Thrombotic issues in transgender medicine: A review.

Clinicians, including hematologists, are more frequently encountering transgender individuals in practice; however, most lack training on the management and complications of transgender medicine. Hormonal therapy forms the backbone of medical interventions for patients undergoing gender transition. While supplementing an individual's intrinsic sex hormone is associated with a variety of hematologic complications including increased rates of venous thrombosis, cardiovascular events, erthyrocytosis, and malignancy, the risks of supplementing with opposing sex hormones are not well understood. Data on the hematologic complications of these therapies are accumulating but remain limited, and clinicians have little experience with their management. This review highlights the current interventions available in transgender medicine and related potential hematologic complications, and it suggests simple, evidence-based management going forward. Am. J. Hematol. 92:204-208, 2017. © 2016 Wiley Periodicals, Inc.

A More Nuanced Story: Pediatric Gender-Affirming Healthcare is Associated With Satisfaction and Confidence.

PURPOSE: Pediatric gender-affirming medical care has strong research evidence and support, and transition-related regret is uncommon. Misinformation about regret has nonetheless been used to limit adolescents from accessing this care. This study is the first of a 3-part initiative to clarify long-term satisfaction and regret related to pediatric gender-affirming care (GAC). METHODS: An anonymous survey was distributed to individuals of age 15 and older who participated in at least one prior appointment at a large pediatric gender clinic. The survey questions included (1) demographics; (2) use of gender-affirming interventions; (3) barriers to accessing medical interventions; (4) reasons for any discontinuation of medical interventions; (5) emotions associated with GAC; and (6) intervention-related regret. RESULTS: Participants (N = 150; Mage = 18.6) were predominantly transmasculine-identified and/or assigned female at birth (86%). The most common emotions associated with GAC were satisfaction (88.0%) and confidence (86.7%). A total of 141 participants reported taking hormones, 30 of whom reported ever discontinuing (21.3%). Among these, 11 have already resumed hormones, and 16 might resume. Of the three with no plan to resume hormones, one is fully satisfied with the results, and the remaining two no longer identify as transgender. Only one participant (0.7% of those who ever took hormones) wishes they had never started testosterone or had top surgery, both of which occurred in adulthood. DISCUSSION: Individuals who accessed GAC as adolescents are largely satisfied with this care. Care-related satisfaction and regret are more nuanced than sometimes portrayed and should not be used to limit access.

A prospective comparison study of subcutaneous and intramuscular testosterone injections in transgender male adolescents.

OBJECTIVES: This prospective study compares testosterone injection type and effects on biochemical changes, clinical effects, and quality of life amongst transgender and gender diverse (TGD) adolescents assigned female at birth (AFAB) over the first 6 months of subcutaneous (SQ) vs. intramuscular (IM) testosterone injections as part of their gender affirming care. METHODS: Subjects were testosterone-naïve transgender adolescents, AFAB, ages 14-18 years old. Subjects were either randomized to injection type or selected a preferred injection type. At enrollment, subjects completed baseline labs and PedsQL™ quality of life questionnaire. At 3 month and 6 month follow up, subjects completed peak and trough testosterone levels, PedsQL™, masculinizing effects, and medication experience questionnaires. RESULTS: Twenty-six subjects participated with a median age 15.5 years. By 6-month follow up, trough testosterone levels were comparable between the two groups. Peak testosterone levels were higher in the IM group at 3-month follow up. Mild adverse effects were rare (12 %, all in SQ subjects) and limited to skin reaction only. Self-reported masculinization effects and quality of life were not statistically different between injection groups. A total of 92 % of participants was self-injecting by 3-month follow up. CONCLUSIONS: In this prospective study, clinical and biochemical effects are similar between SQ and IM testosterone injections for transgender adolescents. Subjects expressed preference for both injection types. Both SQ and IM injection modalities are safe and effective for TGD youth initiating testosterone and both options should be offered to patients.

Regret after Gender-Affirming Surgery: A Multidisciplinary Approach to a Multifaceted Patient Experience.

