Long-term Hormone Therapy Research Articles

Assessing the Influence of Long-Term Gender-Affirming Hormone Therapy on Cardiovascular Risk in Transgender Men through Carotid Intima-Media Thickness.

Background: Transgender men use exogenous androgen for male pattern virilization. Hysterectomy and bilateral salpingo-oophorectomy (HBSO) is performed to stop the endogenous estrogen secretion. Cardiovascular disease (CVD) risk has been shown to increase with long-term use of androgens and the removal of estrogen. We aimed to investigate the CVD risk in these individuals by measuring internal and common carotid artery intima-media thicknesses (CIMT). Methods: In this cohort study, data were collected from transgender men who had undergone HBSO and used androgens for at least two years (median treatment duration was 5 years in our research). Cisgender women in the same age range were selected as the control group. Demographics, vital signs, and hematological values of transgender patients and cisgender women subjects in the control group were noted. CVD markers were compared with sonographically measured CIMT values. Results: The mean age and body mass index (BMI) of the study group were 32.6 and 25.3, respectively. Weight, systolic-diastolic blood pressure, hemoglobin, hematocrit, low-density lipoprotein (LDL), serum triglyceride (TG), HbA1c levels, internal CIMT, and common CIMT values of the study group were higher, while the high-density lipoprotein (HDL) level was significantly lower compared the control group (p1 = 0.025, p2 = 0.010, p3 = 0.002, p4 = 0.001, p5 = 0.001, p6 = 0.012, p7 = 0.008, p8 = 0.007, p9 = 0.013, and p10 = 0.001). There was also an increase in the body weight, BMI, LDL, and TG levels of the study group after the testosterone treatment (p1 = 0.025, p2 = 0.019, p3 = 0.001, p4 = 0.001, and p5 = 0.001). Conclusions: We demonstrated that the use of testosterone therapy in transgender men is associated with higher CIMT values. While further investigation is needed to assess morbidity and mortality rates, we recommend that regular clinical and radiological examinations be performed in these individuals to accurately evaluate the risk of CVD.

Androgen Inhibition of Reproductive Neuroendocrine Function in Females and Transgender Males.

Ovarian function is controlled by pituitary secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH), which in turn are governed by gonadotropin releasing hormone (GnRH) secreted from the brain. A fundamental principle of reproductive axis regulation is negative feedback signaling by gonadal sex steroids back to the brain to fine-tune GnRH and gonadotropin secretion. Endogenous negative feedback effects can be mimicked by exogenous steroid treatments, including androgens, in both sexes. Indeed, a growing number of clinical and animal studies indicate that high levels of exogenous androgens, in the typically male physiological range, can inhibit LH secretion in females, as occurs in males. However, the mechanisms by which male-level androgens inhibit GnRH and LH secretion still remain poorly understood, and this knowledge gap is particularly pronounced in transgender men (individuals designated female at birth but identifying as male). Indeed, many transgender men take long-term gender-affirming hormone therapy that mimics male-level testosterone levels. The impact of such gender-affirming testosterone on the reproductive axis, both at the ovarian and neuroendocrine level, is a long-understudied area that still requires further investigation. Importantly, the few concepts of androgen actions in females mostly come from studies of polycystic ovary syndrome, which does not recapitulate a similar androgen milieu or a pathophysiology of inhibited LH secretion as occurs in testosterone-treated transgender men. This review summarizes clinical evidence indicating that exogenous androgens can impair neuroendocrine reproductive function in both female individuals and transgender men and highlights emerging experimental data supporting this in recently developed transgender rodent models.

Altered Monocyte and Lymphocyte Phenotypes Associated with Pathogenesis and Clinical Efficacy of Progestogen Therapy for Peritoneal Endometriosis in Adolescents.

Background: Immunological imbalances characteristic of endometriosis may develop as early as the primary manifestations of the disease in adolescence. Objective: To evaluate subpopulation dynamics of monocytes and lymphocytes in peripheral blood and peritoneal fluid of adolescents with peritoneal endometriosis at diagnosis and after 1-year progestogen therapy. Methods: This study included 70 girls, 13-17 years old, diagnosed laparoscopically with peritoneal endometriosis (n = 50, main group) or paramesonephric cysts (n = 20, comparison group). Phenotypes of monocytes and lymphocytes of the blood and macrophages of the peritoneal fluid were analyzed by flow cytometry at diagnosis and during progestogen therapy. Results: Differential blood counts of CD16+ (p < 0.001) and CD86+ (p = 0.017) monocytes were identified as independent risk factors for peritoneal endometriosis in adolescents. During the treatment, cytotoxic lymphocytes CD56dimCD16bright (p = 0.049) and CD206+ monocytes (p < 0.001) significantly increased while CD163+ monocytes decreased in number (p = 0.017). The CD56dimCD16bright blood counts before (p < 0.001) and during progestogen therapy (p = 0.006), as well as CD206+ blood counts during the treatment (p = 0.038), were associated with the efficacy of pain relief after 1-year progestogen therapy. Conclusions: Adolescents with peritoneal endometriosis have altered counts of pro- and anti-inflammatory monocytes and lymphocytes both before and after 1-year progestogen therapy, correlating with treatment efficacy and justifying long-term hormonal therapy.

