Article

Exogenous testosterone does not induce or exacerbate the metabolic features associated with pcos among transgender men

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Abstract

Objectives: Polycystic ovarian syndrome (PCOS) is a complex condition which can include menstrual irregularity, metabolic derangement, and increased androgen levels. The mechanism of PCOS is unknown. Some suggest that excess production of androgens by the ovaries may cause or exacerbate the metabolic findings. The purpose of this study was to assess the role of increased testosterone on metabolic parameters on individuals presumed to be chromosomally female by examination of these parameters in hormone-treated transgender men. Methods: In 2015 and 2016, we asked all transgender men who visited the Endocrinology Clinic at Boston Medical Center treated with testosterone for consent for a retrospective anonymous chart review. Of the 36 men, 34 agreed (94%). Serum metabolic factors and body mass index levels for each patient were graphed over time, from initiation of therapy through 6 years of treatment. Bivariate analyses were conducted to analyze the impact of added testosterone. Results: Regressions measuring the impact of testosterone demonstrated no significant change in levels of glycosylated hemoglobin, triglycerides, or low density lipoprotein cholesterol. There was a statistically significant decrease in BMI with increasing testosterone. There was also a statistically significant decrease in high density lipoprotein levels upon initiation of testosterone therapy. Conclusion: Testosterone therapy in transgender men across a wide range of doses and over many years did not result in the abnormalities in HbA1c or dyslipidemia seen with PCOS. Instead, treatment of transgender men with testosterone resulted only in a shift of metabolic biomarkers toward the average physiologic male body. Precis: This retrospective chart review of 34 transgender men found that testosterone therapy does not induce or exacerbate the metabolic features associated with PCOS.

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... 46 In addition, exogenous testosterone does not lead to PCOS-like metabolic findings in transgender men. 6 The use of exogenous testosterone, which has been studied most extensively in hypogonadal cisgender men, does not improve glycemic control to the same extent as estrogen therapy in postmenopausal cisgender women, with studies demonstrating mixed results. 47,48 Transgender Experience ...
... 13 As noted previously, the use of testosterone therapy in transgender men did not demonstrate significant changes in glycemic control or dyslipidemia as would be seen in PCOS patients. 6 Instead, there was a shift in metabolic parameters toward the average physiologic male body. These findings do not support a sexually dimorphic role of testosterone in glucose homeostasis. ...
Article
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... 36,39,41 Evidence regarding alterations in the aforementioned variables in transgender adolescents is in accordance with findings from a study in transgender adult males, which found that exogenous testosterone did not alter metabolic variables associated with polycystic ovarian syndrome. 76 A retrospective pilot study 34 ...
... The physiological effects of oestrogen and testosterone on body composition are well documented, 90 although effects can differ because of individual variation in hormone receptors. CSHs in transgender adults are associated with a redistribution of body fat and musculature; transgender men receiving testosterone have increases in lean body mass, and a reduction in adiposity and BMI, 76 and transgender females receiving oestrogen ...
... 36,39,41 Evidence regarding alterations in the aforementioned variables in transgender adolescents is in accordance with findings from a study in transgender adult males, which found that exogenous testosterone did not alter metabolic variables associated with polycystic ovarian syndrome. 76 A retrospective pilot study 34 ...
... The physiological effects of oestrogen and testosterone on body composition are well documented, 90 although effects can differ because of individual variation in hormone receptors. CSHs in transgender adults are associated with a redistribution of body fat and musculature; transgender men receiving testosterone have increases in lean body mass, and a reduction in adiposity and BMI, 76 and transgender females receiving oestrogen ...
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The Endocrine Society Clinical Practice Guidelines on the treatment of gender incongruent people recommend the use of gender-affirming cross-sex hormone (CSH) interventions in transgender children and adolescents who request this treatment, who have undergone psychiatric assessment, and have maintained a persistent transgender identity. The intervention can help to affirm gender identity by inducing masculine or feminine physical characteristics that are congruent with an individual's gender expression, while aiming to improve mental health and quality-of-life outcomes. Some transgender individuals might also wish to access gender-affirming surgeries during adolescence; however, research to inform best clinical practice for surgeons and other medical professionals is scarce. This Review explores the available published evidence on gender-affirming CSH and surgical interventions in transgender children and adolescents, amalgamating findings on mental health outcomes, cognitive and physical effects, side-effects, and safety variables. The small amount of available data suggest that when clearly indicated in accordance with international guidelines, gender-affirming CSHs and chest wall masculinisation in transgender males are associated with improvements in mental health and quality of life. Evidence regarding surgical vaginoplasty in transgender females younger than age 18 years remains extremely scarce and conclusions cannot yet be drawn regarding its risks and benefits in this age group. Further research on an international scale is urgently warranted to clarify long-term outcomes on psychological functioning and safety.
... Hyperandrogenemia is a salient feature in many women who suffer irregular menses, oligo/anovulation, and infertility, including women with polycystic ovary syndrome (PCOS) (1), classic and nonclassic (late-onset) congenital adrenal hyperplasia (CAH) (2)(3)(4)(5), exogenous testosterone treatment in female to male transsexuals (6)(7)(8)(9)(10), exogenous androgen use (body builders), or environmental toxicity (11). Although each of these conditions feature androgen excess, in some cases (e.g., PCOS), it is not clear whether increased androgen levels are a consequence of reproductive pathology or directly contribute to the progression of reproductive pathology. ...
Article
Many women with hyperandrogenemia suffer from irregular menses and infertility. However, it is unknown whether androgens directly affect reproduction. Since animal models of hyperandrogenemia-induced infertility are associated with obesity, which may impact reproductive function, we have created a lean mouse model of elevated androgen using implantation of low dose dihydrotestosterone (DHT) pellets to separate the effects of elevated androgen from obesity. The hypothalamic-pituitary-gonadal axis controls reproduction. While we have demonstrated that androgen impairs ovarian function, androgen could also disrupt neuroendocrine function at the level of brain and/or pituitary to cause infertility. To understand how elevated androgens might act on pituitary gonadotropes to influence reproductive function, female mice with disruption of the androgen receptor (Ar) gene specifically in pituitary gonadotropes (PitARKO) were produced. DHT treated control mice with intact pituitary Ar (Con-DHT) exhibit disrupted estrous cyclicity and fertility with reduced pituitary responsiveness to GnRH at the level of both calcium signaling and LH secretion. These effects were ameliorated in DHT treated PitARKO mice. Calcium signaling controls GnRH regulation of LH vesicle exotocysis. Our data implicated upregulation of GEM (a voltage-dependent calcium channel inhibitor) in the pituitary as a potential mechanism for androgen's pathological effects. These results demonstrate that gonadotrope AR, as an extra-ovarian regulator, plays an important role in reproductive pathophysiology.
... Furthermore, experimental studies of testosterone therapy in men, with or without T2D, surprisingly report no or modest improvements in insulin sensitivity and no change in glycemic control 11,12 . Similarly, in women, experimental evidence of testosterone administration is insufficient to confirm the apparently metabolically harmful associations in observational studies between testosterone and higher adiposity, risk of polycystic ovary syndrome (PCOS) and other cardiovascular disease risk markers 13,14 . ...
Article
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Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22–1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33–1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76–0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses. Genetic analysis of data from over 400,000 participants in the UK Biobank Study shows that circulating testosterone levels have sex-specific implications for cardiometabolic diseases and cancer outcomes.
Chapter
Up to 20% of women in their reproductive years have polycystic ovary syndrome (PCOS), a complex reproductive, metabolic, and behavioral women's disorder bestowing subfertility, increased obesity, and type 2 diabetes, as well as increased risk of anxiety and depression. While its origins are unknown, PCOS is highly heritable and increasing evidence suggests a combination of genetic, epigenetic, and developmental origins commencing during hyperandrogenic gestations. A reliable biomarker of female fetal hyperandrogenism, elongated anogenital distance, found in newborn daughters of women with PCOS, and in adult PCOS women, considered together with repeated confirmation of PCOS-like phenotype induction in nonhuman primate, sheep, rat, and mouse models by experimental induction of fetal female hyperandrogenism, and transgenerational transmission of induced PCOS-like phenotypes, all suggest in utero hyperandrogenic origins for PCOS pathogenesis. This brief review will focus on the evidence for PCOS pathogenesis in women and underlying molecular gateways enabling its development during hyperandrogenic gestations in animal models.
