Estradiol increases cortical and trabecular bone accrual and bone strength in an adolescent male-to-female mouse model of gender-affirming hormone therapy.

The effects of gender-affirming hormone therapy on the skeletal integrity and fracture risk in transitioning adolescent trans girls are unknown. To address this knowledge gap, we developed a mouse model to simulate male-to-female transition in human adolescents in whom puberty is first arrested by using gonadotrophin-releasing hormone analogs with subsequent estradiol treatment. Puberty was suppressed by orchidectomy in male mice at 5 weeks of age. At 3 weeks post-surgery, male-to-female mice were treated with a high dose of estradiol (~0.85 mg) by intraperitoneal silastic implantation for 12 weeks. Controls included intact and orchidectomized males at 3 weeks post-surgery, vehicle-treated intact males, intact females and orchidectomized males at 12 weeks post-treatment. Compared to male controls, orchidectomized males exhibited decreased peak bone mass accrual and a decreased maximal force the bone could withstand prior to fracture. Estradiol treatment in orchidectomized male-to-female mice compared to mice in all control groups was associated with an increased cortical thickness in the mid-diaphysis, while the periosteal circumference increased to a level that was intermediate between intact male and female controls, resulting in increased maximal force and stiffness. In trabecular bone, estradiol treatment increased newly formed trabeculae arising from the growth plate as well as mineralizing surface/bone surface and bone formation rate, consistent with the anabolic action of estradiol on osteoblast proliferation. These data support the concept that skeletal integrity can be preserved and that long-term fractures may be prevented in trans girls treated with GnRHa and a sufficiently high dose of GAHT. Further study is needed to identify an optimal dose of estradiol that protects the bone without adverse side effects.

Dual-energy x-ray absorptiometry assessment of bone health in Australian men with prostate cancer commencing androgen deprivation therapy.

OBJECTIVE: To determine the prevalence in Australia of bone health assessment of men with prostate cancer by dual-energy x-ray absorptiometry (DXA), from six months before to twelve months after initiation of androgen deprivation therapy (ADT). DESIGN, SETTING: Cross-sectional national study; linkage of de-identified Medicare Benefits Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) data. PARTICIPANTS: Men (18 years or older) first dispensed PBS-subsidised ADT during 1 May 2017 - 31 July 2020. MAIN OUTCOME MEASURES: Prevalence of MBS-subsidised DXA assessments undertaken from six months before to twelve months after first ADT prescription. RESULTS: Of 33 836 men with prostate cancer commencing ADT therapy during 2017-20, 6683 (19.8%) underwent DXA bone heath assessments between six months before and twelve months after commencing ADT; the mean time from first ADT dispensing to DXA scanning was +90 days (standard deviation, 134 days). The proportion of men aged 54 years or younger who had scans (66 of 639, 10%) was smaller than that of men aged 70-84 years (4528 of 19 378, 23.4%; adjusted odds ratio, 0.36; 95% CI, 0.28-0.47). CONCLUSIONS: For about 80% of men with prostate cancer commencing ADT in Australia, therapy initiation was not accompanied by DXA assessment of bone health. Given the excellent long term prognosis for men with prostate cancer and the availability of bone protective therapy, bone health monitoring should be a routine component of prostate cancer care for men receiving ADT.

Differing Effects of Zoledronic Acid on Bone Microarchitecture and Bone Mineral Density in Men Receiving Androgen Deprivation Therapy: A Randomized Controlled Trial.

