Form Of Hormone Replacement Therapy Research Articles

Hormone replacement therapy perspectives.

Hormone replacement therapy (HRT), also known as menopausal hormone therapy (MHT), was looked upon as a fountain of youth that kept women young and reduced cardiovascular disease. This led to a large-scale study called the Women's Health Initiative (WHI) that was conducted to show the cardiovascular benefits of HRT. This study was suspended early because of adverse side effects. The USFDA responded by slapping a "black box" warning on all HRT products. USFDA-approved bioidentical HRT formulations are safe and effective. We propose that these formulations have the "black box" warning removed so that doctors feel more confident in prescribing these products for symptoms of menopause and chronic conditions such as cardiovascular health. We propose eliminating the sale of products containing medroxyprogesterone acetate (MPA) because of the increased risk of heart attacks and breast cancers associated with this medication.

MP50-12 CLINICOPATHOLOGIC ANALYSIS AND DIGITAL EVALUATION OF ORCHIECTOMY SPECIMENS IN PATIENTS WITH GENDER DYSPHORIA

You have accessJournal of UrologyCME1 Apr 2023MP50-12 CLINICOPATHOLOGIC ANALYSIS AND DIGITAL EVALUATION OF ORCHIECTOMY SPECIMENS IN PATIENTS WITH GENDER DYSPHORIA Ivan De La Riva, Ruoji Zhou, Alcino Gama, Bonnie Choy, Bogdan Isaila, Diana Bowen, Robert Brannigan, and Ximing Yang Ivan De La RivaIvan De La Riva More articles by this author , Ruoji ZhouRuoji Zhou More articles by this author , Alcino GamaAlcino Gama More articles by this author , Bonnie ChoyBonnie Choy More articles by this author , Bogdan IsailaBogdan Isaila More articles by this author , Diana BowenDiana Bowen More articles by this author , Robert BranniganRobert Brannigan More articles by this author , and Ximing YangXiming Yang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003298.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Gender-affirmation therapy for transgender individuals is an area of increasing importance in genitourinary pathology. These patients undergo various forms of hormonal replacement therapy (HRT) followed by bilateral orchiectomy. To date, there are very limited studies on the histological and biochemical alterations in these testes. METHODS: We conducted a retrospective search of the database for gender-affirming orchiectomies performed at our institution from 2018 to 2022. Clinical features, including age, length and types of hormonal treatment, and pathologic features, were reviewed and summarized. 19 cases were subjected to whole slide imaging scanning for digital analysis using the Leica system. Immunohistochemistry for OCT4 and CD117 was performed on selected cases. RESULTS: Atrophic changes and decreased spermatogenesis were found in all the gender-affirming orchiectomy specimens examined, with decreased mean tubule diameter (102.9 μm, 202 tubules examined) compared to the tubular size of germ cell neoplasia in situ (GCNIS) and normal testis (139.3 μm and 143.7 μm, 326 and 185 tubules examined, respectively). All cases showed significant maturation arrest, with 55 testes showing aspermatogenesis and the remaining 14 testes showing hypospermatogenesis. Various degrees of basement membrane thickening were observed in all testes, and 55.1% of the testes were found to have focal tubule hyalinization/obliteration. The number of Leydig cells was reduced, with marked cytoplasmic vacuolization and degenerative changes. In a subset of specimens, scattered germ cells displayed prominent nucleomegaly. Using digital analysis, the average nuclear size of these abnormal germ cells was 14.4 μm in diameter (35 cells counted), approaching or exceeding the size of the neoplastic nucleus in GCNIS (mean diameter=12.1 μm, 33 cells counted). However, the enlarged nuclei of these germ cells demonstrated a smooth nuclear membrane, small nucleoli, and fine granular and smudged chromatin, significantly different from the nuclei in GCNIS. Furthermore, immunohistochemistry staining of the germ cells with nucleomegaly in tested cases demonstrated negative staining for both OCT4 and CD117, militating again the possibility of GCNIS. CONCLUSIONS: All the testes from gender-affirming orchiectomies in our study exhibit significantly reduced spermatogenesis, including maturation arrest and atrophic changes. In addition, the presence of scattered germ cells with nucleomegaly in these specimens can mimic GCNIS. Source of Funding: NA © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e689 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ivan De La Riva More articles by this author Ruoji Zhou More articles by this author Alcino Gama More articles by this author Bonnie Choy More articles by this author Bogdan Isaila More articles by this author Diana Bowen More articles by this author Robert Brannigan More articles by this author Ximing Yang More articles by this author Expand All Advertisement PDF downloadLoading ...

MP72-18 GENDER DYSPHORIA IN KLINEFELTER SYNDROME: HORMONE THERAPY IN KLINEFELTER SYNDROME - IS TESTOSTERONE ALWAYS THE ANSWER?