Pure 46, XY gonadal dysgenesis and 46, XY complete androgen insensitivity syndrome: A case report.

Disorders of sex development (DSD) are congenital conditions characterized by atypical development of chromosomal, gonadal, and phenotypic sex. 46, XY DSD can result from disorders of testicular development or androgen synthesis. We present 2 rare cases of 46, XY DSD, specifically XY pure gonadal dysgenesis and complete androgen insensitivity syndrome. Both cases underwent prophylactic gonadectomy due to the elevated risk of gonadal malignancy. Bilateral gonadoblastoma and dysgerminoma were diagnosed on one side, while Leydig cell hyperplasia and only Sertoli cells were diagnosed in the seminiferous tubules on both sides. The normal menstruation for the pure gonadal dysgenesis patient only as CAIS patients never menstruate. Estrogen replacement therapy was administered periodically to promote the development of secondary sexual characteristics and menstruation in pure gonadal dysgenesis case, as well as to prevent osteoporosis. Follow-up examinations revealed no tumor recurrence, and the patient with Swyer syndrome had regular menstrual cycles. Laparoscopic bilateral prophylactic gonadectomy and long-term hormone therapy with patient counseling and support are recommended.

Abstract PO2-11-05: Pregnancy Trends Following Breast Cancer Treatment: Insights from a Large Single-Center Experience

Abstract Background The treatment of breast cancer (BC), particularly chemotherapy and long-term endocrine therapy (ETx), can have an impact on fertility which young women with BC have concerns about. This study was therefore conducted with the objective of providing comprehensive real-world data on pregnancy following BC treatment, aiming to shed light on this crucial aspect of survivorship and potentially guide clinical practice and patient counseling. Methods A retrospective analysis was conducted using medical records of women aged 18-40 years diagnosed with BC at a single tertiary medical center between December 2010 and September 2020. The pregnancy rate and timing in relation to characteristics and treatment were analyzed, along with the outcomes of discontinuing ETx for the purpose of pregnancy. Statistical analyses including Kaplan-Meier curves and Cox regression were performed. Results The study included 995 patients, with a mean age at diagnosis of 31.5 years. Of these, 115 (11.6%) patients became pregnant after BC treatment. Patients with a prior history of pregnancy had a lower likelihood of conception post-treatment (HR=0.39, 95% CI: 0.24-0.67, P&amp;lt; 0.001). Women with hormone receptor positive BC was also associated with lower pregnancy rates than with hormone receptor negative BC (HR=0.52, 95% CI: 0.36-0.77, P=0.001). Age at diagnosis and chemotherapy did not significantly impact pregnancy rates (P=0.251 and P=0.140, respectively). Among 662 women with hormone receptor positive BC, there were 76 (11.5%) women who discontinued ETx for the purpose of pregnancy and 69.7% (53 out of 76) achieved pregnancies. The median duration of medication before cessation among these women was 26.5 months and the duration of ETx did not significantly affect pregnancy rates (P=0.204). Recurrence after discontinuation of ETx for pregnancy was observed in 17% (13 out of 76) of cases. The median breast cancer-free interval among these cohort was 71 months. Late recurrence, occurring after 5 years of treatment, was observed in 77% (10 out of 13) of cases. Among the patients who experienced recurrence, 62% (8 out of 13) were loco-regional, while 38% (5 out of 13) were distant recurrences and the success rate of achieving pregnancy was 69% (9 out of 13), while 31% (4 out of 13) did not get pregnant. Conclusion This study provided real-world data regarding the influence and outcomes of ETx on pregnancy in young BC survivors. The discontinuation of ETx for the purpose of pregnancy appears to result in successful conception. Recurrence rates after therapy discontinuation for pregnancy were observed in a subset of cases, with late and loco-regional recurrences being more common. Results of uni- and multi-variable cox proportional hazards model evaluating time to pregnancy * The pregnancy rate was calculated using Kaplan-Meier (KM) estimates. Pregnancy rate according to ETx and its discontinuation Pregnancy rate according to duration of ETx prior to Discontinuation for pregnancy * The p-value was calculated using Chi-square analysis Citation Format: Young-jin Lee, Tae-Kyung Yoo, Sae Byul Lee, Jisun Kim, Il-Yong Chung, Beom Seok Ko, Jong Won Lee, Byung Ho Son, Hee Jeong Kim, Jeonghee Ahn, Seonok Kim. Pregnancy Trends Following Breast Cancer Treatment: Insights from a Large Single-Center Experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-11-05.