Androgen deprivation therapy (ADT) given to men with prostate cancer causes rapid and severe sex steroid deficiency, leading to increased bone remodeling and accelerated bone loss. To examine the effects of a single dose of zoledronic acid on bone microarchitecture, we conducted a 2-year randomized placebo controlled trial in 76 men, mean age (interquartile range [IQR]) 67.8 years (63.8 to 73.9) with non-metastatic prostate cancer commencing adjuvant ADT; 39 were randomized to zoledronic acid and 37 to matching placebo. Bone microarchitecture was measured using high-resolution peripheral quantitative computed tomography (HR-pQCT). Using a mixed model, mean adjusted differences (MAD; 95% confidence interval [95% CI]) between the groups are reported as the treatment effect at several time points. Over 24 months, zoledronic acid showed no appreciable treatment effect on the primary outcomes for total volumetric bone mineral density (vBMD); radius (6.7 mg HA/cm3 [-2.0 to 15.4], p = 0.21) and tibia (1.9 mg HA/cm3 [-3.3 to 7.0], p = 0.87). Similarly, there were no between-group differences in other measures of microarchitecture, with the exception of a modest effect of zoledronic acid over placebo in total cortical vBMD at the radius over 12 months (17.3 mgHA/cm3 [5.1 to 29.5]). In contrast, zoledronic acid showed a treatment effect over 24 months on areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) at all sites, including lumbar spine (0.10 g/cm2 [0.07 to 0.13]), p < 0.001), and total hip (0.04 g/cm2 [0.03 to 0.05], p < 0.001). Bone remodeling markers were initially suppressed in the treatment group then increased but remained lower relative to placebo (MADs at 24 months CTX -176 ng/L [-275 to -76], p < 0.001; P1NP -18 mg/L [-32 to -5], p < 0.001). These findings suggest that a single dose of zoledronic acid over 2 years is ineffective in preventing the unbalanced bone remodeling and severe microstructural deterioration associated with ADT therapy. © 2020 American Society for Bone and Mineral Research.

Assessment and management of bone health in women with oestrogen receptor-positive breast cancer receiving endocrine therapy: position statement summary.

INTRODUCTION: Representatives appointed by relevant Australian medical societies used a systematic approach for adaptation of guidelines (ADAPTE) to formulate clinical consensus recommendations on assessment and management of bone health in women with oestrogen receptor-positive early breast cancer receiving endocrine therapy. The current evidence suggests that women receiving adjuvant aromatase inhibitors and pre-menopausal woman treated with tamoxifen have accelerated bone loss and that women receiving adjuvant aromatase inhibitors have increased fracture risk. Both bisphosphonates and denosumab prevent bone loss; additionally, denosumab has proven anti-fracture benefit in post-menopausal women receiving aromatase inhibitors for hormone receptor-positive breast cancer. MAIN RECOMMENDATIONS: Women considering endocrine therapy need fracture risk assessment, including clinical risk factors, biochemistry and bone mineral density measurement, with monitoring based on risk factors. Weight-bearing exercise and vitamin D and calcium sufficiency are recommended routinely. Anti-resorptive treatment is indicated in women with prevalent or incident clinical or morphometric fragility fractures, and should be considered in women with a T score (or Z score in women aged < 50 years) of < - 2.0 at any site, or if annual bone loss is ≥ 5%, considering baseline bone mineral density and other fracture risk factors. Duration of anti-resorptive treatment can be individualised based on absolute fracture risk. Relative to their skeletal benefits, risks of adverse events with anti-resorptive treatments are low. CHANGES IN MANAGEMENT AS RESULT OF THE POSITION STATEMENT: Skeletal health should be considered in the decision-making process regarding choice and duration of endocrine therapy. Before and during endocrine therapy, skeletal health should be assessed regularly, optimised by non-pharmacological intervention and, where indicated, anti-resorptive treatment, in an individualised, multidisciplinary approach.

The effects of adjuvant endocrine therapy on bone health in women with breast cancer.

