Testosterone Restores Body Composition, Bone Mass, and Bone Strength Following Early Puberty Suppression in a Mouse Model Mimicking the Clinical Strategy in Trans Boys.

Transgender youth increasingly present at pediatric gender services. Some of them receive long-term puberty suppression with gonadotropin-releasing hormone analogues (GnRHa) before starting gender-affirming hormones (GAH). The impact of GnRHa use started in early puberty on bone composition and bone mass accrual is unexplored. It is furthermore unclear whether subsequent GAH fully restore GnRHa effects and whether the timing of GAH introduction matters. To answer these questions, we developed a mouse model mimicking the clinical strategy applied in trans boys. Prepubertal 4-week-old female mice were treated with GnRHa alone or with GnRHa supplemented with testosterone (T) from 6 weeks (early puberty) or 8 weeks (late puberty) onward. Outcomes were analyzed at 16 weeks and compared with untreated mice of both sexes. GnRHa markedly increased total body fat mass, decreased lean body mass, and had a modest negative impact on grip strength. Both early and late T administration shaped body composition to adult male levels, whereas grip strength was restored to female values. GnRHa-treated animals showed lower trabecular bone volume and reduced cortical bone mass and strength. These changes were reversed by T to female levels (cortical bone mass and strength) irrespective of the time of administration or even fully up to adult male control values (trabecular parameters) in case of earlier T start. The lower bone mass in GnRHa-treated mice was associated with increased bone marrow adiposity, also reversed by T. In conclusion, prolonged GnRHa use started in prepubertal female mice modifies body composition toward more fat and less lean mass and impairs bone mass acquisition and strength. Subsequent T administration counteracts GnRHa impact on these parameters, shaping body composition and trabecular parameters to male values while restoring cortical bone architecture and strength up to female but not male control levels. These findings could help guide clinical strategies in transgender care. © 2023 American Society for Bone and Mineral Research (ASBMR).

Calcifediol (25OH Vitamin D3) Deficiency: A Risk Factor from Early to Old Age.

Vitamin D deficiency is the main cause of nutritional rickets in children and osteomalacia in adults. There is consensus that nutritional access to vitamin D can be estimated by measuring serum concentrations of 25OHD and vitamin D deficiency can thus be considered as calcifediol deficiency. However, the threshold for vitamin D/calcifediol sufficiency remains a matter of debate. Vitamin D/calcifediol deficiency has been associated with musculoskeletal effects but also multiple adverse extra-skeletal consequences. If these consequences improve or if they can be treated with vitamin D supplementation is still unclear. Observational studies suggest a higher infection risk in people with low calcifediol levels. There is also a consistent association between serum calcifediol and cardiovascular events and deaths, but large-scale, long-term intervention studies did not show any benefit on cardiovascular outcomes from supplementation, at least not in subjects without clear vitamin D deficiency. Cancer risk also did not change with vitamin D treatment, although there are some data that higher serum calcifediol is associated with longer survival in cancer patients. In pregnant women, vitamin D supplementation decreases the risk of pre-eclampsia, gestational diabetes mellitus, and low birth weight. Although preclinical studies showed that the vitamin D endocrine system plays a role in certain neural cells as well as brain structure and function, there is no evidence to support a beneficial effect of vitamin D in neurodegenerative diseases. Vitamin D supplementation may marginally affect overall mortality risk especially in elderly subjects with low serum calcifediol concentrations.

Testosterone Reduces Body Fat in Male Mice by Stimulation of Physical Activity Via Extrahypothalamic ERα Signaling.

