 57 differentiated cases from controls. The seven candidates were assessed in an independent validation set with a commercially available ELISA assay. We confirmed that one of these candidates, epidermal growth factor receptor (EGFR), was elevated in cases versus controls. Compared to women in the lowest EGFR quartile, those in the highest quartile has a 2.90-fold (p = 0.0005) increased risk of developing breast cancer. An interaction with use of menopausal hormone therapy was observed such that among current estrogen plus progestin users, those in the highest EGFR quartile had a 9.04-fold (p = 0.0004) increased risk of developing breast cancer. While the performance of EGFR in terms of sensitivity and specificity is insufficient for it to be used on its own clinically, the formal validation of EGFR suggests that there may indeed be changes in the plasma proteome prior to the clinical diagnosis of breast cancer that are detectable and of potential clinical utility.

Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline

Associations between postmenopausal hormone therapy (HT) and cognitive decline may depend on apolipoprotein E (APOE) status or timing of initiation. We included 16,514 Nurses' Health Study participants aged 70–81 years who were followed since 1976 and completed up to 3 telephone cognitive assessments (2 years apart), between 1995 and 2006. The tests assessed general cognition (Telephone Interview of Cognitive Status; TICS), verbal memory, and category fluency. We used longitudinal analyses to estimate differences in cognitive decline across hormone groups. APOE genotype was available in 3697 participants. Compared with never users, past or current HT users showed modest but statistically significant worse rates of decline in the TICS: the multivariable-adjusted difference in annual rate of decline in the TICS among current estrogen only users versus never users was −0.04 (95% confidence interval, −0.07 to −0.004); for current estrogen + progestin users, the mean difference was −0.05 (95% confidence interval, −0.10 to −0.002). These differences were equivalent to those observed in women who are 1–2 years apart in age. We observed no protective associations with early timing of hormone initiation. We found suggestive interactions with APOE e4 status (e.g., on TICS, p interaction, 0.10), where the fastest rate of decline was observed among APOE e4 carriers who were current HT users. Regardless of timing of initiation, HT may be associated with worse rates of decline in general cognition, especially among those with an APOE e4 allele.

Breast Cancer Risk by Breast Density, Menopause, and Postmenopausal Hormone Therapy Use

We determined whether the association between breast density and breast cancer risk and cancer severity differs according to menopausal status and postmenopausal hormone therapy (HT) use. We collected data on 587,369 women who underwent 1,349,027 screening mammography examinations; 14,090 women were diagnosed with breast cancer. We calculated 5-year breast cancer risk from a survival model for subgroups of women classified by their Breast Imaging Reporting and Data System (BIRADS) breast density, age, menopausal status, and current HT use, assuming a body mass index of 25 kg/m(2). Odds of advanced (ie, IIb, III, IV) versus early (ie, I, IIa) stage invasive cancer was calculated according to BIRADS density. Breast cancer risk was low among women with low density (BIRADS-1): women age 55 to 59 years, 5-year risk was 0.8% (95% CI, 0.6 to 0.9%) for non-HT users and 0.9% (95% CI, 0.7% to 1.1%) for estrogen and estrogen plus progestin users. Breast cancer risk was high among women with very high density (BIRADS-4), particularly estrogen plus progestin users: women age 55 to 59 years, 5-year risk was 2.4% (95% CI, 2.0% to 2.8%) for non-HT users, 3.0% (95% CI, 2.6% to 3.5%) for estrogen users, and 4.2% (95% CI, 3.7% to 4.6%) for estrogen plus progestin users. Advanced-stage breast cancer risk was increased 1.7-fold for postmenopausal HT users who had very high density (BIRADS-4) compared to those with average density (BIRADS-2). Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT, especially estrogen plus progestin.

Complex Hyperplasia With and Without Atypia

Limited data exist to inform clinicians and patients as to the likelihood of long-term endometrial hyperplasia response to progestin therapy, especially for atypical hyperplasia. We evaluated women with complex and atypical endometrial hyperplasia, comparing those prescribed progestin with those not prescribed progestin. This retrospective cohort study was conducted in 1985-2005 among women aged 18-88 years at an integrated health plan in Washington State. Women were ineligible if they achieved an outcome (endometrial carcinoma, hysterectomy, or both) within 8 weeks of hyperplasia diagnosis. Exposure was progestin use for at least 14 days by duration and recency. Outcomes included rate of 1) endometrial carcinoma, 2) hysterectomy, or 3) both. Analyses performed included Kaplan-Meier, incident rate ratios, and Cox proportional hazard ratios. One thousand four hundred forty-three eligible women were identified. One thousand two hundred one had complex (n=164 no progestin) and 242 had atypical (n=62 no progestin) hyperplasia. During follow-up, a median of 5.3 years (range 8 weeks to 20.8 years), 71 women were diagnosed with endometrial carcinoma (35 complex, 36 atypia) and 323 underwent hysterectomy (216 complex, 107 atypia). Among women with complex and atypical hyperplasia, rates of endometrial carcinoma among progestin users were 3.6 and 20.5 per 1,000 woman-years, respectively (compared with women who did not use progestin, 10.8 and 101.4). Among women with complex and atypical hyperplasia, rates of hysterectomy among progestin users were 23.3 and 61.4 per 1,000 woman-years, respectively (compared with women who did not use progestin, 55.1 and 297.3). Endometrial carcinoma risk is diminished approximately threefold to fivefold in women diagnosed with complex or atypical endometrial hyperplasia and dispensed progestin; hysterectomy risk is also decreased. II.

