New Human Leukocyte Antigen (HLA) Antibody Formation and Creatinine Elevation With Abaloparatide in Kidney Transplant Recipient.

A 39-year-old female with a history of kidney transplant presented to the endocrinology clinic for osteoporosis evaluation after sustaining an ankle fracture from a fall. Her kidney transplant regimen (mycophenolate mofetil 360 mg twice a day, tacrolimus 0.5 mg every morning and 0.5-1 mg every evening, prednisone 5 mg/day) and baseline creatinine (1.0-1.2 mg/dL) had been stable for several years. After an appropriate secondary workup, she was started on abaloparatide 80 µg subcutaneous daily injections for osteoporosis. She had a good initial biochemical response to therapy. However, 5 months after abaloparatide initiation she was found to have a new elevation in serum creatinine (1.17 to 1.69 mg/dL) despite stable serum tacrolimus trough levels, and two new human leukocyte antigen (HLA) antibodies (anti-HLA antibodies detected to Cw7 and DP28). Abaloparatide was stopped due to concern for immunogenicity. There was no evidence of rejection on kidney biopsy and she was restabilized on her transplant regimen with a new baseline creatinine of 1.3-1.6 mg/dL. The patient was subsequently started on teriparatide 20 µg daily subcutaneous injections for 2 years with good biochemical response, significant improvement in bone mineral density, and stable transplant regimen without additional signs of immunogenicity or rejection. This is the first case report to raise concern about immunogenicity with abaloparatide in solid organ transplant recipients. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Gender-affirming hormone therapy, mental health, and surgical considerations for aging transgender and gender diverse adults.

As the transgender and gender diverse (TGD) population ages, more transfeminine and transmasculine individuals present to clinic to initiate or continue their gender-affirming care at older ages. Currently available guidelines on gender-affirming care are excellent resources for the provision of gender-affirming hormone therapy (GAHT), primary care, surgery, and mental health care but are limited in their scope as to whether recommendations require tailoring to older TGD adults. Data that inform guideline-recommended management considerations, while informative and increasingly evidence-based, mainly come from studies of younger TGD populations. Whether results from these studies, and therefore recommendations, can or should be extrapolated to aging TGD adults remains to be determined. In this perspective review, we acknowledge the lack of data in older TGD adults and discuss considerations for evaluating cardiovascular disease, hormone-sensitive cancers, bone health and cognitive health, gender-affirming surgery, and mental health in the older TGD population on GAHT.

Bad to the bones: prescribing of drugs for the prevention and treatment of osteoporosis in patients on chronic glucocorticoids.

Of patients prescribed systemic glucocorticoids, this study identifies the proportion prescribed osteoporosis pharmacologic treatment and associated characteristics. Overall, 13.2% of patients were prescribed osteoporosis pharmacologic treatment. Predictors included documented osteoporosis, past DXA or fracture, and provision of care within a department using embedded protocols, suggesting electronic medical record-based tools may be beneficial. PURPOSE: This study aimed to identify a cohort of patients at risk for glucocorticoid-induced osteoporosis based on their prescribed glucocorticoid regimens and to quantify the proportion who were also prescribed osteoporosis pharmacologic treatment. The secondary objective was to recognize patient characteristics associated with receiving such treatment. METHODS: A retrospective single-site cohort study used prescription order data to identify 7774 adults prescribed chronic glucocorticoids and measure the proportion also prescribed osteoporosis pharmacologic treatment. RESULTS: Of the total cohort, 1026/7774 (13.2%) had osteoporosis pharmacologic treatment prescribed. Of the subgroups prescribed a prednisone-equivalent of 5, 10, or 20 mg per day or more for at least 180 days, 584/4262 (13.7%), 153/1048 (14.6%), and 47/344 (13.7%) had treatment prescribed. Factors independently associated with osteoporosis pharmacologic treatment initiation included having osteoporosis or osteopenia on the problem list (OR = 4.45, 95% CI 3.70-5.34), history of dual-energy X-ray absorptiometry (DXA) screening (OR = 2.18, 95% CI 1.82-2.62), history of fracture (OR = 1.83, 95% CI 1.54-2.167), and longer duration of glucocorticoid use (OR = 1.33, 95% CI 1.10-1.59). The prescribing department was also a significant predictor of medication initiation, with cardiac transplant (OR = 6.04, 95% CI 3.97-9.17), oncology (OR = 4.11, OR 3.28-5.14), and lung transplant (OR = 1.51, 95% CI 1.08, 2.12) being positively correlated with this outcome, and nephrology (OR = 0.51, 95% CI 0.36-0.72) and kidney transplant (OR = 0.53, 95% CI 0.37, 0.75) being negatively correlated. CONCLUSION: Prescribing rate of osteoporosis pharmacologic treatment in patients using chronic glucocorticoids is low. Examining practices with higher prescribing rates may offer insight into improving protection against osteoporosis-induced fractures.

