SIGIS-SIAMS-SIE position statement of gender affirming hormonal treatment in transgender and non-binary people.

PURPOSE: Gender Incongruence (GI) is a marked and persistent incongruence between an individual's experienced and the assigned gender at birth. In the recent years, there has been a considerable evolution and change in attitude as regards to gender nonconforming people. METHODS: According to the Italian Society of Gender, Identity and Health (SIGIS), the Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Endocrinology (SIE) rules, a team of experts on the topic has been nominated by a SIGIS-SIAMS-SIE Guideline Board on the basis of their recognized clinical and research expertise in the field, and coordinated by a senior author, has prepared this Position statement. Later on, the present manuscript has been submitted to the Journal of Endocrinological Investigation for the normal process of international peer reviewing after a first internal revision process made by the SIGIS-SIAMS-SIE Guideline Board. RESULTS: In the present document by the SIGIS-SIAMS-SIE group, we propose experts opinions concerning the psychological functioning, gender affirming hormonal treatment, safety concerns, emerging issues in transgender healthcare (sexual health, fertility issues, elderly trans people), and an Italian law overview aimed to improve gender non-conforming people care. CONCLUSION: In this Position statement, we propose experts opinions concerning the psychological functioning of transgender people, the gender-affirming hormonal treatment (full/partial masculinization in assigned female at birth trans people, full/partial feminization and de-masculinization in assigned male at birth trans people), the emerging issues in transgender health care aimed to improve patient care. We have also included an overview of Italian law about gender affirming surgery and registry rectification.

Treatment of Urogenital Symptoms in Individuals With a History of Estrogen-dependent Breast Cancer: Clinical Consensus.

SUMMARY: With an estimated 3.8 million breast cancer survivors in the United States, obstetrician-gynecologists often are on the front lines of addressing survivorship issues, including the hypoestrogenic-related adverse effects of cancer therapies or early menopause in survivors (1). Although systemic and vaginal estrogen are used widely for symptomatic relief of genitourinary syndrome of menopause in the general population, among individuals with a history of hormone-sensitive cancer, there is uncertainty about the safety of hormone-based therapy, leading many individuals with bothersome symptoms to remain untreated, with potential negative consequences on quality of life (2). An effective management strategy requires familiarity with a range of both hormonal and nonhormonal treatment options, knowledge about the pharmaceutical mechanisms of action, and the ability to tailor treatment based on individual risk factors. This clinical consensus document was developed using an a priori protocol in conjunction with two authors specializing in urogynecology and gynecologic oncology. This document has been updated to review the safety and efficacy of newer hormonal treatment options as well as nonhormonal modalities.

Characterization of Benign Breast Diseases and Association With Age, Hormonal Factors, and Family History of Breast Cancer Among Women in Sweden.

Importance: Benign breast diseases (BBDs) are common and associated with breast cancer risk, yet the etiology and risk of BBDs have not been extensively studied. Objective: To investigate the risk of BBDs by age, hormonal factors, and family history of breast cancer. Design, Setting, and Participants: This retrospective cohort study assessed 70 877 women from the population-based Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) who attended mammographic screening or underwent clinical mammography from January 1, 2011, to March 31, 2013, at 4 Swedish hospitals. Participants took part in a comprehensive questionnaire on recruitment. All participants had complete follow-up through high-quality Swedish national registers until December 31, 2015. Pathology medical records on breast biopsies were obtained for the participants, and BBD subtypes were classified according to the latest European guidelines. Analyses were conducted from January 1 to July 31, 2020. Exposures: Hormonal risk factors and family history of breast cancer. Main Outcomes and Measures: For each BBD subtype, incidence rates (events per 100 000 person-years) and multivariable Cox proportional hazards ratios (HRs) with time-varying covariates were estimated between the ages of 25 and 69 years. Results: A total of 61 617 women within the mammographic screening age of 40 to 69 years (median age, 53 years) at recruitment with available questionnaire data were included in the study. Incidence rates and risk estimates varied by age and BBD subtype. At premenopausal ages, nulliparity (compared with parity ≥3) was associated with reduced risk of epithelial proliferation without atypia (EP; HR, 0.62; 95% CI, 0.46-0.85) but increased risk of cysts (HR, 1.38; 95% CI, 1.03-1.85). Current and long (≥8 years) oral contraceptive use was associated with reduced premenopausal risk of fibroadenoma (HR, 0.65; 95% CI, 0.47-0.90), whereas hormone replacement therapy was associated with increased postmenopausal risks of epithelial proliferation with atypia (EPA; HR, 1.81; 95% CI, 1.07-3.07), fibrocystic changes (HR, 1.60; 95% CI, 1.03-2.48), and cysts (HR, 1.98; 95% CI, 1.40-2.81). Furthermore, predominantly at premenopausal ages, obesity was associated with reduced risk of several BBDs (eg, EPA: HR, 0.31; 95% CI, 0.17-0.56), whereas family history of breast cancer was associated with increased risk (eg, EPA: HR, 2.11; 95% CI, 1.48-3.00). Conclusions and Relevance: These results suggest that the risk of BBDs varies by subtype, hormonal factors, and family history of breast cancer and is influenced by age. Better understanding of BBDs is important to improve the understanding of benign and malignant breast diseases.