In women with oestrogen receptor (ER)-positive early breast cancer, oestradiol is important for breast cancer development and progression. Endocrine therapy prevents the deleterious effects of oestradiol in breast tissue by systemically depleting oestradiol concentration (aromatase inhibitors) or preventing its local action in breast tissue (selective oestrogen receptor modulators i.e. tamoxifen), thereby improving oncological outcomes. Use of aromatase inhibitors in postmenopausal women and ovarian function suppression with either tamoxifen or aromatase inhibition in premenopausal women, consequent to systemic oestradiol depletion, exerts detrimental effects on skeletal health. The oestradiol-deficient state causes increased bone remodelling and a negative bone balance. This results in bone loss, microstructural deterioration and bone fragility predisposing to fractures. Similar effects are also seen with tamoxifen in premenopausal women. In contrast, use of tamoxifen in postmenopausal women appears to exert protective effects on bone but studies on fracture risk are inconclusive. The longevity of women with ER-positive breast cancer treated with adjuvant endocrine therapy emphasises the need to mitigate the adverse skeletal effects of these therapies in order to maximise benefit. In general, fractures are associated with increased morbidity, mortality and are a high socioeconomic burden. Whilst the efficacy of antiresorptive therapy in preventing bone mineral density loss in postmenopausal women has been established, further clinical trial evidence is required to provide guidance regarding fracture risk reduction, when to initiate and stop treatment, choice of agent and optimal management of bone health in premenopausal women receiving endocrine therapy. In addition, potential oncological benefits of antiresorptive therapies will also need to be considered.

Assessment and management of bone health in women with oestrogen receptor-positive breast cancer receiving endocrine therapy: Position statement of the Endocrine Society of Australia, the Australian and New Zealand Bone & Mineral Society, the Australasian Menopause Society and the Clinical Oncology Society of Australia.

To formulate clinical consensus recommendations on bone health assessment and management of women with oestrogen receptor-positive early breast cancer receiving endocrine therapy, representatives appointed by relevant Australian Medical Societies used a systematic approach for adaptation of guidelines (ADAPTE) to derive an evidence-informed position statement addressing 5 key questions. Women receiving adjuvant aromatase inhibitors and the subset of premenopausal woman treated with tamoxifen have accelerated bone loss and increased fracture risk. Both bisphosphonates and denosumab prevent bone loss; additionally, denosumab has proven antifracture benefit. Women considering endocrine therapy need fracture risk assessment, including clinical risk factors, biochemistry and bone mineral density (BMD) measurement, with monitoring based on risk factors. Weight-bearing exercise, vitamin D and calcium sufficiency are recommended routinely. Antiresorptive treatment should be considered in women with prevalent or incident clinical or morphometric fractures, a T-score (or Z-scores in women <50 years) of <-2.0 at any site, or if annual bone loss is ≥5%, considering baseline BMD and other fracture risk factors. Duration of antiresorptive treatment can be individualized based on absolute fracture risk. Relative to their skeletal benefits, risks of adverse events with antiresorptive treatments are low. Skeletal health should be considered in the decision-making process regarding choice and duration of endocrine therapy. Before and during endocrine therapy, skeletal health should be assessed regularly, optimized by nonpharmacological intervention and where indicated antiresorptive treatment, in an individualized, multidisciplinary approach. Clinical trials are needed to better delineate long-term fracture risks of adjuvant endocrine therapy and to determine the efficacy of interventions designed to minimize these risks.

Effects of androgen deprivation therapy on telomere length.

OBJECTIVE: Recent evidence suggests that androgens either directly or via aromatisation to oestradiol may regulate telomere length, hence providing a mechanism whereby reproductive steroids are linked to biological ageing in men. Using men with prostate cancer initiating androgen deprivation therapy (ADT), we tested the hypothesis that severe sex steroid deprivation would accelerate telomere shortening. DESIGN: We conducted a secondary analysis of a 2-year prospective controlled study among 65 men with nonmetastatic prostate cancer newly commencing adjuvant ADT (n=40) and age- and radiotherapy-matched prostate cancer controls (n=25). METHODS: We measured leucocyte telomere length (LTL) expressed as telomeric/single copy control gene (T/S) ratio at baseline, 6, 12 and 24 months. Generalized linear models determined the mean adjusted difference (MAD) (95% confidence interval) between groups during follow-up. RESULTS: Compared to controls over 24 months, men receiving ADT had no change in LTL, MAD for T/S ratio (0.105 [-0.004; 0.213], P=.235). CONCLUSIONS: Using men with prostate cancer receiving ADT as a model we found no evidence that prolonged and profound sex steroid deprivation is associated with accelerated telomere shortening. Larger studies will be required to confirm or refute these findings.