The role of osteoanabolic agents in the management of patients with osteoporosis.

Reducing fracture risk is the objective of osteoporosis treatment. Bone-forming osteoporosis drugs increase bone mass, restore bone microarchitecture, and reduce fracture risk more effectively than oral bisphosphonates, providing strong justification for the use of these agents as the initial therapy or after anti-remodeling agents in patients at very high risk of fracture. At the end of a 12-to-24-month course of osteoanabolic therapy, transitioning to a potent anti-remodeling agent maintains and enhances the treatment benefit. This review describes the clinical applications of osteoanabolic therapy for osteoporosis.

Postmenopausal Hyperandrogenism: Evaluation and Treatment Strategies.

Evidence of clinical and/or biochemical androgen excess poses a unique differential in postmenopausal women. Some signs and symptoms of postmenopausal hyperandrogenism can be normal and attributed to the natural aging process. However, the causes of androgen excess in this group include both nontumorous and tumorous causes. Treatment of androgen excess may improve both quality of life and long-term metabolic outcomes.

Routine Screening for Transgender and Gender Diverse Adults Taking Gender-Affirming Hormone Therapy: a Narrative Review.

Despite the growing number of adult transgender and gender diverse (TGD) patients seeking health services, there are many unknowns regarding how routine screening recommendations should be applied to TGD persons receiving gender-affirming hormone therapy (GAHT). Patients taking GAHT may have disease risks that differ from what is expected based on their sex assigned at birth or affirmed gender identity. We discuss two patient cases, one transgender man and one transgender woman who present for routine medical care, to review several conditions that may be impacted by the hormones utilized in masculinizing and feminizing GAHT and for which screening recommendations are available for TGD adults: cardiovascular risk factors, osteoporosis, breast cancer, cervical cancer, and prostate cancer. We reviewed the TGD-specific screening recommendations from several major medical organizations and programs and found them to be largely based upon expert opinion due to a lack of evidence. The goal of this narrative review is to assist healthcare professionals in counseling and screening their TGD patients when and where appropriate. Not all TGD adults have the ability or need to receive routine medical care from a specialized TGD health clinic; therefore, it is essential for all healthcare professionals involved in routine and gender-affirming care to have knowledge about these conditions and screenings.

Early-onset Paget's disease of bone in a Mexican family caused by a novel tandem duplication (77dup27) in TNFRSF11A that encodes RANK.

Four heterozygous in-frame tandem duplications of different lengths in TNFRSF11A, the gene that encodes receptor activator of nuclear factor κB (RANK), constitutively activate RANK and lead to high turnover skeletal disease. Each duplication elongates the signal peptide of RANK. The 18-base pair (bp) duplication at position 84 (84dup18) causes familial expansile osteolysis (FEO), the 15-bp duplication at position 84 (84dup15) causes expansile skeletal hyperphosphatasia (ESH), the 12-bp duplication at position 90 (90dup12) causes panostotic expansile bone disease (PEBD), and the 27-bp duplication causes early-onset Paget's disease of bone (PDB2). The severity of the associated skeletal disease seems inversely related to the duplication's length. Additional 15- and 18-bp duplications of TNFRSF11A fit this pattern. Herein, we delineate the skeletal disease of a middle-aged man of Mexican descent who we found to harbor a novel 27-bp tandem duplication at position 77 (77dup27) of TNFRSF11A. His disorder shares features, particularly hand involvement, with the single Japanese (75dup27) and Chinese (78dup27) kindreds with PDB2 (PDB2Jpn and PDB2Chn, respectively). However, his distinct hearing loss developed later in adulthood compared to the other 27-bp families. He reported no morbidities during childhood, but in his late 20s developed unexplained tooth loss, low-trauma fractures, post-operative hypercalcemia, and painless enlargement of his fingers. Biochemical studies showed elevated serum alkaline phosphatase (ALP), bone-specific ALP, C-telopeptide, and osteocalcin consistent with rapid bone remodeling. Radiologic imaging revealed remarkably lucent bones with vertebral compression fractures, calvarial lucencies, and thinned long bone cortices. DXA showed extremely low bone mineral density. His disorder genetically and phenotypically fits best with PDB2 and can be called PDB2Mex.