Comparison of vaginal progesterone gel combined with oral dydrogesterone versus intramuscular progesterone for luteal support in hormone replacement therapy-frozen embryo transfer cycle.

BACKGROUND: It remains under subject of debate regarding the optimal route of luteal support for hormone replacement therapy- frozen embryo transfer (HRT-FET) cycles. We compared efficacy of vaginal progesterone gel combined with oral dydrogesterone and intramuscular progesterone for HRT-FET lutein support. METHODS: This is a retrospective observational study. After matching for propensity score of getting vaginal + oral treatment, a total of 208 FET cycles in the vaginal progesterone combined with oral dydrogesterone and 624 cycles in the intramuscular progesterone group were enrolled. Pregnancy outcomes and neonatal outcomes including chemical pregnancy rate, clinical pregnancy rate, implantation rate, spontaneous abortion rate, live birth rate, gestational weeks, pre-term delivery, birth weight, and congenital anomalies rate were compared. RESULTS: No significant differences were observed in patient characteristics such as age, duration of infertility, type of infertility, or hormone level after matching. Chemical pregnancy rate (68.3 % versus 70.5 %), clinical pregnancy rate (64.9 % versus 64.4 %), implantation rate (52.3 % versus 50.2 %), spontaneous abortion rate (21.5 % versus 18.4 %), and live birth rate (49.0 % versus 51.3 %) were similar in both group without statistically significant difference. No significant differences in neonatal outcomes were observed between the two groups. CONCLUSION: We observed similar pregnancy outcomes in both vaginal progesterone gel combined with oral dydrogesterone and intramuscular progesterone protocol. Vaginal progesterone gel combined with oral dydrogesterone can be substituted for intramuscular progesterone given that vaginal plus oral use has good safety and is more convenient and may be associated with less side effect caused by intramuscular injection.

Neoadjuvant hormone therapy for patients with high-risk prostate cancer: a systematic review and meta-analysis.

This study aimed to identify the pathological outcomes and survival benefits of neoadjuvant hormone therapy (NHT) combined with radical prostatectomy (RP) and radiotherapy (RT) administered to patients with high-risk prostate cancer (HRPCa). We searched PubMed, Embase, and the Cochrane Library for studies comparing NHT plus RP or RT with RP or RT alone, administered to patients with HRPCa. We used a random-effects model to compute risk estimates with 95% confidence intervals (CIs) and quantified heterogeneity using the I "2" statistic. Subgroup and sensitivity analyses were performed to identify potential sources of heterogeneity. We selected 16 studies. NHT before RP significantly decreased lymph node involvement (risk ratio [RR] = 0.69, 95% CI: 0.56-0.87) and increased the rates of pathological downstaging (RR = 2.62, 95% CI: 1.22-5.61) and organ-confinement (RR = 2.24, 95% CI: 1.54-3.25), but did not improve overall survival and biochemical progression-free survival (bPFS). The administration of NHT before RT to patients with HRPCa was associated with significant benefits for cancer-specific survival (hazard ratio [HR] = 0.51, 95% CI: 0.39-0.68), disease-free survival (HR = 0.51, 95% CI: 0.44-0.60), and bPFS (HR = 0.54, 95% CI: 0.46-0.64). Short-term NHT combined with RT administered to patients with HRPCa conferred significant improvements. Although the advantage of local control was observed when NHT was administered before RP, there was no significant survival benefit associated with HRPCa. Therefore, short-term NHT combined with RT is recommended for implementation in standard clinical practice but not for patients who undergo RP.