A Perspective on Middle-Aged and Older Men With Functional Hypogonadism: Focus on Holistic Management.

Context: Middle-aged and older men (≥50 years), especially those who are obese and suffer from comorbidities, not uncommonly present with clinical features consistent with androgen deficiency and modestly reduced testosterone levels. Commonly, such men do not demonstrate anatomical hypothalamic-pituitary-testicular axis pathology but have functional hypogonadism that is potentially reversible. Evidence Acquisition: Literature review from 1970 to October 2016. Evidence Synthesis: Although definitive randomized controlled trials are lacking, evidence suggests that in such men, lifestyle measures to achieve weight loss and optimization of comorbidities, including discontinuation of offending medications, lead to clinical improvement and a modest increase in testosterone. Also, androgen deficiency-like symptoms and end-organ deficits respond to targeted treatments (such as phosphodiesterase-5 inhibitors for erectile dysfunction) without evidence that hypogonadal men are refractory. Unfortunately, lifestyle interventions remain difficult and may be insufficient even if successful. Testosterone therapy should be considered primarily for men who have significant clinical features of androgen deficiency and unequivocally low testosterone levels. Testosterone should be initiated either concomitantly with a trial of lifestyle measures, or after such a trial fails, after a tailored diagnostic work-up, exclusion of contraindications, and appropriate counseling. Conclusions: There is modest evidence that functional hypogonadism responds to lifestyle measures and optimization of comorbidities. If achievable, these interventions may have demonstrable health benefits beyond the potential for increasing testosterone levels. Therefore, treatment of underlying causes of functional hypogonadism and of symptoms should be used either as an initial or adjunctive approach to testosterone therapy.

Hypothyroidism.

BACKGROUND: Hypothyroidism is a common endocrine disorder that mainly affects women and the elderly. OBJECTIVE: This article outlines the aetiology, clinical features, investigation and management of hypothyroidism. DISCUSSION: In the Western world, hypothyroidism is most commonly caused by autoimmune chronic lymphocytic thyroiditis. The initial screening for suspected hypothyroidism is thyroid stimulating hormone (TSH). A thyroid peroxidase antibody assay is the only test required to confirm the diagnosis of autoimmune thyroiditis. Thyroid ultrasonography is only indicated if there is a concern regarding structural thyroid abnormalities. Thyroid radionucleotide scanning has no role in the work-up for hypothyroidism. Treatment is with thyroxine replacement (1.6 µg/kg lean body weight daily). Poor response to treatment may indicate poor compliance, drug interactions or impaired absorption. The significance of elevated TSH associated with thyroid hormones within normal range is controversial; thyroxine replacement may be beneficial in some cases. Unless contraindicated, iodine supplementation should be prescribed routinely in women planning a pregnancy. Where raised TSH levels are detected periconceptually or during pregnancy, specialist involvement should be sought.

Management of side effects of androgen deprivation therapy.

Androgen deprivation therapy (ADT) is a major component of the contemporary management of prostate cancer. ADT's use is increasing rapidly. The side effects of this therapy include loss of bone mass and fractures, increase in fat mass, and worsening of insulin resistance, the metabolic syndrome, diabetes and cardiovascular risk, and anemia and loss of muscle. Neuropsychological and sexual symptoms are common. The impact of these side effects is often overlooked or underestimated in decisions about prostate cancer therapy. This review surveys the data relating to the side effects of ADT and provides recommendations regarding their minimization and management.