Patients with Hypochondriasis (Illness Anxiety Disorder): Key Elements of Effective Communication in the Dental Practice

The world data show a large number of people with illness anxiety disorder (hypochondriasis) among the population all over the world. Russia is no exception: hypochondriacal patients often seek dental care. A dentist should be able to identify this category of patients. As a rule, these patients "know everything": their diagnosis and the most modern and effective methods of treatment. They are truly literate people. Their medical literacy is the result of watching popular shows, reading articles in trendy magazines and medical websites. Frequently, these patients are not emotionally stable; they have been stressed for a long time, or are undergoing long-term hormone therapy. Identifying these patients is the key to the successful practice. This article describes an interesting clinical case of the patient, who was treated for 2 months by 5 different specialists and took strong medications. During treatment her condition only worsened: allergic reaction developed to medications, with lesion of mucous membrane of oral cavity. Her reluctance to stop taking medications, insistence on consulting a dentist-oncologist alerted the attending doctor. Analysis of medical history revealed that the patient had experienced severe stress in the recent past and was currently undergoing a course of hormonal corrective therapy. A clinical psychologist confirmed the dentist's suggestion that the patient had hypochondriacal disorder. Patients with hypochondria - who are they? How to recognize them? If you meet such patients at a dental appointment, how you should communicate with them? How to treat them? A good result is achieved by establishing contact with the patients and their family and friends. Sometimes it is impossible to do without the help of a clinical psychologist. Only this specialist can definitively decide: does the patient have hypochondriacal disorder or not? If necessary, the clinical psychologist provides special treatment. The probability of a favorable outcome with this approach is high.

Behavior of the Respiratory Gases along Ergospirometry in Transgender Women after Long-Term Hormone Therapy: A Cross-Sectional Study

For transgender women (TW) undergoing estrogen therapy (ET), physiological responses while exerting physical effort is unknown at many points.

Incidence of breakthrough bleeding in transgender and gender-diverse individuals on long-term testosterone

BackgroundLittle is known about maintenance of amenorrhea in transgender and gender diverse individuals with uteri using long-term testosterone gender-affirming hormone therapy. Emerging data describes breakthrough bleeding in adolescents on long-term testosterone, as well as in adults seeking gender affirming hysterectomy. More studies are needed to better understand breakthrough bleeding patterns in transgender and gender diverse individuals on testosterone with uteri, including the frequency, timing, and etiology, and how these may differ in adults compared to younger populations. ObjectivesThe primary aim of this study was to characterize the incidence and patterns of breakthrough bleeding in a cohort of transgender and gender diverse individuals who had been on testosterone for greater than 12 months and had uteri in situ. Secondary aims included identifying the time to first bleed for those who experienced breakthrough bleeding as well as risk factors associated with breakthrough bleeding on testosterone. Study DesignThis was an IRB approved, single tertiary center, retrospective chart review of transgender and gender diverse individuals who had been on testosterone for at least one year. A primary survival analysis looking at the incidence of bleeding was combined with descriptive analyses and evaluation of factors associated with bleeding. ResultsOf the 279 patients included in the analysis, the median age of testosterone initiation was 22 years (IQR 19-41), with the median follow-up time 34 months (range 12-278). The absolute proportion of individuals who ever experienced breakthrough bleeding on testosterone was 34% (n=96, 95% CI [29, 40]). Patients who experienced breakthrough bleeding initiated testosterone at a younger age (20.5 vs 22.0 years, p=0.04), had lower mean serum testosterone levels (389.14 vs 512.7 ng/dL, p=0.001), were more likely to have a mean testosterone level <320ng/dL (52% vs 48% , p=.001), and had higher mean estradiol levels (62% vs 49%, p=0.003). Survival analyses estimated a breakthrough bleeding incidence rate of 0.09 per year (95% CI [.07-1.0]). While 58 people underwent a hysterectomy during the follow-up period, 64% of the cohort who maintained a uterus eventually experienced breakthrough bleeding. The median time to the initial bleeding episode was 22 (IQR 12-201) months after testosterone initiation. Conclusion(s)These results suggest a substantial fraction of transgender and gender diverse individuals using testosterone will experience at least one episode of breakthrough bleeding, even after their initial year using testosterone. We recommend that clinicians counsel all patients that breakthrough bleeding is a common occurrence, even after the first year on testosterone.

Трудности диагностики эозинофильного гранулематоза с полиангиитом в клинической практике

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare multisystem immune-mediated vasculitis with damage to medium and small vessels (including capillaries, venules and veins), first described in 1951. The etiology and pathogenesis of this disease associated with a combination of immunocomplex and allergic mechanisms have not been fully studied, and there are no generally accepted techniques to initial therapy. The diversity of the clinical picture at the disease onset, the gradual manifestation of signs, the need to take into account not only clinical but also laboratory parameters, makes it difficult to make a correct diagnosis in the early stages. This article describes a clinical case of a relatively late diagnosis of EGPA, which may be due to a lack of practitioner awareness about such a rare disease and a late referral to a rheumatologist. Not only morphological verification and immunological tests of patients can speed up diagnosis, but also discussion of such clinical cases in the medical community. Currently, the EGPA therapy possibilities have been expanded by including the disease in indications for biological treatments aimed at interleukin 5, which will improve the disease prognosis and reduce the burden of long-term hormonal therapy. KEYWORDS: eosinophilic granulomatosis with polyangiitis, vasculitis, eosinophilia, differential diagnosis, bronchial asthma, clinical case. FOR CITATION: Karoli N.A., Kanaeva T.V., Nikitina N.M. Difficulties in diagnosing eosinophilic granulomatosis with polyangiitis in clinical practice. Russian Medical Inquiry. 2024;8(3):171–175 (in Russ.). DOI: 10.32364/2587-6821-2024-8-3-8.

Outcomes in patients with high- and very high-risk localized prostate cancer treated with definitive IMRT and long-term hormone therapy.