Breast cancer outcome and estrogen plus progestin use in postmenopausal women.

1507 Background: During a mean (SD) 5.6 years (1.3) of intervention, use of estrogen plus progestin in the Women's Health Initiative (WHI) randomized clinical trial increased breast cancer incidence (Chlebowski et al JAMA 2003;289;3243) but breast cancer mortality was not reported. Therefore, we determined combined hormone therapy effects on breast cancer incidence and mortality in the WHI trial over the entire follow-up period (mean [SD] 11.0 [2.7] years) and also in the WHI observational study cohort. Methods: In the clinical trial, 16,608 postmenopausal women with no prior hysterectomy were randomized to conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) (estrogen plus progestin) or placebo. In the observational study, 41,449 postmenopausal women with characteristics similar to clinical trial participants were identified at entry as estrogen plus progestin users (n = 16,121) or not users (n = 25,328). Main outcome measures included invasive breast cancer incidence and breast cancer mortality. Results: In the clinical trial, more breast cancers were diagnosed in the estrogen plus progestin group (385 vs. 293; HR, 1.25; 95% CI, 1.07-1.46, p = 0.004) and the breast cancers were more likely to be node positive (p = 0.02). Deaths directly attributed to breast cancer were greater in the estrogen plus progestin group (25 vs. 12 deaths; HR 1.96 95% CI 1.01-4.05, p = 0.048) as were deaths from all causes occurring after a breast cancer diagnosis (49 vs. 31 deaths; HR 1.51 95% CI 0.97-2.39, p = 0.07). Estrogen plus progestin users in the observational study had somewhat more deaths attributed to breast cancer (HR 1.33 95% CI 0.82-2.16, p = 0.26) and more deaths from all causes occurring after a breast cancer diagnosis (HR 1.82, 95% CI 1.33-2.50, p < 0.001) compared to women not using estrogen plus progestin at entry. Conclusions: Estrogen plus progestin use increases breast cancer incidence with cancers more commonly node positive. Mortality from all causes after a breast cancer occurrence was greater and an adverse trend for deaths attributed to breast cancer is seen with combined hormone therapy use. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Lilly, Novartis, Pfizer, Procter and Gamble, Upsher-Smith Laboratories, Wyeth Abraxis BioScience, AstraZeneca, Novartis Amgen, Lilly, Organon, Procter and Gamble, Wyeth

Does the progesterone receptor genetic polymorphism +331G/A hPR influence the risk of venous thromboembolism among postmenopausal women using hormone therapy? The ESTHER Study

Hormone therapy (HT) increases venous thromboembolism (VTE) risk among postmenopausal women. Data on the influence of steroids receptors polymorphisms on this association remain scarce. Since progesterone receptor (hPR) is expressed in human veins and specific progestogens increase VTE risk, we investigated the impact of the functional +331G/A hPR polymorphism on the association of VTE with HT. Using the data of the ESTHER study, we showed that ORs for VTE in current users of progesterone or progestins were not significantly different by hPR +331G/A genotype status. hPR polymorphism appears not to have a significant effect on VTE risk related to HT.