You have accessJournal of UrologyCME1 Apr 2023MP72-18 GENDER DYSPHORIA IN KLINEFELTER SYNDROME: HORMONE THERAPY IN KLINEFELTER SYNDROME - IS TESTOSTERONE ALWAYS THE ANSWER? Tiffany Kago, Daniel Clark, Kathryn Moore, Benjamin Moore, and Tet Yap Tiffany KagoTiffany Kago More articles by this author , Daniel ClarkDaniel Clark More articles by this author , Kathryn MooreKathryn Moore More articles by this author , Benjamin MooreBenjamin Moore More articles by this author , and Tet YapTet Yap More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003340.18AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Klinefelter Syndrome (KS) is the most common sex aneuploidy (47, XXY). The physical manifestations of the disorder differ for each patient; so, an individualised treatment plan usually in the form of hormone replacement therapy (HRT) with Testosterone is used. However, there is increasing evidence that some KS patients question their gender identity when diagnosed and throughout their KS journey. The aim of this study is to investigate the issues surrounding HRT in KS as well as determine the preference of hormone treatment amongst adolescent and adult patients with KS. METHODS: As part of a registered Quality Improvement Project (QIP), data was collected from a 23-point questionnaire of KS patients’ attitudes to gender identity. This was shared with members of the Klinefelter Syndrome Association (KSA) from February to June 2022, and anonymised responses were collected via SurveyMonkey. The questionnaire was developed by multiple clinicians (including gender psychiatrists, urologists, psychosexual medicine specialists and endocrinologists) and patient Delphi rounds, in collaboration with the KSA. Data was reviewed and analysed by 4 independent researchers within the QIP team. RESULTS: Out of 114 respondents, only 55% of KS patients identified as male and 70% were on testosterone replacement therapy (TRT). 12% of KS patients were receiving Oestrogen as their HRT, with 18% of all patients saying they would prefer to take Oestrogen. 2 testimonies given by patients supported this, expressing the difficulties they found when seeking this form of HRT. 34% believed that HRT (Oestrogen or Testosterone) made them look more like their desired gender, but 11 comments highlighted the negative behavioural side effects they had experienced when using TRT. 11% chose to discontinue their treatment, with the major cause being changes in their personalities, particularly mood swings and aggression. 19% of the cohort were not on HRT and 9% preferred to take neither TRT nor Oestrogen. CONCLUSIONS: Overall, only a third of individuals receiving HRT seemed satisfied with the physical changes they saw. Based on the data collected, a tenth stopped their HRT treatment, including those that were unhappy with the behavioural changes they had experienced on TRT. The data suggests that more research should be done to explore and address the complex needs KS patients may have, including gender identity issues, prior to starting any form of HRT. Patients must be counselled as to short- and long-term risks of each form of HRT. Source of Funding: N/A © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1031 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Tiffany Kago More articles by this author Daniel Clark More articles by this author Kathryn Moore More articles by this author Benjamin Moore More articles by this author Tet Yap More articles by this author Expand All Advertisement PDF downloadLoading ...

Hormone replacement therapy prescribing in menopausal women in the UK: a descriptive study.

Recent studies on the prescribing of hormone replacement therapy (HRT) medicines to treat symptoms of menopause are lacking. To describe the prescribing of HRT in a cohort of UK menopausal women. Population-based drug utilisation study using IQVIA Medical Research Database (IMRD-UK). Primary care data of women with recorded menopause and/or aged ≥50 years between January 2010 and November 2021 were extracted from the database. The incidence rate of women who received their first prescription for HRT was calculated annually using person-years-at-risk (PYAR) as the denominator. Incidence rates of HRT were estimated by type and route of administration. Relative changes in annual incidence rates were expressed as percentages and the average percentage change was assessed using linear regression. Annual prescribing prevalence per 100 women was calculated using mid-year menopausal population estimates. The incidence rate of prescribing of HRT increased from 5.01 in 2010 to 18.16 per 1000 PYAR in 2021, a relative increase of 13.64% (95% confidence interval [CI] = 6.97 to 20.30) per year. The incidence rate of fixed combinations of HRT increased from 3.33 to 12.23 per 1000 PYAR in 2010 and 2021, respectively. Transdermal formulations of HRT increased from 1.48 to 14.55 per 1000 PYAR in 2010 and 2021, respectively. The overall proportion of women in receipt of a prescription for HRT changed from 7.89% in 2010 to 6.86% in 2020. This study shows a steady increase in the number of women receiving their first prescription for HRT during the study period, which suggests regained acceptance of HRT medicines.

Association of hormone replacement therapy with risk of gastric cancer: a systematic review and meta-analysis

Hormone replacement therapy (HRT) is widely used to relieve menopausal symptoms; however, it remains unclear whether the use of HRT was associated with gastric cancer. We conducted a systematic review and meta-analysis to synthesize available evidence. This study followed the PRISMA guideline to report meta-analysis. PubMed, Embase, and Cochrane library were searched from conception through 23 February 2022. Eligible studies reporting risk of gastric cancer after HRT were screened and accessed by two independent reviewers. Random-effects meta-analysis was used to calculate pooled risk estimate as relative risk (RR, 95% CI). Pre-established review protocol was registered in PROSPERO (CRD42021281260). Among the 1095 articles identified, we included 11 studies with 1,919,089 women in this meta-analysis. The combined risk estimate (RR, 0.72; 95% CI 0.64–0.81; I2 = 2%) indicated that the use of HRT was associated with a 28% reduction in risk of gastric cancer compared with those who had no HRT exposure. The narrow prediction interval (0.62–0.84) for gastric cancer risk suggested a low between-study variance. In subgroup analysis defined by HRT formulation, there were reduction in risks of gastric cancer after the use of estrogen-only therapy (Pooled RR, 0.63; 95% CI 0.51–0.77, I2 = 0%) and estrogen-progestin therapy (Pooled RR, 0.70; 95% CI 0.57–0.87; I2 = 0%), as compared with non-users. In this systematic review and meta-analysis, the use of HRT was associated with a reduced gastric cancer risk regardless of HRT formulation. Further investigations are warranted to confirm underlying mechanisms.