Health considerations for transgender women and remaining unknowns: a narrative review.

Transgender (trans) women (TW) were assigned male at birth but have a female gender identity or gender expression. The literature on management and health outcomes of TW has grown recently with more publication of research. This has coincided with increasing awareness of gender diversity as communities around the world identify and address health disparities among trans people. In this narrative review, we aim to comprehensively summarize health considerations for TW and identify TW-related research areas that will provide answers to remaining unknowns surrounding TW's health. We cover up-to-date information on: (1) feminizing gender-affirming hormone therapy (GAHT); (2) benefits associated with GAHT, particularly quality of life, mental health, breast development and bone health; (3) potential risks associated with GAHT, including cardiovascular disease and infertility; and (4) other health considerations like HIV/AIDS, breast cancer, other tumours, voice therapy, dermatology, the brain and cognition, and aging. Although equally deserving of mention, feminizing gender-affirming surgery, paediatric and adolescent populations, and gender nonbinary individuals are beyond the scope of this review. While much of the data we discuss come from Europe, the creation of a United States transgender cohort has already contributed important retrospective data that are also summarized here. Much remains to be determined regarding health considerations for TW. Patients and providers will benefit from larger and longer prospective studies involving TW, particularly regarding the effects of aging, race and ethnicity, type of hormonal treatment (e.g. different oestrogens, anti-androgens) and routes of administration (e.g. oral, parenteral, transdermal) on all the topics we address.

Systemic effects of epidural steroid injections for spinal stenosis.

This analysis of the lumbar epidural steroid injections for spinal stenosis multicenter randomized controlled trial data identifies the degree of and risk factors for cortisol suppression after epidural steroid injections in older adults with spinal stenosis. Four hundred patients aged 50 years and older with back or leg pain and central lumbar spinal stenosis completed baseline demographic and psychosocial measures. Morning serum cortisol levels were measured at baseline and 3 weeks after initial injection. Patients were randomized to receive epidural injections of either local anesthetic with corticosteroid (n = 200) or local anesthetic only (n = 200). The specific corticosteroid was chosen at the treating physician's discretion (methylprednisolone, betamethasone, triamcinolone, or dexamethasone). Thirty-two patients (20.3%) treated with corticosteroid experienced cortisol reduction at 3 weeks of >50% compared with 10 patients (6.7%) treated with lidocaine only (adjusted treatment effect = 3.5, 95% confidence interval: 1.6-7.9, P = 0.002). The effect on 3-week cortisol changes did not differ by demographic or patient-level characteristics. Those treated with methylprednisolone or triamcinolone had an average 3-week cortisol reduction of 41.0% (P = 0.005) and 41.6% (P < 0.001) from baseline, respectively, whereas patients treated with betamethasone or dexamethasone were not significantly different than comparable patients in the lidocaine arm. The higher rates of cortisol suppression at 3 weeks in those receiving epidural corticosteroid injections, particularly with longer-acting insoluble corticosteroid formulations, are consistent with sustained systemic absorption of corticosteroid.

Bone density testing: science, the media, and patient care.

Dual-energy X-ray absorptiometry (DXA) is an inexpensive, noninvasive, widely available method for diagnosing osteoporosis, assessing fracture risk, and monitoring the effects of therapy. By diagnosing high-risk patients before a fracture occurs, clinicians can intervene early to reduce fracture risk. Appropriate use of DXA results in money saving for healthcare systems that might otherwise be spent for fracture-related care. Recent reports of studies evaluating DXA screening criteria and intervals for retesting have received considerable media coverage, sometimes suggesting that DXA is expensive, over-utilized, and unnecessary. This may lead to more patients who might benefit from early detection of osteoporosis remaining undiagnosed. We advocate for the use of current clinical practice guidelines with individualization of patient care factors to determine the optimal intervals for DXA testing.