Postmenopausal Estrogen-Containing Hormone Therapy and the Risk of Breast Cancer

To investigate the relation of various estrogen-containing hormone therapies to the risk of breast cancer, emphasizing the use of the combination of estrogen and testosterone. Using information from a large U.S.-based claims database, we conducted a case-control study in women aged 50 to 64 years who had a first-time diagnosis of breast cancer to estimate the effect in users of conjugated estrogen alone, conjugated estrogen plus progestin, esterified estrogen with methyltestosterone, or esterified estrogen with methyltestosterone plus progestin, compared with nonusers. Four controls were matched to each case on year of birth and index date. Odds ratios (ORs) were calculated using conditional logistic regression. We identified 4,515 cases and 18,058 matched controls. The OR for users of estrogen alone compared with the nonusers was 0.96 (95% confidence interval [CI] 0.88-1.06; 667 cases and 2,900 controls); for users of conjugated estrogen plus progestin, it was 1.44 (95% CI 1.31-1.58; 712 cases and 2,087 controls); and for users of esterified estrogen with methyltestosterone and esterified estrogen with methyltestosterone plus progestin, the ORs were 1.08 (95% CI 0.86-1.36; 98 cases and 380 controls) and 1.69 (95% CI 1.03-2.79; 22 cases and 55 controls), respectively. There was an increased risk among conjugated estrogen plus progestin users of 48 months or more (OR 3.10, 95% CI 2.38- 4.04; 111 cases and 149 controls). There is no materially increased risk of breast cancer in users of estrogen alone or esterified estrogen with methyltestosterone compared with nonusers. There is an increased risk among those using conjugated estrogen plus progestin. In particular, the risk of breast cancer in women who used conjugated estrogen plus progestin for 4 or more years is approximately three times higher than in women who are not exposed to hormone therapy, so that the background incidence rate for women aged 50 to 64 years, which is around 3 per 1,000, would be increased to approximately 9 per 1,000 in women aged 50 to 64 years who have taken conjugated estrogen plus progestin for 48 months or more. II.

Development of an animal experimental model to study the effects of levonorgestrel on the human endometrium.

BACKGROUNDThis study was designed to develop an animal model to test the response of endometrium to local progestin delivery.METHODSProliferative human endometrium was subcutaneously grafted in two groups of SCID mice that received, 2 days before, a subcutaneous estradiol (E2) pellet and, for half of them, an additional implant of levonorgestrel (LNG). Mice were sacrificed 1, 2, 3 or 4 weeks after endometrial implantation and grafts were histologically analysed. Proliferation, steroid hormone receptors, blood vessels and stromal decidualization in both groups (E2 and LNG) were immunohistologically evaluated and compared with proliferative endometrium and endometrium from women with an LNG intrauterine device.RESULTSGrafts presented normal morphological endometrial characteristics. The expression of progesterone receptors was significantly decreased in glands and stroma of the LNG group as compared with the E2 group at all times. A significant decrease was also observed in the stromal expression of estrogen receptor-α in the LNG group. At 4 weeks, the mean cross-sectional area of vessels was significantly higher after LNG treatment.CONCLUSIONSThese morphological and immunohistochemical characteristics are similar to those observed in women treated with local LNG. This mouse model might facilitate further investigations needed to understand the mechanisms responsible for the breakthrough bleeding frequently observed in progestin users.

Hormone therapy initiation after the Women's Health Initiative

To describe hormone therapy (HT) initiation after the 2002 publication of the Women's Health Initiative. Observational cohort (1999-2003) of women ages 40 to 79 years, five health plans, used HT in July 2002 and subsequently discontinued or never used before August 2002. Of discontinuers, 15.8% (3,203 of 20,205) reinitiated HT. Reinitiation was higher among estrogen users (23.8%) versus estrogen with progestin users (11.3%), and lower among those with diabetes (relative risk [RR]=0.68, 95% CI: 0.61-0.76), cardiovascular disease (RR=0.87, 95% CI: 0.83-0.92), and hyperlipidemia (RR=0.83, 95% CI: 0.79-0.88). Only 2.3% (2,072 of 90,261) of never users initiated (August 2002 to December 2003). First-time initiation was associated with cardiovascular disease (RR=1.17, 95% CI: 1.10-1.25) and hyperlipidemia (RR=1.24, 95% CI: 1.17-1.33) and was less common among those with diabetes (RR=0.70, 95% CI: 0.63-0.79). After the Women's Health Initiative, a minority of women reinitiated or became first-time initiators of HT. Women with cardiovascular disease, diabetes, and hyperlipidemia were less likely to reinitiate; women with cardiovascular disease and hyperlipidemia were more likely to be first-time initiators.

Body Mass and Endometrial Cancer Risk by Hormone Replacement Therapy and Cancer Subtype

Epidemiologic studies unequivocally show that greater body mass increases the risk of endometrial cancer, but whether risk varies by use of postmenopausal hormone therapy (HT), location of fat deposition, or cancer subtype is still unclear. We examined these associations among 33,436 postmenopausal women in the Cancer Prevention Study II Nutrition Cohort, who completed questionnaires on diet, lifestyle, and medical history at baseline in 1992. A total of 318 cases were eligible through June 2003. Cox-proportional hazards analyses were used to estimate multivariate-adjusted rate ratios (RR). As expected, adult body mass index (BMI) was a strong predictor of risk [RR, 4.70; 95% confidence interval (CI), 3.12-7.07 for BMI 35+ versus 22.5-25.0, P trend < 0.0001]. Use of estrogen plus progestin postmenopausal HT modified the association. Among never-users, risk was significantly linear across the entire range of BMI examined (RR, 0.51; 95% CI, 0.29-0.92 for <22.5 versus 22.5-25.0; RR, 4.41; 95% CI, 2.70-7.20 for > or =35 versus 22.5-25.0, P trend < 0.0001), but among ever estrogen plus progestin users, the association was not significant (P trend = 1.0; P interaction < 0.0001). We observed no difference in risk according to tendency for central versus peripheral fat deposition. Greater BMI (> or =30 versus <25.0) increased risk of both "type I" (classic estrogen pathway, RR, 4.22; 95% CI, 3.07-5.81) and "type II" (serous, clear cell, and all other high grade) cancers (RR, 2.87; 95% CI, 1.59-5.16). The increased risk of endometrial cancer across the range of BMI in women who never used postmenopausal HT stresses the need to prevent both overweight and obesity in women.