DOES HARVESTING OVARIAN TISSUE TO DELAY REPRODUCTIVE AGING HAVE A NEGATIVE IMPACT ON THE NATURAL AGE OF MENOPAUSE IN HEALTHY WOMEN?

Given the increasing success rates of ovarian tissue cryopreservation and autologous transplantation, ASRM has removed this approach from the list of experimental fertility preservation procedures. The advances in ovarian cryopreservation and transplantation techniques led to the question of whether it can also be used to delay reproductive aging and provide a natural form of hormone replacement therapy. However, it is currently unknown if ovarian biopsies obtained for elective purposes will cause a reduction in reproductive lifespan not matched by the longevity of the transplanted tissue.

Hormone Replacement Therapy, Synthetic Progestogens, and Breast Cancer Risk

Background: Hormone Replacement Therapy (HRT) has been associated with an increased risk of breast cancer. The study objective is to evaluate whether the increased risk is dependent on the formulation used. Methods: We carried out a population-based case-control study using data from the United Kingdom Clinical Practice Research Datalink on women age ≥50 years. Incident cases of breast cancer were age-matched (1:10) with controls of comparable follow-up time with no history of breast cancer. Exposures were classified as ever or never for the following HRT formulations: bioidentical estrogens, animal-derived estrogens, micronized progesterone, and synthetic progestin. Logistic regression analyses were performed to estimate the adjusted effect of HRT formulation on breast cancer. Findings: Between 1995-2014, 43,183 breast cancer cases were identified and matched to 431,830 controls. In adjusted analyses, compared with women who never used HRT, its use was associated with an increased risk of breast cancer (OR 1·12, 95% CI 1·09-1·15). Compared with never users, estrogens were not associated with breast cancer: bioidentical estrogens (OR 1·04,1·00-1·09), animal-derived estrogens (OR 1·01, 0·96-1·06), both (OR 0·96, 0·89-1·03). Progestogens appeared differentially associated with breast cancer: micronized progesterone (OR 0·99, 0·55-1·79), synthetic progestin (OR 1·28, 1·22-1·35), both (OR 1·32, 0·30-5·77). Interpretation: While HRT use appears to be associated with an overall increased risk of breast cancer, it appears uniquely in women prescribed formulations containing synthetic progestin. Hence, synthetic progestins should not be given as part of HRT regimens and counseling regarding the risk of breast cancer should consider the effect of formulation used. Funding Information: Supported by a grant from the Canadian Cancer Society, 703041. Declaration of Interests: Haim Abenhaim has no conflicts of interest to declare. Samy Suissa has been a Scientific Advisory Committee Member for Atara Bio, Boehringer-Ingelheim, Briston-Myers-Squibb, Merck, MorphoSys, and Seqirus. He has also been a speaker for AstraZeneca and Novartis. All work was unrelated to this study. Laurent Azoulay received consulting fees from Janssen and Pfizer for work unrelated to this study. Andrea Spence has no conflicts of interest to declare. Nicholas Czuzoj-Shulman has no conflicts of interest to declare. Togas Tulandi has no conflicts of interest to declare. Ethics Approval Statement: The Independent Scientific Advisory Committee of the Clinical Practice Research Datalink and the Research Ethics Board of the Jewish General Hospital, Montreal, Quebec, Canada approved the study.

Abstract 4374: CE+BZA combination therapy decreases breast cancer outgrowth in part through activation of the AHR pathway

Abstract Menopause occurs in all women, usually between the ages of 45 and 55. As a result of menopause, women often experience undesirable vasomotor symptoms, which can be alleviated by hormone replacement therapy (HRT). The Women's Health Initiative (WHI) trial concluded that PremPro, a HRT formulation that combines conjugated equine estrogens (CE) with medroxyprogesterone acetate, increases the risk of breast cancer. Over the years, the number of women taking HRT has dramatically decreased due to the perceived risk based largely on the results of the WHI trial. Follow-up studies suggest that breast cancer cases from PremPro treatment were primarily due to the outgrowth of occult tumors, not the formation of new disease. Duavee, a more recent form of HRT that combines CE and bazedoxifene (BZA), a selective estrogen receptor modulator (SERM) and degrader (SERD), has been approved by the FDA for treatment of moderate to severe hot flashes and to reduce the risk of osteoporosis. More importantly, this CE+BZA mixture not only relieves symptoms associated with menopause, but it also does not stimulate the breast or uterus. Several preclinical studies suggest that CE+BZA might be protective in the breast, however the mechanism of action of this new combination therapy is not known. Our goal, therefore, was to elucidate the underlying molecular mechanisms by which CE+BZA differentially affects estrogen receptor alpha (ERα) action in the mammary gland. Pathway analysis from RNA-sequencing revealed Aryl Hydrocarbon Receptor (AHR) signaling as the top canonical pathway affected by treatment with CE+BZA. Previous studies reported that 4-hydroxytamoxifen, a metabolite of the SERM tamoxifen, was able to activate the AHR pathway. In our study we determined that BZA treatment activated the AHR pathway in both ERα-positive and ERα-negative cell lines. BZA increased expression of aryl hydrocarbon receptor repressor (AHRR) in cell lines and increased expression of two AHR pathway members, CYP1A1 and CYP1B1, in tumors of estrogen-sensitive polyoma middle T antigen (PyMT) mice. AHRR has been reported to act as a tumor suppressor in breast cancer; therefore activation of AHR by BZA in women taking CE+BZA combination therapy might be one mechanism by which outgrowth of occult tumors is decreased. Further evaluation of the role of AHR in breast cancer is necessary to improve our understanding of CE+BZA action. Citation Format: Anna G. Dembo, Emily S. Aledort, Geoffrey L. Greene. CE+BZA combination therapy decreases breast cancer outgrowth in part through activation of the AHR pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4374.