BACKGROUND: Lasting regret after gender-affirming surgery (GAS) is a difficult multifaceted clinical scenario with profound effects on individual well-being as well as being a politically charged topic. Currently, there are no professional guidelines or standards of care to help providers and patients navigate this entity. This article summarizes the authors' Transgender Health Program's cohesive multidisciplinary lifespan approach to mitigate, evaluate, and treat any form of temporary or permanent regret after GAS. METHODS: A multidisciplinary (primary care, pediatric endocrinology, psychology, social work, plastic surgery, urology, gynecology, and bioethics) workgroup including cisgender, transgender, and gender-diverse professionals met for a duration of 14 months. The incidence of individuals who underwent GAS at the authors' program between 2016 and 2021 and subsequently expressed desire to reverse their gender transition was reported. RESULTS: Among 1989 individuals who underwent GAS, six (0.3%) either requested reversal surgery or transitioned back to their sex assigned at birth. A multidisciplinary assessment and care pathway for patients who request reversal surgery is presented in the article. CONCLUSIONS: A care environment that welcomes and normalizes authentic expression of gender identity, affirms surgical goals without judgment, and destigmatizes the role of mental health in the surgical process are foundational to mitigating the occurrence of any form of regret. The authors hope this can provide a framework to distinguish normal postoperative distress from temporary forms of grief and regret and regret attributable to societal repercussions, surgical outcomes, or gender identity.

Congenital hypothyroidism caused by excess prenatal maternal iodine ingestion.

We report the cases of 3 infants with congenital hypothyroidism detected with the use of our newborn screening program, with evidence supporting excess maternal iodine ingestion (12.5 mg/d) as the etiology. Levels of whole blood iodine extracted from their newborn screening specimens were 10 times above mean control levels. Excess iodine ingestion from nutritional supplements is often unrecognized.

History of the Thyroid.

The history of the thyroid dates from 2697 BCE when the "Yellow Emperor" Hung Ti described the use of seaweed to treat goiter. The English name "thyroid" was coined by Thomas Wharton in 1656 from the Greek word for a shield. Bernard Courtois discovered iodine in 1811 when he noted a residual purplish ash while burning seaweed. Robert Graves is known for his classic 1835 report of "palpitations, goiter, and exophthalmos" in three women, but Caleb Parry observed the same clinical features in 1786. The clinical syndrome we now recognize as hypothyroidism was characterized as "myxoedema" in 1878 by William Ord at St. Thomas Hospital. In 1891, George Murray reported that injection of thyroid extract from sheep led to improvement in symptoms in a woman with myxedema. Thomas Kocher, who reported that patients with goiter who underwent complete thyroidectomy developed cachexia strumipriva, was awarded the Nobel Prize in Physiology and Medicine in 1909. Edward Kendall discovered "thyroxin" on Christmas day in 1914. Studies by David Marine that iodine treatment prevented endemic goiter led to salt iodination, which has largely eradicated endemic cretinism. In 1973, Jean Dussault reported detection of congenital hypothyroidism by screening newborn populations.

A New Virtual Reality: Benefits and Barriers to Providing Pediatric Gender-Affirming Health Care Through Telehealth.

Purpose: Access to early, multidisciplinary, gender-affirming health care significantly improves the psychosocial well-being of transgender and gender diverse youth. The Doernbecher Gender Clinic (DGC) is an interdisciplinary pediatric gender clinic consisting of endocrinology, psychology, and social work. Following the initiation of modified operations in March 2020 due to the COVID-19 pandemic, the DGC converted all interdisciplinary new patient appointments to telehealth. The purpose of this article is to (1) describe the model of care implemented during modified operations, (2) compare the number of new patients seen before and after modified operations, and (3) to contextualize this information with data from a patient satisfaction survey. Method: Retrospective chart review was used to determine how many interdisciplinary new patient appointments occurred before and during modified operations. Additional variables included age, gender, visit modality (phone or video), geographic location, and number of caregivers who participated. In addition, patients and families who attended appointments since modified operations were invited to complete a prospective survey regarding their experience and satisfaction with these appointments, and the narrative responses to questions about advantages and disadvantages were analyzed thematically. Results: Chart review revealed a similar number and make up of new patient appointments before and after the initiation of modified operations. The percentage of patients residing in other urban areas outside of the Portland metro increased over the course of the three time periods, but not to a significant degree. Survey results suggest that both telehealth and in-person visits have advantages and disadvantages with regard to (1) access and (2) comfort. Families appear to differ with regard to their priorities in each area. Conclusion: Telehealth has the potential to provide quality pediatric gender-affirming health care without sacrificing the benefits of an interdisciplinary team-based approach.

Providing Gender-Affirmative Care During the Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic Era: Experiences and Perspectives from Pediatric Endocrinologists in the United States.