Hormone therapy, timing of initiation, and cognition in women aged older than 60 years: the REMEMBER pilot study

The aim of this pilot study was to assess any trends related to the timing of initiation, and duration, of hormone therapy (HT) use on cognitive function to facilitate the design and power calculations for a future large cohort study entitled Research into Memory, Brain function and Estrogen Replacement (REMEMBER). A total of 428 women aged older than 60 years were recruited from a computer-generated random selection of Adelaide households. Demographic and lifestyle characteristics, and HT use history were recorded and confirmed. The Center for Epidemiological Studies-Depression score was used to assess mood. Cognitive tests were administered measuring global cognition (Mini-Mental State Examination), attention and concentration (Trail Making Test Parts A and B), verbal learning and memory (Consortium to Establish a Registry for Alzheimer's Disease [CERAD] word list immediate and delayed recall), and verbal expression (letter fluency [FAS], category fluency [Animals], and the Boston Naming Test [short form]). Analyses were adjusted for age, education, mood, body mass index, smoking, alcohol intake, and history of cerebrovascular disease. HT use was defined as the use of systemic HT for at least 1 year. Early initiation of HT use was defined as commencement of HT before age 56 years for women with a uterus and ovaries, or within 5 years of a hysterectomy and bilateral oophorectomy. Late initiation of HT use was defined as HT commencing after these times. Early initiators of HT performed better than late initiators on the Mini-Mental State Examination (P = 0.04) and were faster than never users on the Trail Making Test Part A (P = 0.02). Women aged 70-79 years who initiated HT early performed better on the FAS test than never users (P = 0.0008). Late initiators performed worse than never users on the Mini-Mental State Examination (P = 0.09), and on the FAS test in the 60-69 year (P = 0.06) and 80 years and older (P = 0.095) age groups. However, late initiators performed better than never users on the FAS test in the 70-79 year age group (P = 0.015). HT users of less than 11 years (P = 0.09), HT users of more than 11 years (P = 0.04), and estrogen-only users (P = 0.024) performed faster than never users on the Trail Making Test Part A. Combined estrogen plus progestin users performed better than never users on the Boston Naming Test short form (P = 0.07). For some cognitive domains, early initiation of HT from around menopause may be beneficial, and initiation of HT in late menopause may be detrimental. The timing of the initiation of HT seems critical. To fully test these hypotheses and to further examine these trends by route and type of HT regimen in this population, a study size of 2,500 women would be required.

Mortality following development of breast cancer while using oestrogen or oestrogen plus progestin: a computer record-linkage study

The literature on the relationship between breast cancer mortality and postmenopausal oestrogen and combined oestrogen/progestin therapy is seemingly contradictory. This study explored survival after exposure to oestrogen or oestrogen plus progestin at or in the year prior to breast cancer diagnosis. Information on patients first diagnosed with invasive breast cancer between 1993 and 1998 was linked with outpatient pharmacy data from 1992 to 2000. Patients were classified according to use of oestrogen alone or oestrogen plus progestin at or in the year prior to diagnosis. Compared to nonusers, and adjusting for age at diagnosis, race/ethnicity, tumour size and grade, oestrogen receptor status, surgery status, and chemotherapy and hormone therapy for breast cancer treatment, oestrogen plus progestin users had lower all-cause mortality (stage I hazard ratio (HR)=0.69, 95% confidence interval (CI)=0.48–0.99; stage II HR=0.53, 95% CI=0.39–0.72) and breast cancer mortality (stage I HR=0.52, 95% CI=0.26–1.04; stage II HR=0.69, 95% CI=0.48–0.98). Oestrogen users experienced little or no survival benefit for all-cause mortality (stage I HR=1.04, 95% CI=0.77–1.42; stage II HR=0.86, 95% CI=0.65–1.14) or breast cancer mortality (stage I HR=1.23, 95% CI 0.72–2.10; stage II HR=1.01, 95% CI 0.72–1.41). Our findings suggest, relative to nonusers, a lower risk of death from all causes and from breast cancer in patients who were diagnosed with breast cancer while exposed to oestrogen plus progestin, but not in patients exposed to oestrogen only.