Adherence to growth hormone therapy guidelines in a real-world French cohort of adult patients with growth hormone deficiency.

OBJECTIVE: Using real-world data from patients with growth hormone deficiency (GHD), we evaluated whether clinical practice in France adheres to international guidelines regarding somatropin dose adjustment, and assessed the long-term effectiveness and safety of somatropin. METHODS: Data were obtained from a national prospective systematic longitudinal routine follow-up programme of naive/non-naive adults with childhood-onset (CO) or adult-onset (AO) GHD treated with Norditropin® (Novo Nordisk A/S). RESULTS: Between 2003 and 2006, 331 treatment-naive and non-naive adults with severe GHD were enrolled and followed for a median duration of approximately 5 years; 328 patients were available for analysis. At baseline, mean patient age was 39.2 years; median standard deviation score (SDS) for insulin-like growth factor-1 (IGF-1) level was -2.2 in naive patients, subsequently fluctuating between -0.1 and +0.3 SDS during the study period. Mean GH doses ranged between 0.25 and 0.51mg/day (naive patients) and 0.39 and 0.46mg/day (non-naive patients). Despite generally receiving a higher somatropin dose, women (naive/non-naive) tended to have lower IGF-1 levels than men. Median somatropin dose was consistently higher in patients with CO-GHD than patients with AO-GHD. Extreme IGF-1 values (<-2 or >+2 SDS) were not systematically accompanied by somatropin dose adjustments. Waist circumference improved in approximately one third of patients, at a mean 3.5 years. Somatropin was well tolerated; there were no cardiovascular or cerebrovascular events during the 5-year analysis period. CONCLUSION: Current clinical practice of physicians in France follows international guidelines regarding somatropin dose adjustment in adults with GHD. However, dose adjustments are not always sufficient, notably in women, and treatment effects may have been delayed due to low somatropin dose (Clinical trial registration NCT01580605).

Hypogonadism and cancer survivorship.

PURPOSE OF REVIEW: Hypogonadism is highly prevalent among not only patients with a history of prior treatment for cancer, but also among those patients with a new oncologic diagnosis who have not yet received any cancer therapy. Hypogonadism can cause a wide array of signs and symptoms including: deceased muscle mass; increased fat mass; decreased energy, mood, and overall sense of well being; diminished bone mineral density; infertility; and impaired libido and sexual function. This purpose of this manuscript is to review the mechanisms by which cancer and oncologic treatment regimens can adversely affect the hypothalamic pituitary gonadal axis, resulting in hypogonadism. Risks and benefits associated with the treatment of testosterone deficiency are also discussed, which are important considerations for clinicians caring for affected patients. RECENT FINDINGS: Hypogonadism has a high prevalence in the setting of cancer and is an important survivorship issue. Recent randomized controlled trials confirm testosterone's therapeutic benefits in terms of sexual function, mood body composition, and bone health, but the specific benefits in terms of quality of life are less clear. SUMMARY: More prospective studies are needed to further delineate the risks, benefits, and overall outcomes of testosterone replacement therapy in patients with cancer and cancer survivors.

Current Evidence of the Oncological Benefit-Risk Profile of Hormone Replacement Therapy.