Article
Background: Previous studies have cross-sectionally described amenorrhea in cohorts of transgender men on intramuscular or subcutaneous testosterone injections. It remains uncertain which testosterone preparations most effectively suppress vaginal bleeding and when amenorrhea occurs after testosterone initiation. Aim:To investigate the clinical effects of various testosterone preparations on vaginal bleeding and spotting in transgender men. Methods: This prospective cohort study was part of the European Network for the Investigation of Gender Incongruence (ENIGI). Data on the persistence and intensity of vaginal bleeding and spotting, serum sex steroid levels and body composition were prospectively and cross-sectionally assessed in 267 transgender men during a three-year follow-up period, starting at the initiation of various testosterone preparations. Results: After three months of testosterone, 17.9% of transgender men reported persistent vaginal bleeding and 26.8% reported spotting. The percentages reporting vaginal bleeding and spotting decreased over the first year of testosterone (bleeding 4.7% and spotting 6.9% at 12 months, respectively), with no participants reporting vaginal bleeding or spotting after 18 months of testosterone. Factors associated with vaginal bleeding or spotting included lower serum testosterone levels and being on testosterone gel as compared to injections (e.g., esters or undecanoate preparations). If vaginal bleeding persisted, starting progestogens at three months resulted in a decrease in the intensity of vaginal bleeding and spotting. Discussion: Transgender men and hormone-prescribing providers can be reassured that vaginal bleeding and spotting usually stop within three months after testosterone initiation. If not, serum testosterone levels should be measured and testosterone dose adjusted to achieve serum testosterone levels in the physiologic male range. Adding a progestin can be considered after three to six months if bleeding persists. Providers should be aware that cessation of bleeding can be more difficult to achieve in transgender men with lower serum testosterone levels or those on testosterone gel.
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: Transgender women have recently been acknowledged as a unique and important risk group in HIV research and care. Although transgender men also face specific problems related to HIV infection, less is known about the risk behaviours and HIV prevalence of this important population. This article highlights key issues relating to the epidemiology, prevention, treatment and management of complications of HIV infection in transgender adults living with HIV, and explores future areas for HIV-related research, with the ultimate goal of improving healthcare provision and quality of life for transgender persons worldwide.
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Primary care providers should have a general understanding of the medical care available to transgender youth throughout childhood and adolescence. Providers and parents should create an affirming environment for young people at every developmental stage, while ensuring thorough and thoughtful evaluations prior to any medical intervention. Transgender teens have unique reproductive health care needs. Transgender boys may seek suppression of menses, and they will need to pay particular attention to pregnancy prevention if they decide to undergo masculinizing hormonal treatment. Transgender girls who undergo feminizing hormonal treatment will also see profound changes to their reproductive and sexual function. Providers should feel comfortable getting detailed sexual histories to properly counsel on and test for sexually transmitted infections. Finally, the effects of medical and surgical transition on a young person's potential for future fertility is a profoundly important concept for both the teen and their parents to understand. [Pediatr Ann. 2019;48(2):e64-e70.].
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Objectives To describe the extent, range and nature of literature examining the nutrition-related intermediate and long-term health outcomes in individuals who are transgender. Specific sub-topics include dietary intake, nutrition-related health disparities, validity and reliability of nutrition assessment methods, and the effects of nutrition interventions/exposures and hormone therapy. Methods A literature search was conducted of Medline, Embase, PsycINFO, CINAHL, Web of Science, and other databases from 1999 though 2019 to identify peer-reviewed articles published in English that addressed the research objective. Conference abstracts and registered trials were eligible if they were published in 2015 or later. Each title/abstract and eligible full-text article was screened by two reviewers and discrepancies were determined by consensus. Data was extracted by one reviewer and confirmed by a second reviewer. Results The literature search identified 3020 original studies, abstracts or registered trials, 424 full-text articles were reviewed for inclusion and 188 were included in qualitative analysis, including 17 systematic reviews. Populations examined included adults (n = 159), adolescents (n = 61) and children (n = 11). The vast majority of included articles examined the effects of hormone therapy on intermediate outcomes (n = 118) such as anthropometric, bone density and laboratory measures, or health outcomes (n = 18) such as cardiovascular disease events or quality of life. There was also considerable research examining the prevalence of health outcomes, such as eating disorders, malnutrition status, or diabetes, in transgender compared to cisgender populations. However, there was a paucity of data describing dietary intake (n = 10), validity and reliability of nutrition assessment methods (n = 1) or the effects of nutrition interventions on nutrition-related outcomes (n = 3) in transgender individuals. Nearly all evidence, except for three hormone trials, was observational in nature. Conclusions There is a need for research that examines medical nutrition therapy to promote health and prevent or treat adverse health outcomes that are prevalent in individuals who are transgender. Funding Sources Academy of Nutrition and Dietetics.
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We aim to make evident that solely referencing cisgender women in the context of sexual and reproductive health-particularly pregnancy planning and care-excludes a diverse group of transgender and gender nonbinary people who have sexual and reproductive health needs and experiences that can be similar to but also unique from those of cisgender women. We call on clinicians and researchers to ensure that all points of sexual and reproductive health access, research, sources of information, and care delivery comprehensively include and are accessible to people of all genders. We describe barriers to sexual and reproductive health care and research participation unique to people of marginalized gender identities, provide examples of harm resulting from these barriers, and offer concrete suggestions for creating inclusive, accurate, and respectful care and research environments-which will lead to higher quality health care and science for people of all genders.
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Propósito/ Contexto. Este artículo busca categorizar las teorías descritas en los estudios empíricos sobre los hombres transgénero, con el propósito de contribuir a los avances epistemológicos y metodológicos en bioética, mediante abordajes transdisciplinares. Metodología/Enfoque. Se hace una revisión cualitativa de la literatura, de tipo narrativo, con objetivo y pregunta de investigación, búsqueda bibliográfica, recuperación de estudios, sistematización, selección, construcción de base de datos, análisis primario, evaluación y análisis por temas. La revisión abarca los estudios empíricos sobre los hombres transgénero que se encontraron en artículos publicados en revistas en PubMed, APA, DOAJ y SciELO, desde enero de 2010 a mayo de 2019, en español e inglés, y sin límite de diseño. Los artículos incluidos se clasificaron por tema emergente y por teoría, de acuerdo con el autor de la publicación. Resultados. De 79 artículos, 46 tuvieron un enfoque cuantitativo, 25 cualitativo y 8 mixto. Las temáticas emergentes se refieren a la discriminación, la diversidad, la educación, la identidad, el mercadeo, la salud, lo social y la violencia. Hay ausencia de fundamentos teóricos en 83.5 % de las publicaciones, en el 15.2 % lo teórico se describe indirectamente y apenas en un 3.85 % las teorías se hacen explícitas, en particular en lo que se refiere a lo queer, al reconocimiento y a la identidad sexual y de género. Discusión/Conclusión/Contribuciones. La producción empírica sobre los hombres transgénero carece de soporte teórico explícito, excepto en 3 artículos. Esto señala la necesidad de trabajar en desarrollos propios, desde la bioética, que impacten en la toma de decisiones individuales y colectivas.
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Introduction Many transgender people take hormone therapy to affirm their gender identity. One potential long-term consequence of gender affirming hormone therapy is increased body mass index (BMI), which may be associated with metabolic syndrome, cardiovascular disease and higher mortality. Only a few published studies explored changes in BMI in transgender people taking gender affirming hormone therapy (GAHT). Objective To examine the changes in BMI longitudinally in response to GAHT in transgender women and men. Methods We conducted a retrospective cohort study of transgender individuals who received GAHT from the endocrinology clinic between January 1, 2000 and September 6, 2018. Subjects who sought GAHT were included if they had two separate measurements of BMI and were excluded if they had a BMI greater than 35 kg/m² or were missing demographic data at entry. We used a linear mixed model to analyze the longitudinal change in BMI. Results There were a total of 227 subjects included in this cohort. Among subjects already on GAHT, transgender women were receiving GAHT longer than transgender men (6.59 ± 9.35 vs 3.67 ± 3.43 years, p-value = 0.04). Over the period of 7 years, there was a significant increase in BMI in transwomen who newly initiated GAHT (p-value 0.004). There were no changes in BMI in transgender men and women already on GAHT or in transgender men who newly initiated GAHT in the study. Conclusion We conclude that BMI significantly increases in transwomen but not in transmen after initiation of GAHT in a single center based in the United States. In transwomen and transmen, BMI appears to be stable following 3 to 6 years of GAHT. Future investigations should examine the causes for increased BMI in transgender women including type of GAHT, diet and lifestyle, and association with risk of metabolic syndrome and cardiovascular disease.