The aim of this study was to evaluate the effectiveness of intensity-modulated radiation therapy in combination with long-term androgen deprivation therapy for high-risk and very high-risk localized prostate cancer while also investigating factors associated with the therapeutic effect. Men who fulfilled criteria for the National Comprehensive Cancer Network high-risk or very high-risk localized prostate cancer and were treated with definitive intensity-modulated radiation therapy (74-78Gy) of the prostate and the seminal vesicle combined with androgen deprivation therapy in our institution from 2007 to 2016 were identified (n=197). In principle, patients received androgen deprivation therapy for 3-6months before radiation, concurrently, and for 2years after completion of intensity-modulated radiation therapy. The median follow-up period was 96months. The 5-year and 10-year overall survival rates in the overall population were 96.9% and 89.3%, respectively. The 5-year and 10-year cumulative incidence rates of biochemical failure were 2.5% and 16.3% in the high-risk group, and 8.6% and 32.0% in the very high-risk group, respectively, indicating a significant difference between the two groups (P=0.023). Grade Group 5 and younger age (cutoff: 70years old) were independent predictors of recurrence (P=0.016 and 0.017, respectively). Patients exhibiting biochemical failure within <18months after completion of androgen deprivation therapy displayed an increased risk of cancer-specific mortality (P=0.039) when contrasted with those who had a longer interval to biochemical failure. Patients with the National Comprehensive Cancer Network very high-risk prostate cancer, particularly those with Grade Group 5 and younger age, showed worse outcomes following intensity-modulated radiation therapy and long-term androgen deprivation therapy.

Cognitive functioning in older transgender individuals receiving long-term gender-affirming hormone therapy

Background Cognitive functioning can be negatively influenced by age, cardiovascular risk (CVR) and mental health challenges, and sex-hormones can have neuroprotective effects. Little is known about cognitive functioning in older transgender individuals receiving long-term gender-affirming hormone therapy (GHT). In a previous, smaller study, cognitive differences between transgender women and cisgender groups were minimal yet statistically significant. Aims This study assessed cognitive differences between larger samples of older transgender and cisgender individuals, and the contribution of CVR and mental/social health to these differences. Methods This cross-sectional study compared 73 transgender women and 39 transgender men (56–84 y) receiving long-term GHT (10–47 y) with matched (age; education level) cisgender women and men from the Longitudinal Aging Study Amsterdam on cognitive functioning assessed with neuropsychological tests. Mean z-scores per cognitive domain were calculated and analyzed using linear regression. Models were subsequently adjusted for CVR ((history of) cardiovascular disease; smoking) and mental/social health (anxiety; loneliness) factors. Results Transgender women had lower scores than cisgender women and men, respectively, on information-processing speed (b = −0.62, 95% CI −0.90 to −0.35; b = −0.33, 95%CI −0.60 to −0.05), episodic memory (b = −1.28, 95%CI −1.53 to −1.04; b = −0.77, 95%CI −1.01 to −0.52), and crystallized intelligence (b = −0.42, 95%CI −0.75 to −0.10; b = −0.41, 95%CI −0.75 to −0.08). Transgender men scored lower on episodic memory than cisgender women but scored equal to cisgender men (b = −0.43, 95%CI −0.79 to −0.08; b = −0.01, 95%CI −0.36 to 0.35). Mental/social health factors (particularly depressive symptoms) largely, and CVR factors slightly, explained cognitive differences between the trans- and cisgender groups. Discussion Small cognitive differences between transgender men and cisgender groups do not suggest adverse or beneficial long-term testosterone effects on cognitive functioning. However, transgender women had lower cognitive functioning than cisgender groups, which was largely explained by mental/social health. This warrants further research and clinical awareness of mental and cognitive health in older transgender individuals.

Benefits for cardiovascular system, bone density, and quality of life of a long-term hormone therapy in hysterectomized women: a 20-year follow-up study.

The safety, consequences, and dosage of long-term hormone therapy (HT) for postmenopausal women remain unclear. Our aim was to analyze the effects of HT after 20 years of therapy in women after hysterectomy, focusing on the symptoms of menopause, blood pressure, lipid profiles, and bone density. A prospective observational longitudinal study was designed. The initial transdermal estradiol dose was reduced in half (0.025 mg/d) at 60 years of age. Different parameters including demographic, cardiovascular, bone density, and metabolic variables, as well as quality of life characteristics, were analyzed using bivariate analyses. Multivariate generalized estimating equations for longitudinal data were fitted for differences over time and between doses (<60 vs ≥60 y) using the R package geepack. After 20 years of HT, the mean age of 56 studied hysterectomized women was 67.1 years. The mean Kupperman index score decreased from 26.7 to 12.0 ( P < 0.001). A trend with total and low-density lipoprotein cholesterol reduction and high-density lipoprotein cholesterol increase was observed over time. A decrease in very-low-density lipoprotein cholesterol ( P = 0.05) and an increase in T score vertebral densitometry ( P = 0.014) were detected after HT. No changes in health outcome were detected in women older than 60 years with the reduced dose of HT. Breast cancer was the reason for dropouts in 0.02% women. HT for up to 20 years after hysterectomy may be beneficial for bone and cardiovascular health and for the overall quality of life. Our data suggest the importance of evaluating the dose and the timing of HT.