Transgender and gender diverse (TGD) youth are at risk of worsened health disparities during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Health care delivery by pediatric endocrinologists, including rapid implementation of telemedicine services, during the pandemic has not been documented. The Pediatric Endocrine Society's Transgender Health Special Interest Group met virtually to survey practice patterns during the SARS-CoV-2 pandemic. The majority of pediatric endocrinologists continued to provide most aspects of medical transition; however, we also identified several barriers to care. Overall, the survey results demonstrated that telemedicine can be utilized as an effective way to provide gender-affirming medical care to TGD youth.

Changes in Anxiety and Depression from Intake to First Follow-Up Among Transgender Youth in a Pediatric Endocrinology Clinic.

Monitoring acute distress in transgender youth initiating gender-affirming care is important given their increased risk for significant mental health symptoms. The current study examined changes in anxiety, depression, and suicidality from initial appointment to first follow-up in 80 youth, ages 11-18. Average time between visits was ∼4 months but varied across participants. Results revealed no change in acute distress from intake to follow-up. Neither distance from medical center nor initiation of hormone therapy was associated with symptom changes. While research shows decreased distress with initiation of hormones, study findings suggest changes may actually take longer to occur.

Outcome of Newborn Screening for Congenital Adrenal Hyperplasia at Two Time Points.

BACKGROUND/AIMS: Screening newborns for congenital adrenal hyperplasia (CAH) is problematic owing to the dynamic changes in serum 17-hydroxyprogesterone (17-OHP) levels following birth. Our study objectives were to determine the accuracy of screening, severity of CAH, and biochemical and clinical outcomes of cases detected by our program which collects specimens at 2 time periods following birth. METHODS: We reviewed all CAH cases detected in the Northwest Regional Newborn Screening Program from 2003 through 2017. Comparison was made of screening and confirmatory serum 17-OHP, neonatal, maternal, and follow-up auxologic data, steroid treatment doses, and 21-hydroxylase genotype in cases detected on the first versus second test. RESULTS: Out of 164 cases of CAH, 25% were detected on the second screen. Infants detected on the second test had a lower screening 17-OHP (147 vs. 294 ng/mL), lower confirmatory serum 17-OHP (7,772 vs. 14,622 ng/dL), and were more likely to have simple virilizing CAH. There were no identifiable neonatal or maternal factors associated with detection on the second test. 21-Hydroxylase genotypes overlapped in first versus second screen cases. CONCLUSION: Early collection of specimens necessitated by early discharge resulted in milder CAH cases falling below the screening 17-OHP cutoff. In our program 25% of cases were detected on a routine second screen.

Using the PHQ-9 and GAD-7 to screen for acute distress in transgender youth: findings from a pediatric endocrinology clinic.

Background Transgender and gender nonconforming (TGNC) youth are at higher risk for anxiety and depression than their peers. The referral rate for those seeking specialty medical care has rapidly increased in recent years. This paper examines the use of brief screening tools with clear cutoffs to assist physicians in rapidly identifying TGNC youth in acute distress. Methods A retrospective chart review was conducted for patients aged 11-18 years being treated in a pediatric endocrinology clinic for gender dysphoria. Patient Health Questionnaires for depression (PHQ-9) and Generalized Anxiety Disorder 7-item (GAD-7) were collected for patients attending an initial consultation (n=79) or follow-up appointment (n=115). Results Screener data identified high rates of acute distress, including depression (47%), anxiety (61%), and suicidal ideation (30%). Distress was not associated with age or gender identity. More youth endorsed clinically significant anxiety at initial consultation appointments versus follow-up appointments. Conclusions The results support the use of the PHQ-9 and GAD-7 as brief, easy-to-use screening measures that can be administered by physicians to rapidly identify acute distress and inform treatment recommendations among TGNC youth seeking medical intervention.

Detecting Congenital Central Hypothyroidism by Newborn Screening: Difficulty in Distinguishing from Congenital Thyroxine-Binding Globulin Deficiency.