Article
Objective The objective of this scoping review is to describe the extent, range, and nature of available literature examining nutrition-related intermediate and long-term health outcomes in individuals who are transgender. Specific sub-topics examined include 1) dietary intake, 2) nutrition-related health disparities, 3) validity and reliability of nutrition assessment methods, 4) the effects of nutrition interventions/exposures, and 5) hormone therapy. Methods A literature search was conducted using MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, and other databases for peer-reviewed articles published from January 1999 until December 5, 2019 to identify studies addressing the research objective and meeting eligibility criteria. Conference abstracts and registered trials published or registered in the five years prior to the search were also included. Findings were reported in a study characteristics table, a bubble chart and heat maps. Results The search of the databases identified 5403 studies, including full peer-reviewed studies, systematic reviews, conference abstracts and registered trials. Following title/abstract screening, 189 studies were included in the narrative analysis. Ten studies reported dietary intake in transgender individuals, 64 studies reported nutrition-related health disparities in transgender compared to cisgender individuals, one study examined validity and reliability of nutrition assessment methods, two studies reported nutrition interventions, and 127 studies reported on the intermediate and health effects of hormone therapy. Conclusion Individuals who are transgender have unique nutrition needs, which may vary according to the stage and type of gender-affirmative therapy that they are undergoing. There is scant research examining effective nutrition therapy methods for nutrition professionals working with transgender individuals. More research is needed in order to inform evidence-based clinical practice guidelines for nutrition practitioners working with transgender individuals.
Article
Full-text available
Background: Previous studies have cross-sectionally described amenorrhea in cohorts of transgender men on intramuscular or subcutaneous testosterone injections. It remains uncertain which testosterone preparations most effectively suppress vaginal bleeding and when amenorrhea occurs after testosterone initiation. Aim: To investigate the clinical effects of various testosterone preparations on vaginal bleeding and spotting in transgender men. Methods: This prospective cohort study was part of the European Network for the Investigation of Gender Incongruence (ENIGI). Data on the persistence and intensity of vaginal bleeding and spotting, serum sex steroid levels and body composition were prospectively and cross-sectionally assessed in 267 transgender men during a three-year follow-up period, starting at the initiation of various testosterone preparations. Results: After three months of testosterone, 17.9% of transgender men reported persistent vaginal bleeding and 26.8% reported spotting. The percentages reporting vaginal bleeding and spotting decreased over the first year of testosterone (bleeding 4.7% and spotting 6.9% at 12 months, respectively), with no participants reporting vaginal bleeding or spotting after 18 months of testosterone. Factors associated with vaginal bleeding or spotting included lower serum testosterone levels and being on testosterone gel as compared to injections (e.g., esters or undecanoate preparations). If vaginal bleeding persisted, starting progestogens at three months resulted in a decrease in the intensity of vaginal bleeding and spotting. Discussion: Transgender men and hormone-prescribing providers can be reassured that vaginal bleeding and spotting usually stop within three months after testosterone initiation. If not, serum testosterone levels should be measured and testosterone dose adjusted to achieve serum testosterone levels in the physiologic male range. Adding a progestin can be considered after three to six months if bleeding persists. Providers should be aware that cessation of bleeding can be more difficult to achieve in transgender men with lower serum testosterone levels or those on testosterone gel.
Article
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Context Hormone treatment (HT) in transgender persons affects many components of the metabolic syndrome (MS). Objective To determine the role of direct hormonal effects, changes in metabolic cytokines and body composition on metabolic outcomes. Design, Setting, and Participants 24 transwomen and 45 transmen from the European Network for the Investigation of Gender Incongruence (ENIGI) investigated at baseline and following 12 months of HT. Outcome Measures Best predictors for changes in components of MS applying least absolute shrinkage and selection operator (LASSO) regression. Results In transwomen, a decrease in triglyceride levels was best explained by a decrease in fat mass and an increase in FGF-21, while a decrease in total and LDL-cholesterol levels was principally due to a decrease in resistin. A decrease in HDL-cholesterol depended on an inverse association with fat mass. In contrast, in transmen, an increase in LDL-cholesterol was predicted by a decrease in FGF-21 and an increase in the waist-to-hip-ratio, while a decrease in the HDL/total cholesterol-ratio depended on a decline in adiponectin levels. In transwomen, worsened insulin resistance and increased early insulin response seemed to be due to a direct treatment effect, while improvements in hepatic insulin sensitivity in transmen were best predicted by a positive association with chemerin, resistin and FGF-21, while they were inversely related to changes in waist-to-hip-ratio, leptin and AFABP levels. Conclusions The effects of HT on different components of the MS are sex-specific and involve a complex interplay of direct hormonal effects, changes in body composition and metabolic cytokine secretion.
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Background. Transgender individuals have a gender identity that differs from the sex they were assigned at birth. The population size of transgender individuals in the United States is not well-known, in part because official records, including the US Census, do not include data on gender identity. Population surveys today more often collect transgender-inclusive gender-identity data, and secular trends in culture and the media have created a somewhat more favorable environment for transgender people. Objectives. To estimate the current population size of transgender individuals in the United States and evaluate any trend over time. Search methods. In June and July 2016, we searched PubMed, Cumulative Index to Nursing and Allied Health Literature, and Web of Science for national surveys, as well as “gray” literature, through an Internet search. We limited the search to 2006 through 2016. Selection criteria. We selected population-based surveys that used probability sampling and included self-reported transgender-identity data. Data collection and analysis. We used random-effects meta-analysis to pool eligible surveys and used meta-regression to address our hypothesis that the transgender population size estimate would increase over time. We used subsample and leave-one-out analysis to assess for bias. Main results. Our meta-regression model, based on 12 surveys covering 2007 to 2015, explained 62.5% of model heterogeneity, with a significant effect for each unit increase in survey year (F = 17.122; df = 1,10; b = 0.026%; P = .002). Extrapolating these results to 2016 suggested a current US population size of 390 adults per 100 000, or almost 1 million adults nationally. This estimate may be more indicative for younger adults, who represented more than 50% of the respondents in our analysis. Authors’ conclusions. Future national surveys are likely to observe higher numbers of transgender people. The large variety in questions used to ask about transgender identity may account for residual heterogeneity in our models. Public health implications. Under- or nonrepresentation of transgender individuals in population surveys is a barrier to understanding social determinants and health disparities faced by this population. We recommend using standardized questions to identify respondents with transgender and nonbinary gender identities, which will allow a more accurate population size estimate.
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Recent reports in the scientific and lay press have suggested that testosterone (T) replacement therapy (TRT) is likely to increase cardiovascular (CV) risk. In a final report released in 2015, the Food and Drug Administration (FDA) cautioned that prescribing T products is approved only for men who have low T levels due to primary or secondary hypogonadism resulting from problems within the testis, pituitary, or hypothalamus (e.g., genetic problems or damage from surgery, chemotherapy, or infection). In this report, the FDA emphasized that the benefits and safety of T medications have not been established for the treatment of low T levels due to aging, even if a man's symptoms seem to be related to low T. In this paper, we reviewed the available evidence on the association between TRT and CV risk. In particular, data from randomized controlled studies and information derived from observational and pharmacoepidemiological investigations were scrutinized. The data meta-analyzed here do not support any causal role between TRT and adverse CV events. This is especially true when hypogonadism is properly diagnosed and replacement therapy is correctly performed. Elevated hematocrit represents the most common adverse event related to TRT. Hence, it is important to monitor hematocrit at regular intervals in T-treated subjects in order to avoid potentially serious adverse events.
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Since the 1990 NIH‐sponsored conference on polycystic ovary syndrome (PCOS), it has become appreciated that the syndrome encompasses a broader spectrum of signs and symptoms of ovarian dysfunction than those defined by the original diagnostic criteria. The 2003 Rotterdam consensus workshop concluded that PCOS is a syndrome of ovarian dysfunction along with the cardinal features hyperandrogenism and polycystic ovary (PCO) morphology. PCOS remains a syndrome and, as such, no single diagnostic criterion (such as hyperandrogenism or PCO) is sufficient for clinical diagnosis. Its clinical manifestations may include: menstrual irregularities, signs of androgen excess, and obesity. Insulin resistance and elevated serum LH levels are also common features in PCOS. PCOS is associated with an increased risk of type 2 diabetes and cardiovascular events.