Growth Hormone Injection Log Analysis with Electronic Injection Device for Qualifying Adherence to Low-Irritant Formulation and Exploring Influential Factors on Adherence.

Although the treatment success of long-term growth hormone therapy (GHT) is dependent on maintaining patients' adherence to treatment, marked variations in adherence levels among children with GHT (eg, 7-71% nonadherence) have been reported. Barriers to or promoters of GHT adherence have been discussed and investigated, and digital health technologies, such as electronic GH injection devices, may have the potential to assess adherence to GHT more accurately. Thus, we conducted a multicenter, retrospective cohort study using GH injection log analysis of an electronic GH device, GROWJECTOR®L, to qualify adherence and explore the factors influencing adherence. This study enrolled 41 patients (median[range] age, 5.8[3.0 ~ 17.0] years) with short stature from nine Japanese medical institutions. The injection log data (12-48 weeks) were read by smartphones and collected into the data center through a cloud server. Although cumulative adherence rates remained higher than 95% throughout the observation period, five (12.2%) patients had low adherence (<85%). Subsequently, subgroup and logistic regression analyses for exploring factors affecting adherence revealed that self-selection of GH device and irregular injection schedule (ie, frequent injections after midnight) significantly affected adherence rate (p=0.034 and 0.048, respectively). In addition, higher rates of irregular injections significantly affected low adherence (median[range], 11.26[0.79 ~ 30.50]% vs 0.26[0.00 ~ 33.33]%, p = 0.029). Our study indicated that injection log analysis using an electronic GH device could detect irregular injection schedules due to a night owl or disturbance in lifetime rhythm affecting low adherence and had significant potential to encourage collaborative monitoring of adherence with healthcare providers and patients themselves/caregivers, along with growing autonomy and shared decision-making. Our study suggests the significance of narrative and personal approaches to adherence of patients with GHT and the usefulness of digital devices for such an approach and for removing various barriers to patient autonomy, leading to improvement and maintenance of adherence.

Impact of Long-term Adjuvant Hormonal Therapy in High-dose IMRT for Unfavorable Locally Advanced Prostate Cancer.

The aim of this study was to evaluate the benefit of adding long-term adjuvant hormonal therapy to high-dose intensity-modulated radiation therapy for locally advanced prostate cancer patients with multiple unfavorable risks. All cT3-4N0M0 prostate cancer patients with Gleason score 8-10 and prostate-specific antigen ≥30 ng/ml who received intensity-modulated radiation therapy to the prostate and seminal vesicle alone (78 Gy in 39 fractions) between September 2000 and June 2017 at our institution were analyzed retrospectively. All patients received short-term neoadjuvant hormonal therapy. Before May 2011, salvage hormonal therapy was initiated when prostate-specific antigen levels exceeded 4.0 ng/ml (early salvage hormonal therapy cohort). In June 2011, 2-year adjuvant hormonal therapy was added (adjuvant hormonal therapy cohort). Clinical outcomes were retrospectively compared using the log-rank test. In total, 88 patients (44 in both cohorts) were analyzed. Median follow-up periods were 10.9 and 6.1 years in early salvage hormonal therapy and adjuvant hormonal therapy cohorts, respectively. No significant difference in overall survival rates was observed (p=0.58). Disease controls were significantly better in the adjuvant hormonal therapy cohort: 95.5 versus 73.6% for castration-resistant prostate cancer-free rate (p=0.04), and 73.6 versus 34.1% for biochemical failure-free rate (p<0.001), both at 8 years, respectively. Among locally advanced prostate cancer patients with multiple unfavorable risks, adding long-term adjuvant hormonal therapy to high-dose intensity-modulated radiation therapy resulted in significantly better disease control than short-term hormonal therapy, even when salvaged early after biochemical failure.

Cancer screening and management in the transgender population: Review of literature and special considerations for gender affirmation surgery.

Literature focused on cancer screening and management is lacking in the transgender population. To action to increase contributions to the scientific literature that drives the creation of cancer screening and management protocols for transgender and gender nonconforming (TGNC) patients. We performed a systematic search of PubMed on January 5th, 2022, with the following terms: "TGNC", OR "transgender", OR "gender non-conforming", OR "gender nonbinary" AND "cancer screening", AND "breast cancer", AND "cervical cancer", AND "uterine cancer", AND "ovarian cancer", AND "prostate cancer", AND "testicular cancer", AND "surveillance", AND "follow-up", AND "management". 70 unique publications were used. The findings are discussed under "Screening" and "Management" categories. Screening: Current cancer screening recommendations default to cis-gender protocols. However, long-term gender-affirming hormone therapy and loss to follow-up from the gender-specific specialties contribute to a higher risk for cancer development and possible delayed detection. The only known screening guidelines made specifically for this population are from the American College of Radiology for breast cancer. Management: Prior to undergoing Gender Affirmation Surgery (GAS), discussion should address cancer screening and management in the organs remaining in situ. Cancer treatment in this population requires consideration for chemotherapy, radiation, surgery and/or reconstruction. Modification of hormone therapy is decided on a case-by-case basis. The use of prophylactic vs aesthetic techniques in surgery is still debated. When assessing transgender individuals for GAS, a discussion on the future oncologic risk of the sex-specific organs remaining in situ is essential. Cancer management in this population requires a multidisciplinary approach while the care should be highly individualized with considerations to social, medical, surgical and gender affirming surgery related specifications. Special considerations have to be made during planning for GAS as surgery will alter the anatomy and may render the organ difficult to sample for screening purposes. A discussion with the patient regarding the oncologic risk of remaining organs is imperative prior to GAS. Other special considerations to screening such as the conscious or unconscious will to unassociated with their remaining organs is also a key point to address. We currently lack high quality studies pertinent to the cancer topic in the gender affirmation literature. Further research is required to ensure more comprehensive and individualized care for this population.