Hormone replacement therapy (HRT) remains the most effective treatment for menopausal symptoms and has been shown to prevent bone loss and fracture. The progestogen is added to provide endometrial protection in women with an intact uterus. After the publication of the initial WHI (Women's Health Initiative) results in 2002 reporting an overall increased risk of breast cancer, many women discontinued HRT. Despite the re-analysis of the results by subgroups of patients and updates with extended follow-up, much controversy remains, which we will analyze later in the text. Different types of estrogen or progestogen, as well as different formulations, doses, and durations, may play a role in HRT's effects on breast tissue. Evidence states that conjugated equine estrogen (CEE), compared to estro-progestin therapy, shows a better profile risk (HR 0.79, CI 0.65-0.97) and that, among different type of progestins, those structurally related to testosterone show a higher risk (RR 3.35, CI 1.07-10.4). Chronic unopposed endometrial exposure to estrogen increases the risk of endometrial hyperplasia and cancer, whereas the association with progestins, especially in continuous combined regimen, seems to reduce the risk (RR 0.71, CI 0.56-0.90). HRT was also associated with a protective effect on colon cancer risk (HR 0.61, CI 0.42-0.87). Data about ovarian and cervical cancer are still controversial.

Risk-Reducing Bilateral Salpingo-Oophorectomy for BRCA Mutation Carriers and Hormonal Replacement Therapy: If It Should Rain, Better a Drizzle than a Storm.

Women carrying a BRCA mutation have an increased risk of developing breast and ovarian cancer. The most effective strategy to reduce this risk is the bilateral salpingo-oophorectomy, with or without additional risk-reducing mastectomy. Risk-reducing bilateral salpingo-oophorectomy (RRBSO) is recommended between age 35 and 40 and between age 40 and 45 years for women carriers of BRCA1 and BRCA2 mutations, respectively. Consequently, most BRCA mutation carriers undergo this procedure prior to a natural menopause and develop an anticipated lack of hormones. This condition has a detrimental impact on various systems, affecting both the quality of life and longevity; in particular, women carrying BRCA1 mutation, who are likely to have surgery earlier as compared to BRCA2. Hormonal replacement therapy (HRT) is the only effective strategy able to significantly compensate the hormonal deprivation and counteract menopausal symptoms, both in spontaneous and surgical menopause. Although recent evidence suggests that HRT does not diminish the protective effect of RRBSO in BRCA mutation carriers, concerns regarding the safety of estrogen and progesterone intake reduce the use in this setting. Furthermore, there is strong data demonstrating that the use of estrogen alone after RRBSO does not increase the risk of breast cancer among women with a BRCA1 mutation. The additional progesterone intake, mandatory for the protection of the endometrium during HRT, warrants further studies. However, when hysterectomy is performed at the time of RRBSO, the indication of progesterone addition decays and consequently its potential effect on breast cancer risk. Similarly, in patients conserving the uterus but undergoing risk-reducing mastectomy, the addition of progesterone should not raise significant concerns for breast cancer risk anymore. Therefore, BRCA mutation carriers require careful counselling about the scenarios following their RRBSO, menopausal symptoms or the fear associated with HRT use.

Hypothyroidism in Pregnancy.

Thyroid hormone is essential for pregnancy and ensuring fetal development. Pregnancy also places substantial demands on the thyroid axis. Overt hypothyroidism is associated with substantial adverse obstetric and offspring outcomes and requires treatment. Borderline thyroid dysfunction is common in women and associated with adverse obstetric and offspring outcomes, although benefits of screening for and treating borderline thyroid function are unclear. Many women are established on thyroid hormone replacement before pregnancy and doses need increasing during pregnancy. Care is taken to prevent overreplacement. Universal thyroid screening in pregnancy is being undertaken in several countries, although it remains a matter of debate.

Veterans Health Administration Primary Care Provider Adherence to Prescribing Guidelines for Systemic Hormone Therapy in Menopausal Women.