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The Standards of Care (SOC) for the Health of Transsexual, Transgender, and Gender Nonconforming People is a publication of the World Professional Association for Transgender Health (WPATH). The overall goal of the SOC is to provide clinical guidance for health professionals to assist transsexual, transgender, and gender nonconforming people with safe and effective pathways to achieving lasting personal comfort with their gendered selves, in order to maximize their overall health, psychological well-being, and self-fulfillment. This assistance may include primary care, gynecologic and urologic care, reproductive options, voice and communication therapy, mental health services (e.g., assessment, counseling, psychotherapy), and hormonal and surgical treatments. The SOC are based on the best available science and expert professional consensus. Because most of the research and experience in this field comes from a North American and Western European perspective, adaptations of the SOC to other parts of the world are necessary. The SOC articulate standards of care while acknowledging the role of making informed choices and the value of harm reduction approaches. In addition, this version of the SOC recognizes that treatment for gender dysphoria i.e., discomfort or distress that is caused by a discrepancy between persons gender identity and that persons sex assigned at birth (and the associated gender role and/or primary and secondary sex characteristics) has become more individualized. Some individuals who present for care will have made significant self-directed progress towards gender role changes or other resolutions regarding their gender identity or gender dysphoria. Other individuals will require more intensive services. Health professionals can use the SOC to help patients consider the full range of health services open to them, in accordance with their clinical needs and goals for gender expression.
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Context/objective: Current diagnostic criteria for polycystic ovary syndrome (PCOS) have generated distinct PCOS phenotypes, based on the different combinations of diagnostic features found in each patient. Our aim was to assess whether either each single diagnostic feature or their combinations into the PCOS phenotypes may predict insulin resistance in these women. Patients/design: A total of 137 consecutive Caucasian women with PCOS, diagnosed by the Rotterdam criteria, underwent accurate assessment of diagnostic and metabolic features. Insulin sensitivity was measured by the glucose clamp technique. Results: Among women with PCOS, 84.7% had hyperandrogenism, 84.7% had chronic oligoanovulation, and 89% had polycystic ovaries. According to the individual combinations of these features, 69.4% of women had the classic phenotype, 15.3% had the ovulatory phenotype, and 15.3% had the normoandrogenic phenotype. Most subjects (71.4%) were insulin resistant. However, insulin resistance frequency differed among phenotypes, being 80.4%, 65.0%, and 38.1%, respectively, in the 3 subgroups (P < .001). Although none of the PCOS diagnostic features per se was associated with the impairment in insulin action, after adjustment for covariates, the classic phenotype and, to a lesser extent, the ovulatory phenotype were independently associated with insulin resistance, whereas the normoandrogenic phenotype was not. Metabolic syndrome frequency was also different among phenotypes (P = .030). Conclusions: There is a scale of metabolic risk among women with PCOS. Although no single diagnostic features of PCOS are independently associated with insulin resistance, their combinations, which define PCOS phenotypes, may allow physicians to establish which women should undergo metabolic screening. In metabolic terms, women belonging to the normoandrogenic phenotype behave as a separate group.
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Introduction. Long-term effects and side effects of cross-sex hormone treatment in transsexual persons are not well known. Aim. The aim of this study is to describe the effects and side effects of cross-sex hormone therapy in both transsexual men and women. Main Outcome Measures. Hormone levels were measured by immunoassays. Physical health was assessed by physical examination and questionnaires on general health and specific side effects, areal bone parameters by dual energy X-ray absorptiometry. Methods. Single center cross-sectional study in 100 transsexual persons post-sex reassignment surgery and on average 10 years on cross-sex hormone therapy. Results. Transsexual men did not experience important side effects such as cardiovascular events, hormone-related cancers, or osteoporosis. In contrast, a quarter of the transsexual women had osteoporosis at the lumbar spine and radius. Moreover, 6% of transsexual women experienced a thromboembolic event and another 6% experienced other cardiovascular problems after on average 11.3 hormone treatment years. None of the transsexual women experienced a hormone-related cancer during treatment. Conclusion. Cross-sex hormone treatment appears to be safe in transsexual men. On the other hand, a substantial number of transsexual women suffered from osteoporosis at the lumbar spine and distal arm. Twelve percent of transsexual women experienced thromboembolic and/or other cardiovascular events during hormone treatment, possibly related to older age, estrogen treatment, and lifestyle factors. In order to decrease cardiovascular morbidity, more attention should be paid to decrease cardiovascular risk factors during hormone therapy management. Wierckx K, Mueller, S, Weyers S, Van Caenegem E, Roef G, Heylens G, and T'Sjoen G. Long-term evaluation of cross-sex hormone treatment in transsexual persons. J Sex Med **;**:**–**.
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Aim. Testosterone treatment is essential for the induction and maintenance of virilization of female-to-male transsexuals. This study tested the suitability of a novel testosterone preparation for this purpose. Methods. Parenteral long-acting testosterone undecanoate (TU) was administered to 12 female-to-male transsexuals. Observations were made while subjects received treatment. Main Outcome Measures. Virilization of female-to-male transsexuals and side effects of testosterone administration. Results. The testosterone levels were largely identical to those in hypogonadal men receiving testosterone treatment with TU. There were no side effects. There was a small but significant decrease in plasma cholesterol and low-density lipoprotein, but plasma high-density lipoprotein did not change significantly. Both levels of hemoglobin and hematocrit rose upon administration but remained within the physiological range. Conclusions. TU is suited for induction of virilization in female-to-male transsexuals without significant side effects. Jacobeit JW, Gooren LJ, and Schulte HM. Long-acting intramuscular testosterone undecanoate for treatment of female-to-male transgender individuals. J Sex Med 2007;4:1479–1484.
Article
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Our objective was to update the guidelines for the evaluation and treatment of androgen deficiency syndromes in adult men published previously in 2006. The Task Force was composed of a chair, selected by the Clinical Guidelines Subcommittee of The Endocrine Society, five additional experts, a methodologist, and a medical writer. The Task Force received no corporate funding or remuneration. We recommend making a diagnosis of androgen deficiency only in men with consistent symptoms and signs and unequivocally low serum testosterone levels. We suggest the measurement of morning total testosterone level by a reliable assay as the initial diagnostic test. We recommend confirmation of the diagnosis by repeating the measurement of morning total testosterone and, in some men in whom total testosterone is near the lower limit of normal or in whom SHBG abnormality is suspected by measurement of free or bioavailable testosterone level, using validated assays. We recommend testosterone therapy for men with symptomatic androgen deficiency to induce and maintain secondary sex characteristics and to improve their sexual function, sense of well-being, muscle mass and strength, and bone mineral density. We recommend against starting testosterone therapy in patients with breast or prostate cancer, a palpable prostate nodule or induration or prostate-specific antigen greater than 4 ng/ml or greater than 3 ng/ml in men at high risk for prostate cancer such as African-Americans or men with first-degree relatives with prostate cancer without further urological evaluation, hematocrit greater than 50%, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms with International Prostate Symptom Score above 19, or uncontrolled or poorly controlled heart failure. When testosterone therapy is instituted, we suggest aiming at achieving testosterone levels during treatment in the mid-normal range with any of the approved formulations, chosen on the basis of the patient's preference, consideration of pharmacokinetics, treatment burden, and cost. Men receiving testosterone therapy should be monitored using a standardized plan.
Article
Background Transgender individuals receive cross sex hormonal therapy to induce desired secondary sexual characteristics despite limited data of the effects on cardiovascular health. Methods A comprehensive search of several databases to April 7th 2015 was conducted for studies evaluating the effect of sex steroids use on lipids, myocardial infarction, stroke, venous thromboembolism (VTE) and mortality in transgender individuals. Pairs of reviewers selected and appraised studies. A random effects model was used to pool weighted mean differences and 95% confidence intervals (CI). Results We found 29 eligible studies at moderate risk of bias. In female-to-male (FTM), sex steroid therapy was associated with a statistically significant increase in serum triglycerides (TGs) at 3-6 months and at ≥ 24 months (21.4 mg/dl, 95%CI: 0.14, 42.6) and in LDL-C levels at 12 months and ≥ 24 months (17.8 mg/dl, 95%CI: 3.5, 32.1). HDL-C levels decreased significantly across all follow up time periods (highest at ≥ 24 months, -8.5 mg/dl, 95%CI: -13.0, -3.9). In male-to-female (MTF), serum TGs were significantly higher at ≥ 24 months (31.9 mg/dl, CI: 3.9, 59.9) without any changes in other parameters. Few myocardial infarction, stroke, VTE and death events were reported, more frequently in MTF. Conclusions Low quality evidence suggests that sex steroid therapy may increase LDL-C and TG and decrease HDL-C levels in FTM, while oral estrogens may increase TGs in MTF. Data about patient important outcomes remain sparse.