Side effects and impacts of extended adjuvant endocrine therapy: A qualitative study among women with HR+/HER2- breast cancer.

e12509 Background: Extended (≥5-year) adjuvant endocrine therapy (ET) is generally the preferred treatment approach for patients with hormone receptor–positive (HR+) breast cancer at high risk of recurrence. However, due to side effect burden and other challenges, patient adherence to extended adjuvant ET is often suboptimal, presenting challenges for patients and healthcare providers alike. To further understand potential barriers to adherence, the objective of this study was to explore the side effects and impacts of extended adjuvant ET among women with HR+ breast cancer through in-depth qualitative interviews. Methods: Individual qualitative interviews were conducted with 20 US women with a self-reported clinical diagnosis of nonmetastatic HR+/HER2− breast cancer who had undergone ≥4 years of adjuvant ET and were currently taking ET or had concluded their regimen within the past 12 months. Using thematic analysis methods, interview transcripts and interviewers’ field notes were analyzed to identify important concepts and dominant trends. Results: Interview participants averaged 52.8 years in age and were diverse in race, education level, and employment status. The most commonly reported ET side effects among the 20 participants were hot flashes (n = 16), joint pain (n = 15), difficulty sleeping (n = 15), difficulty with weight management (n = 15), fatigue (n = 15), reduced interest in sex (n = 14), and feeling irritable (n = 14). Participants most frequently identified joint pain (n = 8), reduced interest in sex (n = 4), and discomfort with intercourse (n = 4) as the most bothersome ET side effects. Participants generally reported that the frequency and severity of side effects that they experienced remained constant throughout the extended adjuvant period; only 3 reported having switched ET regimens to manage side effects. Participants reported numerous impacts from ET side effects, including to cognitive and physical functioning (most common), social interactions, and work/productivity. Several participants spoke about the tradeoffs they make in enduring ET side effects and impacts to reduce risk of recurrence. For most participants, the primary benefit of extended adjuvant ET was the perceived reduction of risk of recurrence; some reported “peace of mind” from taking ET, knowing they were doing everything possible to reduce their risk of recurrence. Several participants expressed reluctance to stop taking ET despite the side effects because adherence to their medication made them feel less anxious or worried about recurrence. Conclusions: Patients receiving ET for HR+/HER2− breast cancer continue to experience significant side effects during extended adjuvant ET, and these side effects impact quality of life in many ways. Some patients are nonetheless motivated to continue with long-term ET to reduce risk of recurrence and/or because of the emotional benefit it affords.

In the thicket of fears, doubts, and murky facts: some reflections on treatment modalities for endometriosis-associated pain.

Endometriosis-associated pain can be managed by either surgery or hormonal therapy. The final decision as to which treatment modality to take is based on efficacy and possible complications of different treatment modalities, risk of recurrence, and the patient's wishes and preferences. But in the thicket of fears, doubts, and murky facts, the choice may ultimately be the trade-off between irrational fears and ignorance versus scientific evidence. We elaborate some pros and cons of the two treatment modalities and highlight some notable downsides of hormonal therapy, in particular the possible yet unquantified risk of long-term hormonal therapy for malignant transformation, perhaps with the only exception of combined oral contraceptives. Thus, when discussing with patients, we advocate the approach of discussing the advantages and disadvantages of all treatment options in detail, accounting for the known pros and cons with a full understanding of the predictive irrationality of human beings. For endometriosis-associated pain, surgery is definitely not a failure of medicine but, rather, a viable option, especially given the recently surfaced undercurrent of wariness and dissatisfaction with the current hormonal drugs among patients with endometriosis. Above all, there is a pressing need to fill the knowledge gap of perioperative interventions intended to reduce the risk of recurrence and to fulfill the demand for the development of safe and efficacious non-hormonal therapeutics.

Arterial Stiffness in Transgender Men Receiving Long-term Testosterone Therapy.