Abstract P6-05-03: Exogenous steroid hormone exposure and the biology of lobular breast cancer

Abstract Introduction. Invasive lobular carcinoma (ILC) accounts for 10-15% of breast cancer diagnoses and is characterized by a high rate of estrogen and progesterone receptor (ER and PR) expression, low rate of HER2 amplification, and a defining lack of e-cadherin expression. Multiple population-based, observational studies have shown that the risk of ILC is significantly elevated with the intake of combined estrogen/progestin (E+P) hormone replacement therapy (HRT) but not with estrogen-alone (E alone) HRT. In addition, recent studies have revealed that ILCs might respond differently to hormone therapies than IDCs. We sought to understand the influence of exogenous hormone exposure in the form of HRT on biological pathways in ILCs compared to the more common histologic subtype, ER+ invasive ductal carcinoma (IDC). Specimens and Methods. We assessed 297 ER+/HER2- FFPE breast carcinomas, 165 IDCs and 132 ILCs, previously collected from an epidemiological study of HRT use and breast cancer in post-menopausal women. These tumors were characterized for histopathological features and protein marker expression by immunohistochemistry along with the extensive clinical and demographic data, including HRT use, collected in the parent study. Using the Nanostring nCounter assay, we measured expression of ~1000 genes representing canonical cancer-promoting pathways and steroid hormone-associated pathways to determine the relationship between HRT use and pathway alterations in ER+ breast cancer subtypes. Results. From the histopathological assessment, we observed that ILCs had lower overall lymphocyte response than IDCs (p=0.005), but HRT use shifted the lymphocyte response higher than what was observed in ILCs from never/former HRT users (p=0.002). In the gene expression analysis, we found that IDCs and ILCs have distinct expression profiles after adjusting for HRT use, including genes in cell cycle, steroid hormone-response pathways, and cytokine/cytokine receptor interactions, with increased signaling seen in the IL6/12-like family. When comparing gene expression between the HRT-use groups, adjusting for histology, we observed that E+P and E alone are both associated with down-regulation of cell cycle and DNA repair genes compared to the never/former use group. When we focused on expression patterns specific to progestin exposure, (i.e., E+P versus all others), we found decreased expression of genes related to DNA replication initiation and G1/S transition and WNT4. Unsupervised hierarchical clustering revealed additional subgroups within each histologic subtype including a group of low-grade, low-proliferating IDCs enriched for E+P exposure, which clusters with the majority of the ILCs. While many gene expression changes with HRT use are shared across the tumors, we observed alterations that are specific to either ILCs or IDCs, suggesting different steroid hormone-responsive pathways between the subtypes. Conclusions. Our study demonstrates there are potentially specific pathways differentially activated between ILCs and IDCs dependent on the type of hormone exposure. Further, while our study is focused on tumor molecular pathways modulated in response to HRT use, steroid hormone exposure can come from multiple sources, and we propose that the results from this study can provide insight into hormonally-driven breast cancers that develop with excess estrogen and/or progesterone exposure. This could have implications in clinical management of ILCs and IDCs that arise in HRT users. Citation Format: Jamie Guenthoer, Isaac C Jenkins, Beti Thompson, Mei-Tzu C Tang, Nancy E Davidson, Ryan L Ashley, Christopher I Li, Li Hsu, Peggy L Porter. Exogenous steroid hormone exposure and the biology of lobular breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-05-03.

Lung cancer incidence and mortality in relationship to hormone replacement therapy use among women participating in the PLCO trial: a post hoc analysis.

To evaluate the impact of hormone replacement therapy (HRT) on the incidence and mortality of lung cancer among female participants in the prostate, lung, colorectal, and ovary (PLCO) trial. All women participating in the PLCO trial with complete information about HRT exposure were included in the current analysis. All study population were aged 55-74years without prior history of lung cancer at the time of study enrollment. Multivariate Cox regression analysis was used to evaluate the impact of HRT exposure on lung cancer incidence and mortality. For both end points, the model was adjusted for: age, body mass index, study arm, race, cigarette smoking and family history of lung cancer. A total of 77,911 female participants were included in the current analysis, including 27,663 participants who never used HRT before inclusion into the PLCO trial and 50,248 participants who used some form of HRT before inclusion into the PLCO trial. Prior exposure to HRT seems to be protective against the development of lung cancer in a multivariate analysis (hazard ratio for ever exposure versus never exposure 0.876; 95% CI 0.783-0.981; P = 0.022). Similarly, prior exposure to HRT seems also to be protective against death from lung cancer in a multivariate analysis (hazard ratio for ever exposure versus never exposure 0.814; 0.709-0.934; P = 0.003). Further multivariate Cox regression analysis showed that current HRT usage at the time of PLCO trial entry (and not former HRT usage) seemed to be protective against lung cancer development (hazard ratio for current versus never users 0.842; 0.743-0.954; P = 0.007) and lung cancer-specific mortality (hazard ratio for current versus never users 0.800; 0.686-0.932; P = 0.004). HRT use at the time of PLCO trial entry seems to be associated with lower probability of lung cancer development and death. Further studies are needed to elucidate the biological mechanisms behind this observation.