Article
Women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency often have a polycystic ovary-like syndrome, consisting of hyperandrogynism, infertility, menstrual irregularities, and elevated LH levels. This is generally considered secondary to poor control of the congenital adrenal hyperplasia. However, our experience led us to suspect that ovarian hyperandrogenism occurs even when congenital adrenal hyperplasia is well controlled on glucocorticoid therapy. Therefore, we tested the hypothesis that congenital adrenal virilizing disorders result in ovarian hyperandrogenism. We studied eight women with congenital adrenal virilizing disorders, seven with well controlled classic 21-hydroxylase deficiency and one with congenital virilizing adrenal carcinoma removed at 1.7 yr of age. We also studied six women with late-onset 21-hydroxylase deficiency, without signs of congenital virilization. An ovarian source of androgens was assessed after suppressing adrenal function with dexamethasone and then testing pituitary-ovarian function by a GnRH agonist (nafarelin) test. Five women with congenital adrenal virilizing disorders (four with classic 21-hydroxylase deficiency and one with congenital virilizing adrenal carcinoma) and one women with late-onset 21-hydroxylase deficiency had ovarian hyperandrogenism as determined by subnormal suppression of free testosterone after dexamethasone and/or by increased 17-hydroxyprogesterone response to nafarelin while on dexamethasone. All women with congenital adrenal virilization and ovarian hyperandrogenism had elevated LH levels after dexamethasone or elevated early LH response to nafarelin, which suggests that LH excess is the cause of their ovarian hyperandrogenism. This was not the case for the late-onset 21-hydroxylase-deficient woman. Our data are compatible with the hypothesis that congenital adrenal virilization programs the hypothalamic-pituitary axis for hypersecretion of LH at puberty. This is postulated to frequently cause ovarian hyperandrogenism even when adrenal androgen excess is subsequently controlled by glucocorticoid therapy.(J Clin Endocrinol Metab 79:1328-1333, 1994).
Article
Hyperinsulinemia is a common finding in hyperandrogenic women, during pregnancy, and in women using oral contraceptives. To test whether sex hormone treatment can induce insulin resistance in healthy subjects, we studied the effects of administration of testosterone to 13 female to male and of ethinyl estradiol to 18 male to female transsexuals. Utilization and production of glucose and levels of sex steroids were measured during a three-step hyperinsulinemic-euglycemic clamp before and after 4 months of hormone administration. Females were treated with im injections of testosterone esters (250 mg/2 weeks); males were treated with ethinyl estradiol alone (0.1 mg/day, orally) or a combination of ethinyl estradiol and cyproterone acetate (100 mg/day, orally). Similar insulin levels were achieved at each of the three steps of the clamp studies before and during hormone administration. During step 1 of each clamp, with insulin levels in the physiological range, glucose utilization decreased from 3.5 ± 1.2 to 2.6 ± 0.9 mmol/kg lean body mass (LBM).h in women treated with testosterone esters (P < 0.001) and from 3.2 ± 0.7 to 2.5 ± 0.5 mmol/kg lean body mass.h in men treated with ethinyl estradiol (P < 0.001). The effects of sex steroids during steps 2 and 3 of the clamp at higher (supraphysiological) insulin levels were less clear. Endogenous glucose production (measured by isotope dilution with tritiated glucose) was not affected by hormone administration, indicating that the observed changes in glucose requirement were determined by a diminished peripheral glucose uptake. We conclude that sex hormone administration, i.e. testosterone treatment in females and ethinyl estradiol treatment in males, can induce insulin resistance in healthy subjects.
Article
Polycystic ovary syndrome (PCOS) was hypothesized to result from functional ovarian hyperandrogenism (FOH) due to dysregulation of androgen secretion in 1989-95. Subsequent studies have supported and amplified this hypothesis. When defined as otherwise unexplained hyperandrogenic oligoanovulation, two-thirds of PCOS cases have functionally typical FOH, characterized by 17-hydroxyprogesterone hyper-responsiveness to gonadotropin stimulation. Two-thirds of the remaining PCOS have FOH detectable by testosterone elevation after suppression of adrenal androgen production. About 3% of PCOS have a related isolated functional adrenal hyperandrogenism. The remaining PCOS cases are mild and lack evidence of steroid secretory abnormalities; most of these are obese, which we postulate to account for their atypical PCOS. Approximately half of normal women with polycystic ovarian morphology (PCOM) have subclinical FOH-related steroidogenic defects. Theca cells from polycystic ovaries of classic PCOS patients in long-term culture have an intrinsic steroidogenic dysregulation that can account for the steroidogenic abnormalities typical of FOH. These cells overexpress most steroidogenic enzymes, particularly cytochrome P450c17. Overexpression of DENND1A.V2, a protein identified by genome-wide association screening, in normal theca cells has reproduced this PCOS phenotype in vitro. A metabolic syndrome of obesity-related and/or intrinsic insulin resistance occurs in about half of PCOS patients, and the compensatory hyperinsulinism has tissue-selective effects, which include aggravation of hyperandrogenism. PCOS seems to arise as a complex trait that results from the interaction of diverse genetic and environmental factors. Heritable factors include PCOM, hyperandrogenemia, insulin resistance and insulin secretory defects. Environmental factors include prenatal androgen exposure and poor fetal growth, while acquired obesity is a major postnatal factor. The variety of pathways involved and lack of a common thread attests to the multifactorial nature and heterogeneity of the syndrome. Further research into the fundamental basis of the disorder will be necessary to optimally correct androgen levels, ovulation, and metabolic homeostasis. The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited.
Article
Objective: Transgender patients may seek hormone therapy to induce physical changes to simulate their expressed or experienced gender. However, many providers are uncomfortable prescribing transgender hormones due to fears over safety. The goal of this study was to determine if transgender hormone therapy with estrogen and spironolactone for male-to-female (MtF) patients or with testosterone for female-to-male (FtM) patients had adverse anthropomorphic or metabolic effects. Methods: This retrospective chart review study analyzed changes over time for 33 MtF and 19 FtM endocrine clinic patients at an academic endocrine practice with follow up for up to 18 months after hormone initiation. Results: Compared to baseline labs obtained prior to initiation of hormone therapy statistically significant changes for the MtF cohort included an increase in HDL and decrease in creatinine; however, triglycerides did not show a statistically significant change. In the FtM cohort, there was a statistically significant increase in body mass index, creatinine, hemoglobin, and hematocrit. These changes were minimal for both cohorts. Conclusion: In our practice, hormone therapy was found to be safe in this retrospective study.
Article
To describe weight, body mass index (BMI), blood pressure (BP), lipids, and hormone levels in transgender women and men presenting for initiation of cross-sex hormone therapy at a community clinic in the United States. Twenty-three transgender women (persons assigned male at birth who identify as female and want to use estrogen to develop female secondary sex characteristics) and 34 transgender men (persons assigned female at birth who identify as male and want to use testosterone to develop male secondary sex characteristics) presenting for initiation of hormone therapy at a community health center were enrolled. Body mass index, BP, lipids, and sex hormone levels were measured at baseline and 6 months. Persistence of menses at 6 months in transgender men was recorded. Sixteen transgender women and 31 transgender men completed the study. Baseline and 6-month median BPs and lipid values were within a normal clinical range. Median systolic BP in transgender women dropped from baseline 130.5 mmHg (interquartile range 11.5) to 120.5 mmHg (interquartile range 15.5) at 6 months (P=.006). Testosterone levels remained elevated in 33% and estradiol (E2) levels were supratherapeutic in 19% of transgender women at 6 months. Median BMI for transgender men was 29.1 kg/m (interquartile range 11.2) at baseline and 30.0 kg/m (interquartile range 11.4) at 6 months (P=.024). Six-month total testosterone levels were subtherapeutic in 32% and E2 levels remained elevated in 71% of transgender men. In transgender women, estrogen therapy, with or without antiandrogen therapy, was associated with lower BP. In transgender men, testosterone therapy was associated with increased BMI. The study had insufficient power to detect other associations. Monitoring of hormone levels to guide therapy appears to be useful. LEVEL OF EVIDENCE:: III.