The effects of androgen therapy on arterial function in transgender men (TM) are not fully understood, particularly concerning long-term androgen treatment. To evaluate arterial stiffness in TM receiving long-term gender-affirming hormone therapy by carotid-femoral pulse wave velocity (cf-PWV). A cross-sectional case-control study at the Gender Dysphoria Unit of the Division of Endocrinology, HC-FMUSP, Sao Paulo, Brazil. Thirty-three TM receiving intramuscular testosterone esters as regular treatment for an average time of 14 ± 8 years were compared with 111 healthy cisgender men and women controls matched for age and body mass index. Aortic stiffness was evaluated by cf-PWV measurements using Complior device post-testosterone therapy. The main outcome measure was aortic stiffness by cf-PWV as a cardiovascular risk marker in TM and control group. The cf-PWV after long-term testosterone therapy was significantly higher in TM (7.4 ± 0.9 m/s; range 5.8-8.9 m/s) than in cisgender men (6.6 ± 1.0 m/s; range 3.8-9.0 m/s, P < .01) and cisgender women controls (6.9 ± .9 m/s; range 4.8-9.1 m/s, P = .02). The cf-PWV was significantly and positively correlated with age. Analysis using blood pressure as a covariate showed a significant relationship between TM systolic blood pressure (SBP) and cf-PWV in relation to cisgender women but not to cisgender men. Age, SBP, and diagnosis of hypertension were independently associated with cf-PWV in the TM group. The TM group on long-term treatment with testosterone had higher aging-related aortic stiffening than the control groups. These findings indicate that aortic stiffness might be accelerated in the TM group receiving gender-affirming hormone treatment, and suggest a potential deleterious effect of testosterone on arterial function. Preventive measures in TM individuals receiving testosterone treatment, who are at higher risk for cardiovascular events, are highly recommended.

Abstract P5-05-04: Estrogen receptor 1 (ESR1) mutations in circulating tumor DNA (ctDNA) from patients with ER+/HER2- metastatic breast cancer (mBC) treated with lasofoxifene or fulvestrant in the ELAINE 1 study

Abstract Introduction: Acquired ESR1 mutations (mutESR1) after long-term endocrine therapy drive treatment resistance, metastasis, and poor prognosis for patients (pts) with ER+/HER2- metastatic breast cancer (mBC). Lasofoxifene (LAS), a selective estrogen receptor modulator, alone or with a CDK4/6 inhibitor (CDK4/6i) reduced tumor growth better than fulvestrant (Fulv) in mutESR1 BC xenograft models. ELAINE 1 is a randomized trial of LAS vs Fulv in pts with mutESR1 and prior progression on aromatase inhibitor and CDK4/6i. Preliminary results (ESMO 2022) showed that LAS prolonged median progression-free survival (mPFS) compared with Fulv with a favorable safety profile. Here, we report changes in ESR1 ctDNA mutant allele frequency (MAF) from baseline to 8 wks and their associations with clinical benefit (CB) and mPFS. Methods: ELAINE 1 pts were randomized to oral LAS 5 mg daily or IM Fulv 500 mg on days 1, 15, and 29, then every 4 wks, until disease progression or severe toxicity. ctDNA mutESR1 mutations (baseline and 8 wks) were assessed using the Sysmex Inostics OncoBeam or SafeSeq assays—which detect mutESR1 at low allele fractions. MAF changes from baseline to wk 8 were characterized as decreased (decrease in ESR1 MAF or fully cleared), increased (increase in MAF), or equivocal (polyclonal patients [&amp;gt;1 mutESR1] with some increasing and decreasing MAF trends); correlations with PFS and CB were explored. Efficacy measures included objective response rate (ORR), PFS, and CB at 24 wks (CB defined as response or stable disease ≥24 wks). Results: 103 pts received LAS (n=52) or Fulv (n=51). Most common baseline ESR1 variants detected were D538G (56%), Y537S (39%), Y537N (29%), E380Q (22%); 56 (54%) pts were polyclonal. Of the 61 pts with evaluable baseline and wk 8 ctDNA, LAS decreased mutESR1 MAF in 29/35 pts (83% [11 complete clearance]) while Fulv decreased mutESR1 MAF in 16/26 pts (61.5% [6 complete clearance]) (Table). mPFS with LAS was 8 and 4 mos for pts with decreased/cleared MAF and increased MAF, respectively, and with Fulv was 4.5 and 2.8 mos, respectively (Table). LAS decreased the common mutESR1 variants more frequently than Fulv (median relative change -87.1% vs -14.7%). In pts with decreased MAF, CB was observed in 16/29 LAS pts (55%) and 4/16 Fulv pts (25%). The predictiveness of ESR1 MAF clearance for CB was also explored. Of 11 pts with ESR1 MAF clearance taking LAS, 10 achieved CB, yielding a positive predictive value (PPV) of 90.9%. In contrast, 2/6 pts with ESR1 MAF clearance taking Fulv had CB for a PPV of 33.3%. Sensitivity for predicting CB based on direction of ESR1 MAF change was 94% with LAS and 80% with Fulv. In pts with Y537S MAF (n=33), LAS decreased Y537S in 13/15 (87%), with a median relative MAF decrease of 89%. In marked contrast, Fulv increased Y537S MAF in 11/18 pts (61%), corresponding to an MAF relative increase of 82%. LAS and Fulv resulted in complete clearance of Y537S MAF in 33% and 6% of pts, respectively. Conclusion: Our data demonstrate that LAS more effectively decreased or cleared mutESR1 than Fulv. Further, mutESR1 clearance was associated with prolonged PFS and more CB in LAS but not Fulv pts, suggesting that LAS results in robust mutESR1 target engagement. Taken together, our data suggest mutESR1 as a potential liquid biomarker for predicting response to LAS in mutESR1, endocrine-resistant mBC pts. Table. Change from baseline to week 8 in ESR1 MAF and clinical benefit at 24 weeks. CI, confidence interval; MAF, mutant allele fraction; ND, none detected; PFS, progression-free survival. Citation Format: Matthew P. Goetz, Einav Gal-Yam, Daniel Stover, Sarah L. Sammons, Stephanie L. Graff, Grace Wang, Massimo Cristofanilli, Gary Riordan, Hillary S. Sloane, Dominic Carroll, Paul V. Plourde, David J Portman. Estrogen receptor 1 (ESR1) mutations in circulating tumor DNA (ctDNA) from patients with ER+/HER2- metastatic breast cancer (mBC) treated with lasofoxifene or fulvestrant in the ELAINE 1 study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-05-04.