BACKGROUND: Systemic hormone therapy (HT) is effective for treating menopausal symptoms but also confers risks. Therefore, experts have developed clinical guidelines for its use. PURPOSE: We assessed primary care guideline adherence in prescribing systemic HT, and associations between adherence and provider characteristics, in four Veterans Health Administration (VA) facilities. METHODS: We abstracted medical records associated with new and renewal systemic HT prescriptions examining adherence to guidelines for documenting indications and contraindications; prescribing appropriate dosages; and prescribing progesterone. RESULTS: Average guideline adherence was 58%. Among new prescriptions, 74% documented a guideline-adherent indication and 28% documented absence of contraindications. Among renewals, 39% documented a guideline-adherent indication. In prescribing an appropriate dose, 45% of new prescriptions were guideline-adherent. Among renewal prescriptions with conjugated equine estrogen doses ≥0.625 mg or equivalent, 16% documented the dosing rationale. Among 116 prescriptions for systemic estrogen in women with a uterus, progesterone was not prescribed in 8. CONCLUSIONS: Guideline adherence in prescribing systemic HT was low among VA primary care providers. Failures to coprescribe progesterone put women at increased risk for endometrial cancer. IMPLICATIONS: Intervention development is urgently needed to improve guideline adherence among primary care prescribers of systemic HT for menopause. Similar assessments should be conducted in community settings.

Best practices in care for menopausal patients: 16 years after the Women's Health Initiative.

The Women's Health Initiative (WHI) was a large, randomized clinical trial funded by the National Institutes of Health to determine whether menopause hormone therapy (MHT) prevented heart disease, breast and colorectal cancer, and osteoporotic fractures in postmenopausal women. Two WHI trials were stopped early, and the findings had a profound effect on the clinical practice guidelines related to postmenopausal health. This article provides an overview of the WHI MHT clinical trials and findings, discusses the early stoppage of the trials and subsequent implications, and details the current nomenclature and treatment options for women transitioning through menopause in light of the WHI. This study is based on a comprehensive literature review and an education activity developed by the American Association of Nurse Practitioners. To best serve patients and individualize therapy, clinicians must provide the best estimate of potential risks or benefits to the individual patient. It is important to balance evidence of symptom relief with long-term risks and benefits that fit the patient's characteristics of family and personal health history. Armed with evidence to support various hormonal and non-hormonal options, well-informed clinicians can counsel women about MHT and potentially avoid negative impact on quality of life.

Effect of adjuvant hormone therapy in patients with prostate cancer: A meta-analysis of randomized controlled trials.

OBJECTIVES: To summarize the evidence regarding the treatment effect of adjuvant hormone therapy (AHT) in patients with prostate cancer (PCa). AHT following radiotherapy, chemotherapy, or surgery is widely used in patients with PCa. However, the treatment effect is inconsistent in individual trials. METHODS: The electronic databases including PubMed, EmBase, and Cochrane Library were searched to identify randomized controlled trials (RCTs) in September 2016. RCTs that evaluated the effects of AHT in patients with PCa were included. Hazard ratio (HR) and relative risks (RR) were used to measure the treatment effects of AHT using a random effects model. The analyses were further stratified by factors that could affect the treatment efficacy. RESULTS: A total of 14,594 potential studies were identified, and 27 RCTs were included. Compared with the control group, patients who received AHT were associated with a significant improvement in overall survival (OS) (HR: 0.78; 95% confidence interval [CI]: 0.71-0.85; P <.001), disease-free survival (DFS) (HR: 0.50; 95% CI: 0.39-0.65; P <.001), total mortality (RR: 0.90; 95% CI: 0.85-0.96; P = .001), recurrence (RR: 0.70; 95% CI: 0.60-0.81; P <.001), and disease-specific mortality (RR: 0.70; 95% CI: 0.56-0.87; P <.001). However, no significant difference was observed between AHT and control for response rate (RR: 1.75; 95% CI: 0.91-3.37; P = .095). CONCLUSIONS: The findings of this meta-analysis confirmed that patients who received AHT had a significant improvement in OS, DFS, total mortality, recurrence, and disease-specific mortality. Further, large-scale RCTs are required to evaluate the treatment effect in specific subpopulations.

Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline.