Article
In an effort to elucidate the aetiology of female-to-male transsexualism (FM-TS) 12 out of an annual sample of 16 untreated female-to-male transsexuals (FMT), aged 19 years 7 months (19;7) to 44 years 8 months (44;8) [median age (M) 27;5] were assessed by means of sexual-medical questionnaires, physical and endocrinological examination. The control group consisted of 15 healthy women (CF), aged 19 years 2 months (19;2) to 36 years 1 month (36;1) (M 22;7) without gender identity disorder, who were not under hormonal medication (including contraceptives). Baseline levels of testosterone (T; ng/dl), androstenedione (A4; ng/dl), dehydroepiandrosterone sulfate (DHEAS; ng/ml), luteinizing hormone (LH; IU/l), follicle stimulating hormone (FSH; IU/l), and sex-hormone binding globuline (SHBG; μg/dl) were measured. A standard single-dose ACTH stimulation test (250 μg ACTH IV; Synacthen) was performed with all subjects. Aldosterone (ALDO), corticosterone (B), deoxycorticosterone (DOC), progesterone (PROG), 17-hydroxyprogesterone (17OHP), 11-deoxycortisol (S), cortisol (F), cortisone (E), pregnenolone (PREG) and 17-hydroxypregnenolone (OHPREG) were assessed before and 60 min after ACTH stimulation. Transvaginal ultrasound was performed in nine out of 12 FMT (20;11 to 44;8, M 27;5; m 29.1 ± 7.5) but not in CF. Results showed that 10 FMT (83.3%) and five CF (33.3%) were above normal values for at least one of the measured androgens. Baseline levels of T and A4 were significantly higher in FMT than in CF (T: 54.0 ± 13.8 vs. 41.1 ± 12.8; A4: 244.8 ± 73.0 vs. 190.5 ± 49.3; p < .05), whereas DHEAS, SHBG, LH and FSH did not differ between the groups. Unbound T (T/SHBG ratio) was higher in FMT (72.0 ± 67.6) than in CF (26.4 ± 15.1). Baseline levels of 17OHP, OHPREG and DOC were higher in FMT than in CF (p < .05). After ACTH stimulation 17OHP and OHPREG remained higher in FMT than in CF (p < .05). Single case analysis of ACTH stimulation test together with physical examination revealed symptoms for non-classical congenital adrenal hyperplasia (NC-CAH) in six FMT (50%) and two CF (13.3%). Eight out of nine FMT who were assessed by means of transvaginal ultrasound (i.e. 88.9%; 50.0% of 16) had polycystic ovaries (PCO). Oligomenorrhoea or menstrual dysregularities (81.7% of 16 FMT vs. 0% of CF), hirsutism (56.2% of 16 FMT vs. 13.3% of 15 CF) and adiposity (25.0% vs. 0%) were frequent in FMT, but not in CF. Hyperandrogenism with polycystic ovarian syndrome (PCOS) and adrenocortical hyperresponsiveness to ACTH seems to be a common finding in FMT. This offers support for a hormonal factor in the genesis of FM-TS. Because the prevalence of PCOS and NC-CAH in the female population is higher than FM-TS, the true nature of this factor and its interaction with environmental influences remain unknown.
Article
Life-long apolipoprotein lipid metabolic dysfunction in women with PCOS exaggerates the risk for cardiovascular disease (CVD) with aging. The dysfunction has involved insulin resistance (IR), which occurs in most women with PCOS. Women with PCOS have androgen excess, IR, variable amounts of estrogen exposure, and many environmental factors, all of which can influence lipid metabolism. On average, women with PCOS were higher triglyceride [26.39 95% CI (17.24, 35.54)], lower HDL-cholesterol [6.41 95% CI (3.69, 9.14)], and higher non HDL cholesterol levels [18.82 95% CI (15.53, 22.11)] than their non-PCOS counterparts. They have higher ApoCIII/ApoCII ratios and higher ApoCI even if they are not obese. ApoC1 elevation in women with PCOS needs to be further evaluated as a marker of dysfunction and potential CVD risk. ApoB measurements track with non-HDL cholesterol as a surrogate for increased atherogenic circulating small LDL particles. Elevated triglycerides and waist circumference predict CVD risk and women with PCOS often have these phenotypes. Diet and exercise interventions followed by selective lipid lowering medications are encouraged to normalize the dyslipidemia.
Article
Cross-sex hormone therapy (CSHT) is known to lead to alterations in the serum lipid profile. However, the available reports in the literature are problematic, because of methodological limitations. To assess changes in the fasting serum lipid profile during CSHT, including long-term follow-up. Retrospective chart analysis of all 89 male-to-female (MtF) and 80 female-to-male (FtM) transsexuals who underwent standard CSHT at the Department of Gynecologic Endocrinology of the Medical University of Vienna (university hospital, tertiary care center), from 1995 to 2009. The results of the lipid profile were analyzed, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and the TC-to-HDL ratio, at the time of treatment initiation (time point "0") and at 3, 12, 24, and 60 months after the start of CSHT. The mean age of patients about to commence CSHT was 35.7 ± 11.4 years (MtF) and 26.0 ± 6.3 years (FtM). For MtF transsexuals, consistent follow-up for 24 and 60 months was available in 83 (93.3%) and 58 (65.2%) patients, respectively; for FtM transsexuals, follow-up was available in 57 (71.3%) and 39 (48.8%) patients, respectively. When testing for an association between the lipid parameters and the time after treatment initiation, significant increases for TG (P < 0.001), TC (P = 0.021), and HDL (P = 0.001) were found for MtF transsexuals, whereas TG, TC, and LDL (P < 0.001) increased and HDL (P < 0.001) decreased in FtM patients. Both MtF and FtM transsexuals experience alterations in the serum lipid profile because of CSHT, with the changes in FtM patients possibly more relevant in terms of atherogenesis.
Article
Data from National Health and Nutrition Examination Survey (NHANES) II (1976 to 1980), NHANES III (1988 to 1994), and NHANES 1999 to 2006 were examined to assess trends in total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol, triglycerides (TGs), lipid-lowering medication use, and obesity. Age-adjusted decreases in TC (210 to 200 mg/dl) and LDL cholesterol (134 to 119 mg/dl) were observed. Those with high TC showed a decrease of 9% from NHANES II to NHANES 1999 to 2006, whereas those with LDL cholesterol ≥160 mg/dl showed a decrease of 8%. A significant increase in mean high-density lipoprotein cholesterol was observed (50 to 53 mg/dl, p <0.001), most likely due to changes in methods. Those with TG levels ≥150 mg/dl showed a decrease from NHANES II to NHANES III from 30% to 27% but then an increase from NHANES III to NHANES 1999 to 2006 from 27% to 33%. Since NHANES III, mean TG levels have increased 12% from 130 to 146 mg/dl. In the 2 most recent surveys, self-reported "high cholesterol" increased from 17% to 27%, and self-reported lipid medication use by those with high cholesterol increased from 16% to 38%. Mean body mass index increased from 26 to 29 kg/m(2), and prevalence of obesity doubled and was significantly associated with increased TG. In conclusion, recent favorable trends in TC and LDL cholesterol are likely due to increased awareness of high cholesterol and the greater use of lipid-lowering drugs. However, countertrends in obesity and TG levels, if continued, will likely have a negative impact on cardiovascular disease in the future.