NAMS-gallup survey on women's knowledge, information sources, and attitudes to menopause and hormone replacement therapy.

The North American Menopause Society (NAMS) sponsored a Gallup Organization survey of 833 women aged 45-60 to determine attitudes and experience with menopause and various forms of hormone replacement therapy (HRT). The results of this survey are presented herein.

Hormone Replacement Therapy: Would it be Possible to Replicate a Functional Ovary?

Background: Throughout history, menopause has been regarded as a transition in a woman’s life. With the increase in life expectancy, women now spend more than a third of their lives in menopause. During these years, women may experience intolerable symptoms both physically and mentally, leading them to seek clinical advice. It is imperative for healthcare providers to improve the quality of life by reducing bothersome menopausal symptoms and preventing disorders such as osteoporosis and atherosclerosis. The current treatment in the form of hormone replacement therapy (HRT) is sometimes inadequate with several limitations and adverse effects. Objective and rationale: The current review aims to discuss the need, efficacy, and limitations of current HRT; the role of other ovarian hormones, and where we stand in comparison with ovary-in situ; and finally, explore towards the preparation of an HRT model by regeneration of ovaries tissues through stem cells which can replicate a functional ovary. Search methods: Four electronic databases (MEDLINE, Embase, Web of Science and CINAHL) were searched from database inception until 26 April 2018, using a combination of relevant controlled vocabulary terms and free-text terms related to ‘menopause’, ‘hormone replacement therapy’, ‘ovary regeneration’, ‘stem cells’ and ‘ovarian transplantation’. Outcomes: We present a synthesis of the existing data on the efficacy and limitations of HRT. HRT is far from adequate in postmenopausal women with symptoms of hormone deprivation as it fails to deliver all hormones secreted by naïve ovarian tissue. Moreover, the pharmacokinetics of synthetic hormones makes them substantially different from natural ones. Not only does the number and type of hormones given in HRT matter, but the route of delivering and their release in circulation are also imperative. The hormones are delivered either orally or topically in a non-physiological uniform manner, which brings along with it several side effects. These identify the need for a hormone delivery system which replicates, integrates and reacts as per the requirement of the female body. Wider implications: The review outlines the strengths and weaknesses of HRT and highlights the potential areas for future research. There is a tremendous potential for research in this field to understand the collective roles of the various ovarian hormones and to devise an auto-regulated hormone delivery system which replicates the normal physiology. Its clinical applications can prove to be transformative for postmenopausal women helping them to lead a healthy and productive life.

Hormone replacement therapy after prophylactic risk-reducing salpingo-oophorectomy and breast cancer risk in BRCA1 and BRCA2 mutation carriers: A meta-analysis

Hormone replacement therapy (HRT) has been tested in women with BRCA1 and BRCA2 mutations who underwent risk-reducing salpingo-oophorectomy (RRSO), but its effect on breast cancer (BC) risk has never been appraised using meta-analysis comparison. We performed the first meta-analysis aimed to clarify whether HRT after RRSO could negatively impact on BC risk in women carriers of BRCA1 and BRCA2 mutations. Pubmed and Scopus databases were searched to retrieve articles written in the English language. Trials comparing RRSO with or without HRT were identified and only those trials with available BC events were included. BC risk was the main endpoint. Three trials with 1100 patients were included. There was not a significantly higher BC risk in BRCA1 and BRCA2 mutation carriers receiving HRT after RRSO (HR = 0.98; 95% CI 0.63-1.52). There was a slightly but not significantly, benefit in BC risk reduction in favor of estrogen alone HRT versus estrogen plus progesterone HRT formulation (OR = 0.53; 95% CI 0.25-1.15). HRT use after RRSO in BRCA 1 and BRCA2 mutation carries does not affect BC risk. Comparison of the different HRT types suggests that estrogen alone should be related to lowest BC risk.

Abstract 948: Preventing estrogen receptor alpha-positive breast cancer outgrowth with the use of hormone replacement therapy