Symptomatic reduction in free testosterone levels secondary to crizotinib use in male cancer patients.

BACKGROUND: Crizotinib is a tyrosine kinase inhibitor active against ALK, MET, and ROS1. We previously reported that crizotinib decreases testosterone in male patients. The detailed etiology of the effect, its symptomatic significance, and the effectiveness of subsequent testosterone replacement have not been previously reported. METHODS: Male cancer patients treated with crizotinib had total testosterone levels measured and results compared with non-crizotinib-treated patients. Albumin, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), and/or luteinizing hormone (LH) were tracked longitudinally. A subset of patients had free testosterone levels measured and a hypogonadal screening questionnaire administered. Patients receiving subsequent testosterone supplementation were assessed for symptomatic improvement. RESULTS: Mean total testosterone levels were -25% below the lower limit of normal (LLN) in 32 crizotinib-treated patients (27 of 32 patients below LLN, 84%) compared with +29% above LLN in 19 non-crizotinib-treated patients (6 of 19 below LLN, 32%), P = .0012. Levels of albumin and SHBG (which both bind testosterone) declined rapidly with crizotinib, but so did FSH, LH, and free testosterone, suggesting a centrally mediated, true hypogonadal effect. Mean free testosterone levels were -17% below LLN (19 of 25 patients below LLN, 76%). Eighty-four percent (16 of 19) with low free levels, and 79% (19/24) with low total levels had symptoms of androgen deficiency. Five of 9 patients (55%) with low testosterone given testosterone supplementation had improvement in symptoms, coincident with increases in testosterone above LLN. CONCLUSIONS: Symptoms of androgen deficiency and free or total/free testosterone levels should be tracked in male patients on crizotinib with consideration of testosterone replacement as appropriate.

Rapid-onset hypogonadism secondary to crizotinib use in men with metastatic nonsmall cell lung cancer.

BACKGROUND: The objective of this study was to document the differences in testosterone (T) levels between crizotinib-treated and noncrizotinib-treated patients with metastatic nonsmall cell lung cancer (NSCLC). METHODS: Testosterone levels were measured in 19 men with metastatic NSCLC who received crizotinib and in 19 men with metastatic NSCLC who did not receive crizotinib. Clinical characteristics of the patients were compared, and additional hormone assays were performed as appropriate. Two patients who began crizotinib and 4 patients who had dose interruptions or who stopped crizotinib therapy had serial hormone measurements, permitting the documentation of dynamic hormone changes on and off crizotinib treatment. RESULTS: Total T levels were low (<241 ng/dL) in 19 of 19 (100%) crizotinib-treated men and in 6 of 19 men (32%) with metastatic NSCLC who did not receive crizotinib (mean T levels, 131 ng/dL and 311 ng/dL, respectively; P = .0002). Only 1 in 5 patients who had anaplastic lymphoma kinase (ALK) gene rearrangements and had not yet received crizotinib had low T. The initiation of crizotinib in 2 patients who had previously normal T levels was associated with a rapid decreases in T and in luteinizing hormone and follicle stimulating hormone levels within 14 to 21 days. Discontinuation of crizotinib led to increases back to normal T levels. CONCLUSIONS: Crizotinib therapy caused rapid suppression of T levels in men. The current results indicated that the site of action must include a central (hypothalamic or pituitary) effect, but additional direct testicular effects could not be excluded. Further work is required to assess the correlation between low T levels and crizotinib side effects as well as the exact molecular mechanism and site of drug toxicity.

Reexamination of testosterone, dihydrotestosterone, estradiol and estrone levels across the menstrual cycle and in postmenopausal women measured by liquid chromatography-tandem mass spectrometry.

Measuring serum androgen levels in women has been challenging due to limitations in method accuracy, precision sensitivity and specificity at low hormone levels. The clinical significance of changes in sex steroids across the menstrual cycle and lifespan has remained controversial, in part due to these limitations. We used validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays to determine testosterone (T) and dihydrotestosterone (DHT) along with estradiol (E2) and estrone (E1) levels across the menstrual cycle of 31 healthy premenopausal females and in 19 postmenopausal females. Samples were obtained in ovulatory women in the early follicular phase (EFP), midcycle and mid luteal phase (MLP). Overall, the levels of T, DHT, E2 and E1 in premenopausal women measured by LC-MS/MS were lower overall than previously reported with immunoassays. In premenopausal women, serum T, free T, E2, E1 and SHBG levels peaked at midcycle and remained higher in the MLP, whereas DHT did not change. In postmenopausal women, T, free T, SHBG and DHT were significantly lower than in premenopausal women, concomitant with declines in E2 and E1. These data support the hypothesis that the changes in T and DHT that occur across the cycle may reflect changes in SHBG and estrogen, whereas in menopause, androgen levels decrease. LC-MS/MS may provide more accurate and precise measurement of sex steroid hormones than prior immunoassay methods and can be useful to assess the clinical significance of changes in T, DHT, E2 and E1 levels in females.