Abstract P5-05-02: Estrogen receptor 1 (ESR1) mutations in circulating tumor DNA (ctDNA) from patients with ER+/HER2- metastatic breast cancer (mBC) treated with lasofoxifene plus abemaciclib in the ELAINE 2 study

Abstract Introduction: Use of long-term endocrine therapy (ET) for ER+ breast cancer often leads to acquired ESR1 mutations (mutESR1), causing endocrine resistance, tumor progression, and poor prognosis. An unmet clinical need exists for treating ER+ mBC patients with mutESR1, particularly after progression on CDK4/6 inhibitors (CDK4/6i). ELAINE 2 is an open-label, phase 2, multicenter trial evaluating safety and efficacy of lasofoxifene (LAS [selective estrogen receptor modulator]) plus abemaciclib (Abema [CDK4/6i], provided by Eli Lilly) in patients with ER+/HER2- and mutESR1 mBC who progressed after prior ET. Preliminary data with LAS plus Abema showed median progression-free survival of 55.7 wks, objective response rate of 50%, and 24-wk clinical benefit (CB) rate of 69%, with an acceptable safety and tolerability profile. Here, we report ESR1 ctDNA mutant allele frequency (MAF) and correlations of ESR1 MAF changes with CB. Methods: ELAINE 2 patients with detectable ctDNA mutESR1 at baseline (BL) were analyzed. Oral LAS 5 mg/day and Abema 150 mg BID were taken until disease progression, death, unacceptable toxicity, or withdrawal from the study. ctDNA was assessed by the Sysmex-Inostics SafeSeq assay—which detects mutESR1 at low allele fractions—at BL, every 4 wks, and end of treatment. MAF changes from BL to wk 4 were characterized as decreased (decrease in ESR1 MAF or none detected [ND]), increased (increase in MAF), or equivocal (in polyclonal patients [&amp;gt;1 mutESR1] with some MAF increasing and decreasing trends). Correlations of MAF change at 4 wks with CB at 24 wks were explored. Results: 29 patients (median of 2 prior metastatic therapies: 97% CDK4/6i, 79% fulvestrant, 48% chemotherapy) had BL mutESR1 of Y537S (66%), D538G (45%), Y537N (28%), and other less frequently detected mutations; 14 (48.3%) patients were polyclonal. 26 of 29 patients had evaluable BL and wk-4 ctDNA results: 21 patients had decreased MAF (81% [54% with ND]), 3 (12%) had increased, and 2 (8%) had equivocal ESR1 MAF changes (Table). CB at 24 wks was seen in 17 patients with a decrease, 2 with an increase, and 1 with equivocal MAF change. A sensitivity of 89.5% and specificity of 20% were calculated for predicting CB based on direction of ESR1 MAF change. The positive predictive value (PPV) for CB with decreased MAF was 81% and the negative predictive value (NPV) for an increased MAF was 33%. Of the 14 (54%) patients with ND ESR1 MAF, 13 had CB resulting in 87% sensitivity, 50% specificity, 93% PPV, and 33% NPV. Conclusion: In ELAINE 2, 81% of patients had decrease/cleared (ND) mutESR1 after 4 wks of LAS plus Abema, which correlated with clinical benefit. All mutESR1 detected appear targeted with this therapy. High sensitivity and favorable PPV were observed in patients with decreased MAF, and even more so in those with ND MAF; however, increased MAF was less specific and not as predictive of treatment failure. Our results indicate that ESR1 liquid biopsy evaluation may be an adequate non-invasive surrogate marker for monitoring patients on treatment. Further study in a larger population of women with endocrine-resistant mBC and acquired mutESR1 is warranted to explore this potential for monitoring treatment response or resistance to this novel LAS-Abema combination. Table. Change from baseline to week 4 in ESR1 MAF and clinical benefit at 24 weeks. CI, confidence interval; MAF, mutant allele fraction; ND, none detected; NPV, negative predictive value; PPV, positive predictive value. *Sensitivity and specificity analyses do not include equivocal results. Citation Format: Senthil Damodaran, Halle Moore, Ciara C. O’Sullivan, Paul V. Plourde, Gary Riordan, Hillary S. Sloane, Debu Tripathy, Dominic Carroll, David J Portman. Estrogen receptor 1 (ESR1) mutations in circulating tumor DNA (ctDNA) from patients with ER+/HER2- metastatic breast cancer (mBC) treated with lasofoxifene plus abemaciclib in the ELAINE 2 study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-05-02.