Article
There is no standardized assay of testosterone in women. Liquid chromatography mass spectrometry (LC/MS) has been proposed as the preferable assay by an Endocrine Society Position Statement. The aim was to compare assay results from a direct RIA with two LC/MS. We conducted a blinded laboratory study including masked duplicate samples at three laboratories--two academic (University of Virginia, RIA; and Mayo Clinic, LC/MS) and one commercial (Quest, LC/MS). Baseline testosterone levels from 596 women with PCOS who participated in a large, multicenter, randomized controlled infertility trial performed at academic health centers in the United States were run by varying assays, and results were compared. We measured assay precision and correlation and baseline Ferriman-Gallwey hirsutism scores. Median testosterone levels were highest with RIA. The correlations between the blinded samples that were run in duplicate were comparable. The correlation coefficient (CC) between LC/MS at Quest and Mayo was 0.83 [95% confidence interval (CI), 0.80-0.85], between RIA and LC/MS at Mayo was 0.79 (95% CI, 0.76-0.82), and between RIA and LC/MS at Quest was 0.67 (95% CI, 0.63-0.72). Interassay variation was highest at the lower levels of total testosterone (≤50 ng/dl). The CC for Quest LC/MS was significantly different from those derived from the other assays. We found similar correlations between total testosterone levels and hirsutism score with the RIA (CC=0.24), LC/MS at Mayo (CC=0.15), or Quest (CC=0.17). A testosterone RIA is comparable to LC/MS assays. There is significant variability between LC/MS assays and poor precision with all assays at low testosterone levels.
Article
To summarize the available evidence on the cardiovascular effects of cross-sex steroid use in transsexuals. We searched relevant electronic databases and sought additional references from experts. Eligible studies reported on cardiovascular events, venous thromboembolism, blood pressure and fasting serum lipids. Data were extracted in duplicate. We used the random-effects model to estimate the pooled weighted mean difference (WMD) and 95% confidence intervals (CIs). We found 16 eligible studies, mostly uncontrolled cohorts of varied follow-up durations (1471 male-to-female (MF) and 651 female-to-male (FM) individuals). In the MF individuals, cross-sex hormone use was associated with a statistically significant increase in fasting serum triglycerides without changes in the other parameters (WMD = 23.39 mg/dl; 95% CI = 4.82-41.95). In the FM individuals, there was a similar increase of triglycerides (WMD = 31.35 mg/dl; 95% CI = 7.53-55.17) and a reduction of high density lipoprotein (HDL)-cholesterol (WMD = -6.09 mg/dl; 95% CI = -11.44 to -0.73). There was a statistically significant but clinically trivial increase in systolic blood pressure (WMD = 1.74 mmHg; 95% CI = 0.21-3.27). Analyses were associated with significant heterogeneity across studies. There were very few reported cardiovascular events (deaths, strokes, myocardial infarctions or venous thromboembolism), more commonly among MF individuals. Very low quality evidence, downgraded due to methodological limitations of included studies, imprecision and heterogeneity, suggests that cross-sex hormone therapies increase serum triglycerides in MF and FM and have a trivial effect on HDL-cholesterol and systolic blood pressure in FM. Data about patient important outcomes are sparse and inconclusive.
Article
There have not been reports analyzing in detail the reproductive hormone changes in hypogonadal men after usual therapeutic injections of testosterone cypionate (TC). In 11 hypogonadal men 200 mg intramuscular TC caused a threefold rise in serum T (peak values, days 2 to 5), a 33% increase in % free T (%FT) (days 2 to 7), and a 4.5-fold rise of absolute FT (peak on days 2 to 3), a 66% increase in % nonsex hormone-binding globulin-bound T (%non-SHBG-T) (peak days 2 to 7), a sixfold increase in absolute non-SHBG-T (peak days 4 to 5), and a threefold rise of estradiol (days 2 to 7). Many of the men achieved androgen concentrations (T, FT, and non-SHBG-T) above the respective normal concentrations between days 2 and 7; then steroid values declined to basal levels by days 13 to 14. Non-SHBG-T showed the largest-fold absolute increase and on day 4 to day 5 averaged three times the mean in normal men. Five men achieved non-SHBG-T values several times the upper limit of our total normal range. Luteinizing hormone became suppressed in men receiving their first intramuscular TC injection and remained suppressed in men receiving chronic TC. Thus, in hypogonadal men, biweekly injections of 200 mg TC result in wide variations in circulating androgen levels, from high to elevated shortly after intramuscular TC declining to basal by days 13 to 14.
Article
In search of a non-invasive, long-term acting form of androgen to be used in female-to-male transsexuals, testosterone undecanoate (Andriol, Organon) was investigated from clinical and laboratory points of view. The therapy resulted in a significant elevation of androgens with a considerable increase of the free testosterone fraction, desired virilization and somatic changes to a masculine phenotype. Testosterone undecanoate provides sufficiently high androgen levels without significant influence on the hypothalamo-pituitary-gonadal axis. The treatment impaired neither liver function nor glucose tolerance. It is concluded that this drug is suitable for hormonal preparation before the reconstructive therapy to males.
Article
Hyperinsulinemia is a common finding in hyperandrogenic women, during pregnancy, and in women using oral contraceptives. To test whether sex hormone treatment can induce insulin resistance in healthy subjects, we studied the effects of administration of testosterone to 13 female to male and of ethinyl estradiol to 18 male to female transsexuals. Utilization and production of glucose and levels of sex steroids were measured during a three-step hyperinsulinemic-euglycemic clamp before and after 4 months of hormone administration. Females were treated with im injections of testosterone esters (250 mg/2 weeks); males were treated with ethinyl estradiol alone (0.1 mg/day, orally) or a combination of ethinyl estradiol and cyproterone acetate (100 mg/day, orally). Similar insulin levels were achieved at each of the three steps of the clamp studies before and during hormone administration. During step 1 of each clamp, with insulin levels in the physiological range, glucose utilization decreased from 3.5 +/- 1.2 to 2.6 +/- 0.9 mmol/kg lean body mass (LBM).h in women treated with testosterone esters (P < 0.001) and from 3.2 +/- 0.7 to 2.5 +/- 0.5 mmol/kg lean body mass.h in men treated with ethinyl estradiol (P < 0.001). The effects of sex steroids during steps 2 and 3 of the clamp at higher (supraphysiological) insulin levels were less clear. Endogenous glucose production (measured by isotope dilution with tritiated glucose) was not affected by hormone administration, indicating that the observed changes in glucose requirement were determined by a diminished peripheral glucose uptake. We conclude that sex hormone administration, i.e. testosterone treatment in females and ethinyl estradiol treatment in males, can induce insulin resistance in healthy subjects.
Article
Sex differences are found in most components of the insulin resistance syndrome and the associated cardiovascular risk profile. These differences are attributed to sex-specific sex steroid profiles, but the effects of sex steroids on the individual components of the insulin resistance syndrome remain incompletely understood. Prospective, intervention study. In 37 young (age range 16-36 years), nonobese [body mass index (BMI) < 29], transsexual subjects, effects of ethinyl oestradiol (100 micro g/day) + cyproterone acetate (100 mg/day) administration were evaluated in 20 male-to-female transsexuals and of testosterone-ester administration [250 mg intramuscularly (i.m.)/2 weeks] in 17 female-to-male transsexuals. We studied lipid spectrum, postheparin hepatic lipase (HL) and lipoprotein lipase (LPL) activity, blood pressure, glucose utilization (by euglycaemic hyperinsulinaemic clamp), and fat areas (by magnetic resonance imaging) at baseline and during 1-year cross-sex hormone administration. Oestrogens + antiandrogens increased high-density lipoprotein (HDL)-cholesterol and decreased LDL-cholesterol, and HL activity, which are considered beneficial. But this combination also increased triglycerides, blood pressure, subcutaneous fat and visceral fat, and decreased the LDL-particle size, LPL activity and insulin sensitivity, which are all considered detrimental. Testosterone reduced HDL-cholesterol and the LDL-particle size, and increased triglycerides and HL activity. An android fat distribution was induced (i.e. decreased subcutaneous and increased visceral fat). Blood pressure, total and LDL-cholesterol, LPL activity and insulin sensitivity were mainly unaffected. The effects of cross-sex hormone treatment - in the dosages used in this study - in healthy, nonobese, young transsexual subjects do not show unequivocally that female sex steroids, given in large amounts to male subjects, have beneficial effects on cardiovascular profile and that high dose testosterone administration to female subjects is detrimental with respect to cardiovascular risk.