Bisphosphonate treatment in polyostotic fibrous dysplasia of the cranium: case report and literature review.

OBJECTIVE: To report the case of a patient with polyostotic fibrous dysplasia of the cranium who showed dramatic improvement after treatment with intravenous zoledronic acid. METHODS: We present the clinical findings, laboratory test results, surgical pathology report, and imaging studies of a man with extensive fibrous dysplasia of the cranium and review the literature regarding the use of bisphosphonates in patients with this debilitating skeletal disorder. RESULTS: A 32-year-old man presented with chronic occipital headache, and computed tomography of the head revealed extensive bony lesions of the middle and posterior cranial fossa. Bone biopsy confirmed the diagnosis of fibrous dysplasia. Laboratory blood test results revealed elevated serum alkaline phosphatase (140 U/L [reference range, 39-117 U/L]) and elevated serum bone-specific alkaline phosphatase (30.6 µg/L [reference range, 6-20 µg/L]). The patient was treated with intravenous pamidronate without improvement, and therapy was switched to zoledronic acid, which resulted in rapid resolution of headache symptoms, decrease in bone-specific alkaline phosphatase levels to 24.9 µg/L, and dramatic radiologic improvement on repeated computed tomography of the head. CONCLUSIONS: The treatment options for fibrous dysplasia of the cranium have been limited to conservative follow-up or surgery, and the use of zoledronic acid in this condition has not been previously reported. Intravenous bisphosphonate therapy is suggested to be a useful option in the treatment of cranial fibrous dysplasia.

The neuroendocrine effects of traumatic brain injury.

Neuroendocrine dysfunction after traumatic brain injury (TBI) is under-diagnosed, under-treated, and may adversely affect the rate of recovery. Single or multiple pituitary-target hormone disruption occurs in up to two-thirds of persons with TBI, most commonly affecting the gonadal and growth hormone axes. The time course of decline in and recovery of pituitary function in relation to cognitive dysfunction and rehabilitation progress are not well described. This article reviews the clinical spectrum of neuroendocrine deficits after TBI and their underlying mechanisms. Future studies of the effects of hormonal replacement on recovery are recommended.

The role of gonadotropin releasing hormone in normal and pathologic endocrine processes.

PURPOSE OF REVIEW: Gonadotropin releasing hormone is the hypothalamic hormone that activates pituitary gonadotropin production and, ultimately, determines reproductive competence. This review will highlight advances in the basic biology of the gonadotropin releasing hormone neuron that give insight into disorders of pubertal development, and clinical studies with gonadotropin releasing hormone analogs in infertility and prostate cancer treatment. RECENT FINDINGS: Factors that control gonadotropin releasing hormone neuronal migration such as fibroblast growth factor receptor-1 and others that modulate secretion at puberty including kisspeptin/G-protein-coupled receptor 54 have been identified. Mutations in these pathways cause disorders during puberty. Clinical trials have defined the utility of gonadotropin releasing hormone agonists and antagonists for ovulation induction, and the effects of long-term administration for prostate cancer. SUMMARY: Research into the role of the fibroblast growth factor receptor-1 and kisspeptin/G-protein-coupled receptor 54 pathways in gonadotropin releasing hormone neuronal development may identify the molecular defects in idiopathic hypogonadotropic hypogonadism and refine our understanding of normal negative and positive feedback by sex steroids. Clarification of the advantages and disadvantages of gonadotropin releasing hormone analog use in ovulation induction may improve the cost and success of infertility treatment. Insight into long-term effects of gonadotropin releasing hormone analogs in prostate cancer may lead to directed therapies to combat these consequences. Together these studies outline effects of modulation of gonadotropin releasing hormone in normal and pathophysiologic states.