Abstract Menopause occurs in all women, usually between the ages of 45 and 55. As a result of menopause, women often experience undesirable vasomotor symptoms, which can be alleviated by hormone replacement therapy (HRT). The Women's Health Initiative (WHI) trial concluded that PremPro, a HRT formulation that combines conjugated equine estrogens (CE) with medroxyprogesterone acetate, increases the risk of breast cancer. Over the years, the number of women taking HRT has dramatically decreased due to the perceived risk based largely on the results of the WHI trial. Follow-up sudies suggest that breast cancer cases from PremPro treatment were primarily due to the outgrowth of occult tumors, not the formation of new disease. Duavee, a more recent form of HRT that combines CE and bazedoxifene (BZA), a selective estrogen receptor modulator (SERM) and degrader (SERD), has been approved by the FDA for treatment of moderate to severe hot flashes and to reduce the risk of osteoporosis. More importantly, this CE+BZA mixture not only relieves symptoms associated with menopause, but it also does not stimulate the breast or uterus. Several preclinical studies suggest that CE+BZA might be protective in the breast, however the mechanism of action of this new combination therapy is not known. Our goal, therefore, is to elucidate the underlying molecular mechanisms by which CE+BZA differentially affects estrogen receptor alpha (ERα) action in the mammary gland, using transcriptome and whole genome occupancy analysis in breast cancer cell lines. RNA-Seq and ChIP-Seq studies suggest that CE+BZA decreases pathways related to S-phase entry, cell cycle regulation and BRCA1. We are also studying the effects of CE+BZA on early mammary cancer progression in the estrogen-sensitive polyoma middle T antigen (PyMT) transgenic mouse model and have observed that treatment with CE+BZA delayed the onset of tumors and decreased their rate of growth. Mice treated with CE+BZA also survived longer. In addition, CE+BZA was able to decrease the rate of tumor growth in an ERα-positive patient-derived xenograft (PDX) mouse model. An improved understanding of the molecular mechanisms of CE+BZA action in hormone sensitive breast cancer cell and animal models should have important implications for women considering HRT. Citation Format: Anna G. Dembo, Emily S. Aledort, Geoffrey L. Greene. Preventing estrogen receptor alpha-positive breast cancer outgrowth with the use of hormone replacement therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 948.

Hormone replacement therapy for women previously treated for endometrial cancer.

Endometrial cancer is the sixth most common cancer in women worldwide and most commonly occurs after the menopause (75%) (globocan.iarc.fr). About 319,000 new cases were diagnosed worldwide in 2012. Endometrial cancer is commonly considered as a potentially 'curable cancer,' as approximately 75% of cases are diagnosed before disease has spread outside the uterus (FIGO (International Federation of Gynecology and Obstetrics) stage I). The overall five-year survival for all stages is about 86%, and, if the cancer is confined to the uterus, the five-year survival rate may increase to 97%. The majority of women diagnosed with endometrial cancer have early-stage disease, leading to a good prognosis after hysterectomy and removal of the ovaries (oophorectomy), with or without radiotherapy. However, women may have early physiological and psychological postmenopausal changes, either pre-existing or as a result of oophorectomy, depending on age and menopausal status at the time of diagnosis. Lack of oestrogen can cause hot flushes, night sweats, genital tract atrophy and longer-term adverse effects, such as osteoporosis and cardiovascular disease. These changes may be temporarily managed by using oestrogens, in the form of hormone replacement therapy (HRT). However, there is a theoretical risk of promoting residual tumour cell growth and increasing cancer recurrence. Therefore, this is a potential survival disadvantage in a woman who has a potentially curable cancer. In premenopausal women with endometrial cancer, treatment induces early menopause and this may adversely affect overall survival. Additionally, most women with early-stage disease will be cured of their cancer, making longer-term quality of life (QoL) issues more pertinent. Following bilateral oophorectomy, premenopausal women may develop significant and debilitating menopausal symptoms, so there is a need for information about the risk and benefits of taking HRT, enabling women to make an informed decision, weighing the advantages and disadvantages of using HRT for their individual circumstances. To assess the risks and benefits of HRT (oestrogen alone or oestrogen with progestogen) for women previously treated for endometrial cancer. We searched the Cochrane Register of Controlled Trials (CENTRAL 2017, Issue 5), MEDLINE (1946 to April, week 4, 2017) and Embase (1980 to 2017, week 18). We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of review articles. We included randomised controlled trials (RCTs), in all languages, that examined the efficacy of symptom relief and the safety of using HRT in women treated for endometrial cancer, where safety in this situation was considered as not increasing the risk of recurrence of endometrial cancer above that of women not taking HRT. Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. We used standard methodological procedures expected by Cochrane. We identified 2190 unique records, evaluated the full text of seven studies and included one study with 1236 participants. This study reported tumour recurrence in 2.3% of women in the oestrogen arm versus 1.9% of women receiving placebo (risk ratio (RR) 1.17, 95% confidence interval (CI) 0.54 to 2.50; very low-certainty evidence). The study reported one woman in the HRT arm (0.16%) and three women in the placebo arm (0.49%) who developed breast cancer (new malignancy) during follow-up (RR 0.80, 95% CI 0.32 to 2.01; 1236 participants, 1 study; very low-certainty evidence). The study did not report on symptom relief, overall survival or progression-free survival for HRT versus placebo. However, they did report the percentage of women alive with no evidence of disease (94.3% in the HRT group and 95.6% in the placebo group) and the percentage of women alive irrespective of disease progression (95.8% in the HRT group and 96.9% in the placebo group) at the end of the 36 months' follow-up. The study did not report time to recurrence and it was underpowered due to closing early. The authors closed it as a result of the publication of the Women's Health Initiative (WHI) study, which, at that time, suggested that risks of exogenous hormone therapy outweighed benefits and had an impact on study recruitment. No assessment of efficacy was reported. Currently, there is insufficient high-quality evidence to inform women considering HRT after treatment for endometrial cancer. The available evidence (both the single RCT and non-randomised evidence) does not suggest significant harm, if HRT is used after surgical treatment for early-stage endometrial cancer. There is no information available regarding use of HRT in higher-stage endometrial cancer (FIGO stage II and above). The use of HRT after endometrial cancer treatment should be individualised, taking account of the woman's symptoms and preferences, and the uncertainty of evidence for and against HRT use.