Article
Notwithstanding the potential public health impact of the polycystic ovary syndrome (PCOS), estimates regarding its prevalence are limited and unclear. Between July 1998 and October 1999, 400 unselected consecutive premenopausal women (18-45 yr of age) seeking a preemployment physical at the University of Alabama at Birmingham were studied (223 Black, 166 White, and 11 of other races). Evaluation included a history and physical examination, a modified Ferriman-Gallwey hirsutism score, and serum screening for hyperandrogenemia, hyperprolactinemia, and 21-hydroxylase-deficient nonclassical adrenal hyperplasia. PCOS was diagnosed by the presence of the following: 1) oligoovulation, 2) hyperandrogenemia and/or hirsutism (modified Ferriman-Gallwey score > or = 6), and 3) the exclusion of related disorders. Confirmed PCOS was established in those individuals whose evaluation was complete and indicative of PCOS, and possible PCOS was established when the hormonal evaluation was not complete or was unavailable, but the clinical phenotype was otherwise suggestive of the disorder. The individual probability of PCOS in women with possible PCOS was assigned a weight based on the findings in similar subjects whose evaluation was complete, and the total number of PCOS cases arising from these individuals was calculated (i.e. individual probability of PCOS x total number of subjects in the group). The cumulative prevalence of PCOS in our population was 6.6% (26.5 of 400), including 15 subjects among the 347 women completing their evaluation and a calculated prevalence of 11.5 subjects among the remainder. The prevalence rates of PCOS for Black and White women were 8.0 and 4.8%, respectively, not significantly different. These data from a large representative unselected population support the concept that PCOS is the most common endocrine abnormality of reproductive-aged women in the United States.
Article
Polycystic ovary syndrome (PCOS) and the metabolic syndrome have many features in common and may share the same pathogenesis. This study was performed to determine the prevalence and predictors of the metabolic syndrome in PCOS. The clinical, hormonal, and oral glucose tolerance test results were analyzed in 394 PCOS women who were screened for participation in a multicenter trial to evaluate the effects of troglitazone on ovulation and hirsutism. A multicenter clinical trial is presented. The subjects were women with PCOS who had or lacked the metabolic syndrome. Waist circumference, fasting glucose, high-density lipoprotein cholesterol and triglyceride concentrations, and blood pressure were the main outcome measures. Twenty-six (6.6%) subjects had diabetes; among the 368 nondiabetics, the prevalence for individual components comprising the metabolic syndrome were: waist circumference greater than 88 cm in 80%, high-density lipoprotein cholesterol less than 50 mg/dl in 66%, triglycerides greater than or equal to 150 mg/dl in 32%, blood pressure greater than or equal to 130/85 mm Hg in 21%, and fasting glucose concentrations greater than or equal to 110 mg/dl in 5%. Three or more of these individual criteria were present in 123 (33.4%) subjects overall. The prevalence of the metabolic syndrome did not differ significantly between racial/ethnic groups. The prevalence of the metabolic syndrome from lowest to highest quartile of free testosterone concentration was 19.8, 31.3, 46.9, and 35.0%, respectively [P = 0.056 adjusted for body mass index (BMI)]. None of the 52 women with a BMI less than 27.0 kg/m2 had the metabolic syndrome; those in the top BMI quartile were 13.7 times more likely (95% confidence interval, 5.7-33.0) to have the metabolic syndrome compared with those in the lowest quartile. Thirty-eight percent of those with the metabolic syndrome had impaired glucose tolerance compared with 19% without the metabolic syndrome (P < 0.001). The metabolic syndrome and its individual components are common in PCOS, particularly among women with the highest insulin levels and BMI. Hyperinsulinemia is a likely common pathogenetic factor for both PCOS and the metabolic syndrome.
Article
To evaluate the effect of testosterone (T) on adiponectin serum levels in transsexual female patients. We measured adiponectin, leptin, luteinizing hormone and follicle stimulating hormone, T, estradiol, lipid profile, biochemical parameters and body composition in 16 transsexual female patients at baseline and after 6 months of T treatment (100 mg Testoviron Depot /10 days, i.m.). Adiponectin levels were 16.9 +/- 7.3 mg/mL at baseline and 13.5 +/- 7.4 mg/mL at month 6 of T treatment (P < 0.05). Leptin and high-density lipoprotein cholesterol decreased significantly, whereas body mass index, waist circumference and lean body mass increased significantly after 6 months of T treatment. No changes in insulin or Homeostasis Model Assessment were detected. T can significantly reduce adiponectin serum levels in transsexual female patients.
Article
The most common treatment regimen in female-to-male transsexuals is administration of short-acting testosterone esters im every 2 wk. Our objective was to report the effects of administering long-acting testosterone undecanoate every 3 months on hormonal and clinical changes, mortality, morbidity, and safety during the first year of treatment in female-to-male transsexuals. This was a 1-yr observational study. Setting: The setting was an outpatient department at a university hospital. Patients: A total of 35 female-to-male transsexuals completed the first year of observation, whereas two patients discontinued the treatment regimen due to serious hypertension. The intervention was 1-yr im treatment with long-acting testosterone undecanoate every 3 months. Gonadotropins, steroid hormones, liver enzymes, lipids, blood and coagulation parameter, body mass index, blood pressure, bone mineral density, and endometrium thickness were measured at the beginning of cross-sex hormone treatment and after 12 months. The mortality, morbidity, adverse effects, and desired clinical changes were recorded. There was a significant decrease in LH, prolactin, SHBG, high-density lipoprotein levels, and endometrium thickness, and a significant increase in body mass index, systolic and diastolic blood pressure, total testosterone and calculated androgens, triglycerides, hemoglobin, and hematocrit levels. No mortality was observed. Two cases of hypertension were noted. The patients reported a desirable increase in libido and clitoral growth. Acne was observed in five patients (14.3%). The treatment of female-to-male transsexuals with long-acting testosterone undecanoate may be a feasible and safe option for testosterone augmentation in these subjects. However, monitoring of blood pressure should not be ignored during the treatment, to identify patients liable to develop hypertension.
Article
Transsexuals receive cross-sex hormone treatment. Its short-term use appears reasonably safe. Little is known about its long-term use. This report offers some perspectives. The setting was a university hospital serving as the national referral center for The Netherlands (16 million people). From the start of the gender clinic in 1975 up to 2006, 2236 male-to-female and 876 female-to-male transsexuals have received cross-sex hormone treatment. In principle, subjects are followed up lifelong. Male-to-female transsexuals receive treatment with the antiandrogen cyproterone acetate 100 mg/d plus estrogens (previously 100 microg ethinyl estradiol, now 2-4 mg oral estradiol valerate/d or 100 microg transdermal estradiol/d). Female-to-male transsexuals receive parenteral testosterone esters 250 mg/2 wk. After 18-36 months, surgical sex reassignment including gonadectomy follows, inducing a profound hypogonadal state. Outcome measures included morbidity and mortality data and data assessing risks of osteoporosis and cardiovascular disease. Mortality was not higher than in a comparison group. Regarding morbidity, with ethinyl estradiol, there was a 6-8% incidence of venous thrombosis, which is no longer the case with use of other types of estrogens. Continuous use of cross-sex hormones is required to prevent osteoporosis. Androgen deprivation plus an estrogen milieu in male-to-female transsexuals has a larger deleterious effect on cardiovascular risk factors than inducing an androgenic milieu in female-to-male transsexuals, but there is so far no elevated cardiovascular morbidity/mortality. Low numbers of endocrine-related cancers have been observed in male-to-female transsexuals. Cross-sex hormone treatment of transsexuals seems acceptably safe over the short and medium term, but solid clinical data are lacking.
Secular changes in U.S. prediabetes prevalence defined by hemoglobin A 1c and fasting plasma glucose: National Health and Nutrition Examination Surveys
  • Kmk Bullard
  • S H Saydah
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Bullard KMK, Saydah SH, Imperatore G, et al. Secular changes in U.S. prediabetes prevalence defined by hemoglobin A 1c and fasting plasma glucose: National Health and Nutrition Examination Surveys, 1999-2010. Diabetes Care. 2013;36:2286-93.
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Wild RA. Dyslipidemia in PCOS. Steroids. 2012;77:295-299.
The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The hypothesis of PCOS as functional ovarian hyperandrogenism revisited
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Rosenfield RL, Ehrmann DA. The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr Rev. 2016;37:467-520. DOI:10.4158/EP-2017-0247 © 2018 AACE.
Long-term administration of testosterone undecanoate every 3 months for testosterone supplementation in female-to-male transsexuals
  • A Mueller
  • F Kiesewetter
  • H Binder
  • M W Beckmann
  • R Dittrich
Mueller A, Kiesewetter F, Binder H, Beckmann MW, Dittrich R. Long-term administration of testosterone undecanoate every 3 months for testosterone supplementation in female-to-male transsexuals. J Clin Endocrinol Metab. 2007;92:3470-5. DOI:10.4158/EP-2017-0247 © 2018 AACE.