Objective: To update the "Testosterone Therapy in Men With Androgen Deficiency Syndromes" guideline published in 2010. Participants: The participants include an Endocrine Society-appointed task force of 10 medical content experts and a clinical practice guideline methodologist. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. Consensus Process: One group meeting, several conference calls, and e-mail communications facilitated consensus development. Endocrine Society committees and members and the cosponsoring organization were invited to review and comment on preliminary drafts of the guideline. Conclusions: We recommend making a diagnosis of hypogonadism only in men with symptoms and signs consistent with testosterone (T) deficiency and unequivocally and consistently low serum T concentrations. We recommend measuring fasting morning total T concentrations using an accurate and reliable assay as the initial diagnostic test. We recommend confirming the diagnosis by repeating the measurement of morning fasting total T concentrations. In men whose total T is near the lower limit of normal or who have a condition that alters sex hormone-binding globulin, we recommend obtaining a free T concentration using either equilibrium dialysis or estimating it using an accurate formula. In men determined to have androgen deficiency, we recommend additional diagnostic evaluation to ascertain the cause of androgen deficiency. We recommend T therapy for men with symptomatic T deficiency to induce and maintain secondary sex characteristics and correct symptoms of hypogonadism after discussing the potential benefits and risks of therapy and of monitoring therapy and involving the patient in decision making. We recommend against starting T therapy in patients who are planning fertility in the near term or have any of the following conditions: breast or prostate cancer, a palpable prostate nodule or induration, prostate-specific antigen level > 4 ng/mL, prostate-specific antigen > 3 ng/mL in men at increased risk of prostate cancer (e.g., African Americans and men with a first-degree relative with diagnosed prostate cancer) without further urological evaluation, elevated hematocrit, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled heart failure, myocardial infarction or stroke within the last 6 months, or thrombophilia. We suggest that when clinicians institute T therapy, they aim at achieving T concentrations in the mid-normal range during treatment with any of the approved formulations, taking into consideration patient preference, pharmacokinetics, formulation-specific adverse effects, treatment burden, and cost. Clinicians should monitor men receiving T therapy using a standardized plan that includes: evaluating symptoms, adverse effects, and compliance; measuring serum T and hematocrit concentrations; and evaluating prostate cancer risk during the first year after initiating T therapy.

Annual report of the Women's Health Care Committee, Japan Society of Obstetrics and Gynecology, 2017.

To improve women's quality of life, the activity of the Women's Health Care Committee over a year up to July 2017 focused upon: (i) breast management; (ii) the influence of gynecological disease therapy on physical condition; (iii) non-surgical management of pelvic organ prolapse; (iv) survey of infectious diseases in obstetrics and gynecology in Japan; (v) health care for female athletes; (vi) a training program for women's health care advisors; (vii) revising the Japanese guidelines on hormone replacement therapy; and (viii) revising the 2016 Japanese guidelines for the proper use of emergency contraceptives. The detailed activity of the eight subcommittees is described herein. This report is based on the Japanese version of our annual report (Acta Obst Gynaec Jpn 2017;69(6):1480-1491), to publicize the activities of our committee.

European Association of Urology Position Statement on the Role of the Urologist in the Management of Male Hypogonadism and Testosterone Therapy.

Testosterone is a crucial sex hormone important for the health and development of men of all ages. It plays a role in the integrity and maintaining the function of several systems and organs. Testosterone deficiency is linked to a number of signs and symptoms potentially affecting every man in his complexity and masculinity, and is therefore of strong urological interest. For this reason, urologists should attach importance to the need for knowledge, vocational education, and training in this specific area.

Use of hormone therapy for menopausal symptoms and quality of life in breast cancer survivors. Safe and ethical?

Breast cancer is the most prevalent cancer in women and presently, the breast cancer survivors are an important group of women that faced the several consequences of estrogen deficiency, which is especially common in women after chemotherapy. The most bothersome is the vasomotor symptoms, which are effectively relieved by hormonal therapy (HT). Also, the increased risk of osteoporosis and coronary artery disease is major problem to be resolved in pos of maintaining a good quality of life. Fearing cancer recurrence, most physicians do not offer HT to women with a history of breast cancer. Over this issue reviews the available evidence of the use of HT and tibolone in women treated for breast cancer.