Role of C-Reactive Protein at Sites of Inflammation and Infection.

C-reactive protein (CRP) is an acute inflammatory protein that increases up to 1,000-fold at sites of infection or inflammation. CRP is produced as a homopentameric protein, termed native CRP (nCRP), which can irreversibly dissociate at sites of inflammation and infection into five separate monomers, termed monomeric CRP (mCRP). CRP is synthesized primarily in liver hepatocytes but also by smooth muscle cells, macrophages, endothelial cells, lymphocytes, and adipocytes. Evidence suggests that estrogen in the form of hormone replacement therapy influences CRP levels in the elderly. Having been traditionally utilized as a marker of infection and cardiovascular events, there is now growing evidence that CRP plays important roles in inflammatory processes and host responses to infection including the complement pathway, apoptosis, phagocytosis, nitric oxide (NO) release, and the production of cytokines, particularly interleukin-6 and tumor necrosis factor-α. Unlike more recent publications, the findings of early work on CRP can seem somewhat unclear and at times conflicting since it was often not specified which particular CRP isoform was measured or utilized in experiments and whether responses attributed to nCRP were in fact possibly due to dissociation into mCRP or lipopolysaccharide contamination. In addition, since antibodies for mCRP are not commercially available, few laboratories are able to conduct studies investigating the mCRP isoform. Despite these issues and the fact that most CRP research to date has focused on vascular disorders, there is mounting evidence that CRP isoforms have distinct biological properties, with nCRP often exhibiting more anti-inflammatory activities compared to mCRP. The nCRP isoform activates the classical complement pathway, induces phagocytosis, and promotes apoptosis. On the other hand, mCRP promotes the chemotaxis and recruitment of circulating leukocytes to areas of inflammation and can delay apoptosis. The nCRP and mCRP isoforms work in opposing directions to inhibit and induce NO production, respectively. In terms of pro-inflammatory cytokine production, mCRP increases interleukin-8 and monocyte chemoattractant protein-1 production, whereas nCRP has no detectable effect on their levels. Further studies are needed to expand on these emerging findings and to fully characterize the differential roles that each CRP isoform plays at sites of local inflammation and infection.

Visible-Near Infrared Spectroscopic Assessment of Urogenital Tissue in Premenopausal and Postmenopausal Women.

Background:A clinical study was conducted to evaluate the feasibility of using visible and near-infrared (NIR) spectroscopy as a potential noninvasive measure of genital skin health in premenopausal and postmenopausal women.Methods:A total of 45 female subjects (aged 21-70 years), all of whom gave fully informed consent to participate, were enrolled in the study and assigned to 1 of 3 groups: 15 premenopausal (Pre-M), 15 postmenopausal receiving hormone replacement therapy (Post-M HRT), and 15 postmenopausal receiving no form of hormone replacement therapy (Post-M non-HRT). Spectral measurements were taken at the vaginal mucosa, and spectral data were evaluated for the erythema index (EI), hemoglobin index (HI), bilirubin/β-carotene, and melanin. The color index (CI; calculated as the ratio of absorbance at 480 nm/540 nm) was also determined. Results were compared with previously published results on biomarkers and physical characteristic of genital tissue measured on the same groups of women.Results:Spectral measurements from the Post-M Non-HRT subjects indicated a significant reduction in HI compared with the Pre-M group (P = .0003) and to the Post-M HRT group (P < .0001). Similarly, EI was reduced in the Post-M Non-HRT (P < .0001 and P = .0041 for the Pre-M and Post-M HRT groups, respectively). In contrast, the Post-M Non-HRT subjects exhibited a significant increase in β-carotene compared with the Pre-M subjects (P = .0098). Bilirubin and melanin were not significantly affected. The Post-M Non-HRT group exhibited a significant increase in CI, indicating a shift away from the hemoglobin absorption region (510-620 nm wavelength) and toward the bilirubin/β-carotene absorption region (450-490 nm wavelength). This change was significant when compared with both the Pre-M group (P < .0001) and the Post-M HRT group (P = .0048). The changes in spectral measurements were consistent with previously reported changes in physical parameters (vaginal atrophy, increased pH, decreased skin temperature) and with decreased concentrations of the biomarkers histamine and histidine.Conclusions:Hemodynamic spectral characteristics differ in postmenopausal vaginal tissue compared with tissue in premenopausal women, with decreased absorbance in the hemoglobin absorption region (510-620 nm wavelength) and an increased absorbance in the bilirubin/β-carotene absorption region (450-490 nm wavelength). A change in absorbance in the visible and NIR wavelengths is a promising, additional measure of genital skin health related to menopause and vulvovaginal atrophy.

Variation in Pediatric Organ Donor Management Practices Among US Organ Procurement Organizations.