BACKGROUND/AIMS: Congenital central hypothyroidism (CH-C) can be detected on newborn screening (NBS) by programs using thyroxine (T4)-reflex thyroid-stimulating hormone (TSH) test approach. CH-C must be distinguished from T4-binding globulin (TBG) deficiency. We sought to determine whether thyroid function tests reliably separate CH-C from TBG deficiency. METHODS: We analyzed NBS and serum free and total T4, T3 resin uptake (T3RU) or TBG, and TSH for infants in the Northwest Regional NBS Program (NWRSP) between the years 2008 and 2015 with either CH-C or TBG deficiency. RESULTS: We discovered a significant overlap in T3RU and TBG levels amongst 21 cases of CH-C and 250 cases of TBG deficiency. Mean serum TBG levels were lower in CH-C cases (20.3 µg/mL, range 14.2-33.3) than what is reported in healthy infants (28.6 µg/mL, range 19.1-44.6). Serum free T4 was lower in CH-C cases than TBG deficiency but did not always differentiate between the two conditions. CONCLUSION: CH-C benefits from detection on NBS but must be distinguished from TBG deficiency. The diagnosis of CH-C rests solely on subnormal serum free T4, but is supported by the demonstration of other pituitary hormone deficiencies. As an overlap exists, serum TBG (or T3RU) levels do not play a role in the diagnosis of CH-C.

A degradation fragment of type X collagen is a real-time marker for bone growth velocity.

Despite its importance as a key parameter of child health and development, growth velocity is difficult to determine in real time because skeletal growth is slow and clinical tools to accurately detect very small increments of growth do not exist. We report discovery of a marker for skeletal growth in infants and children. The intact trimeric noncollagenous 1 (NC1) domain of type X collagen, the marker we designated as CXM for Collagen X Marker, is a degradation by-product of endochondral ossification that is released into the circulation in proportion to overall growth plate activity. This marker corresponds to the rate of linear bone growth at time of measurement. Serum concentrations of CXM plotted against age show a pattern similar to well-established height growth velocity curves and correlate with height growth velocity calculated from incremental height measurements in this study. The CXM marker is stable once collected and can be accurately assayed in serum, plasma, and dried blood spots. CXM testing may be useful for monitoring growth in the pediatric population, especially responses of infants and children with genetic and acquired growth disorders to interventions that target the underlying growth disturbances. The utility of CXM may potentially extend to managing other conditions such as fracture healing, scoliosis, arthritis, or cancer.

Neonatal estrogen exposure results in biphasic age-dependent effects on the skeletal development of male mice.

Peak bone mass, one of the most important predictors for fracture risk later in life, is attained during puberty and adolescence and influenced by neonatal and pubertal sex-specific gonadal hormones and GH-IGF-I secretion patterns. This study examined the effects of brief neonatal estrogen (NE) exposure on growth and skeletal development in C57BL/6J mice. A single injection of 100-µg estradiol or vehicle was administered on the first day of life. Growth parameters were monitored and skeletal phenotyping performed at 16 weeks in female mice and at 4 and 16 weeks in male mice. NE exposure negatively impacted adult femoral length in both sexes, but adult body weight, areal bone density, and bone strength in female mice were unaffected. In contrast, somatic growth was attenuated in estrogen-exposed male mice throughout the study period. At the prepubertal time point, the estrogen-exposed males exhibited higher bone mineral density, cortical volume, and cortical thickness compared with controls. However, by the time of peak bone mass acquisition, the early skeletal findings had reversed; estrogen-exposed mice had lower bone density with reduced cross-sectional area, cortical volume, and cortical thickness, resulting in cortical bones that were less resistant to fracture. NE exposure also resulted in reduced testicular volume and lower circulating IGF-I. Male mice exposed to estrogen on the first day of life experience age-dependent changes in skeletal development. Prepubertal animals experience greater endocortical bone acquisition as a result of estrogen exposure. However, by adulthood, continued developmental changes result in overall reduced skeletal integrity.

Detection of neonates with mild congenital hypothyroidism (primary) or isolated hyperthyrotropinemia: an increasingly common management dilemma.

Anywhere from 10% to 40% of neonates detected by newborn screening programs have mild congenital hypothyroidism (thyroid-stimulating hormone [TSH] 6 to 20 mU/l with borderline low free T4) or isolated hyperthyrotropinemia. The increasing frequency of such cases appears to be chiefly the result of lowering screening TSH cutoffs. In some cases, the etiology is a mild form of dysgenesis or dyshormonogenesis; most cases, however, on imaging have gland in situ of unexplained etiology. Re-evaluation after age 3 years shows some with transient hypothyroidism, a minority with permanent hypothyroidism, while the majority have persistent, mild TSH elevation and normal free T4. There is limited data on neurodevelopmental outcome to guide management. In cases where the TSH is trending down and free T4 is normal, we recommend re-checking serum TSH and free T4 at weekly intervals. If serum TSH does not normalize by 4 weeks of age, we recommend treatment, with re-evaluation after age 2-3 years.