Reports of actual pediatric organ donor management practice among US organ procurement organizations are sparse, and the use of standardized management guidelines is unknown. A recent consensus statement from the Society of Critical Care Medicine, the American College of Chest Physicians, and the Association of Organ Procurement Organizations offers guidelines for the management of the pediatric organ donor. To describe the use of guidelines and routine practices in the management of the pediatric organ donor with respect to hemodynamics, lung and ventilator management, fluid and electrolytes, hormonal replacement therapy, the use of blood products, thermoregulation, and prophylactic antibiotics. Cross-sectional observational study using a survey and follow-up telephone interview with respondents from all 58 US organ procurement organizations. All 58 US Organ Procurement Organizations participated. A majority employed written guidelines for the management of pediatric donor hemodynamics, thermoregulation, fluids, and electrolytes. Management of blood products, the lung, and mechanical ventilation were less commonly committed to written guidelines, but common practices were described. All used various forms of hormonal replacement therapy and the majority administered empiric antibiotic therapy. Wide variation was observed in the management of the lung, mechanical ventilation, and glycemic control. Most OPOs used forms of standardized donor management for the pediatric organ donor although variation in the content of that management exists. Barriers to an evidence-based approach to the pediatric donor need to be determined and addressed.

Bioidentical, Synthetic, and Animal Based Hormone Replacement Therapies and Risk of Breast Cancer [1M

INTRODUCTION: Hormone Replacement Therapy (HRT) has been associated with an increased risk of breast cancer. Our study objective was to evaluate whether the increased risk is dependent on the formulation used. METHODS: We carried out a population-based case-control study using data from the United Kingdom Clinical Practice Research Datalink on women aged &gt;50. Newly diagnosed breast cancer cases were age-matched with women of comparable follow-up time with no history of breast cancer at a 1:10 ratio. Exposures were classified as ever/never for the HRT formulations: Bioidentical Estrogens (BE), Conjugated Equine Estrogens (CEE), Micronized Progesterone (MP), and Synthetic Progestogens (SP). Logistic regression estimated adjusted effects of HRT formulation on breast cancer. RESULTS: Between 1995-2014, 43,183 cases of breast cancer were identified and matched to 431,830 controls. Compared with women who had never used HRT, HRT use was associated with an overall increased risk of breast cancer OR 1.12 (1.09-1.15), p &lt; 0.0001. Compared to never users, estrogens were not associated with breast cancer: BE (OR 1.04 (1.00-1.09), p=0.07), CEE (OR 1.01 (0.96-1.05), p=0.78), both (OR 1.32 (0.30-5.77), p=0.25). As compared to never users, progestogens appeared differentially associated with breast cancer: MP (OR 0.99 (0.55-1.79), p=0.98), SP (OR 1.28 (1.22-1.35), p &lt; 0.0001), both (OR 1.32 (0.30-5.77), p=0.72). CONCLUSION: While HRT use is associated with an overall increased risk of breast cancer, this association appears to be uniquely in women having been given synthetic progestogens. Synthetic progestogens should not be given as part of HRT and counseling regarding the risk of breast cancer should consider the effect of formulation used.

Abstract P3-04-19: Inhibition of ER-positive breast cancer progression with duavee, a new form of hormone replacement therapy

Abstract Menopause occurs in all women between the ages of 45 and 55 and often results in undesirable vasomotor symptoms. Hormone replacement therapy (HRT) can alleviate these symptoms, including hot flashes, difficulty sleeping, fatigue, and vaginal atrophy, and also prevents osteoporosis. PremPro, a HRT formulation that combines conjugated equine estrogens (CE) with medroxyprogesterone acetate, was found to increase the risk of breast cancer in the Women's Health Initiative (WHI) trial. Due to the perceived risk based largely on the results of the WHI trial, the number of women taking HRT has dramatically decreased. Studies suggest that breast cancer cases from PremPro treatment were primarily due to the outgrowth of occult tumors, not the formation of new disease. Duavee, a new form of HRT that combines CE and bazedoxifene (BZA), a selective estrogen receptor modulator (SERM) and degrader (SERD), has been approved by the FDA for treatment of moderate to severe hot flashes and to reduce the risk of osteoporosis. Importantly, this CE+BZA mixture not only relieves symptoms associated with menopause, but it also does not stimulate the breast or uterus. Several preclinical studies suggest that CE+BZA might be protective in the breast, however the mechanism of action of this new combination therapy is not known. Our goal, therefore, is to elucidate the underlying molecular mechanisms by which CE+BZA differentially affects estrogen receptor alpha (ERα) action in the mammary gland, using transcriptome and whole genome occupancy analysis in breast cancer cell lines. We are also studying the effects of CE+BZA on early mammary cancer progression in the polyoma middle T antigen (PyMT) transgenic mouse model, which is sensitive to estrogens. In addition, we are studying the effects of CE+BZA in an ERa-positive patient-derived xenograft (PDX) mouse model. We have determined that CE modulates gene expression in MCF7 cells similar to 17β-estradiol (E2), and that BZA is able to inhibit these effects. We have also observed that CE increases ERα occupancy, similar to E2, at response elements associated with some estrogen target genes, whereas CE+BZA decreases this occupancy. In the PyMT mouse model, CE+BZA delays the onset of mammary tumors in ovariectomized mice and prolongs their survival when compared to E2 and CE treatment alone. In the PDX model, the CE+BZA tumor growth curve is below vehicle, although it does not quite reach statistical significance. An improved understanding of the molecular mechanisms of CE+BZA action in hormone sensitive breast cancer cell and animal models should have important implications for women considering HRT. Citation Format: Dembo AG, Aledort E, Greene GL. Inhibition of ER-positive breast cancer progression with duavee, a new form of hormone replacement therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-19.