Testosterone (T) reduces male fat mass, but the underlying mechanisms remain elusive, limiting its clinical relevance in hypogonadism-associated obesity. Here, we subjected chemically castrated high-fat diet-induced adult obese male mice to supplementation with T or the nonaromatizable androgen dihydrotestosterone (DHT) for 20 weeks. Both hormones increased lean mass, thereby indirectly increasing oxygen consumption and energy expenditure. In addition, T but not DHT decreased fat mass and increased ambulatory activity, indicating a role for aromatization into estrogens. Investigation of the pattern of aromatase expression in various murine tissues revealed the absence of Cyp19a1 expression in adipose tissue while high levels were observed in brain and gonads. In obese hypogonadal male mice with extrahypothalamic neuronal estrogen receptor alpha deletion (N-ERαKO), T still increased lean mass but was unable to decrease fat mass. The stimulatory effect of T on ambulatory activity was also abolished in N-ERαKO males. In conclusion, our work demonstrates that the fat-burning action of T is dependent on aromatization into estrogens and is at least partially mediated by the stimulation of physical activity via extrahypothalamic ERα signaling. In contrast, the increase in lean mass upon T supplementation is mediated through the androgen receptor and indirectly leads to an increase in energy expenditure, which might also contribute to the fat-burning effects of T.

Treatment of Men with Central Hypogonadism: Alternatives for Testosterone Replacement Therapy.

Central hypogonadism is a clinical condition, characterized by sexual symptoms and low serum testosterone levels, due to an impaired function of the hypothalamus or pituitary gland. Testosterone replacement therapy (TRT) is the standard treatment for hypogonadism, but it has some disadvantages. TRT is not a good option in men wishing to preserve fertility, nor in men with (a high risk of) prostate cancer, polycythemia, thrombophilia and severe cardiovascular disease. In this review, we discuss alternative treatments for central hypogonadism. If reversible causes are present, non-pharmacological interventions can be therapeutic. Gonadotropins are a good alternative to TRT when fertility is desired in the near future though they require frequent injections. Clomiphene citrate and tamoxifen seem to be a safe alternative for the treatment of functional central hypogonadism in men, as several studies reported a significant increase in testosterone levels with these drugs. However, their use is off-label and data supporting the efficacy of clomiphene citrate and tamoxifen on hypogonadal symptoms are insufficient. For this reason, clomiphene citrate and tamoxifen should not be used in routine clinical practice to treat sexual symptoms in men with central hypogonadism.

Aromatase inhibitors and selective estrogen receptor modulators: Unconventional therapies for functional hypogonadism?

INTRODUCTION: Functional hypogonadism increases in prevalence due to aging as well as an overall increase of obesity. Aromatase inhibitors (AIs) and selective estrogen receptor modulators (SERMs) could be an alternative for testosterone replacement therapy (TRT), but have not yet been established as common clinical practice. METHODS: We conducted a thorough search of the literature published between 2009 and 2018. Only RCTs published in English were included. We assessed the impact of AIs and SERMs on gonadal steroids, sexual function and semen parameters, body composition and glucose homeostasis, physical function, bone mineral density (BMD), anemia, as well as potential adverse effects. RESULTS: Twelve RCTs were included, with a total number of 645 patients. A total of 145 men were included in RCTs comparing AIs versus placebo or TRT and 476 men in RCTs with SERMs versus placebo or TRT. One RCT compared AIs versus SERMs in 24 men. Inclusion criteria were heterogenic. Most studies only included a small number of patients (range 11-256) and follow-up time was relatively short (6 weeks to 12 months). AIs as well as SERMs increased serum testosterone levels. Overall, there was no effect on sexual symptoms nor on semen parameters. Following aromatase inhibition, only minimal improvement of body composition and physical function was observed in some of the trials, but spinal BMD decreased. SERMs only induced a small improvement in body composition. The effect of SERMs on physical function and on BMD was not assessed. No major adverse effects occurred. CONCLUSION: AIs are not recommended as treatment for functional hypogonadism because of insufficient efficacy as well as a decrease in BMD. SERMs might be an alternative for TRT, but more research is needed to evaluate their effect on hypogonadal signs and symptoms, as well as on their long-term safety profile.

Nutritional rickets: Historic overview and plan for worldwide eradication.

Rickets was first described in great detail in the mid 17th century and was affecting a great number of children in major European cities. The disease, however, existed already in the Roman times. The etiology of this disease remained enigmatic until the 1920s when two different mechanisms, lack of exposure to sunlight and lack of a dietary factor were finally solved by the discovery of vitamin D and its dual origin. Soon thereafter, the implementation of vitamin D supplementation for all infants and small children largely eliminated nutritional rickets in Europe and North America. It took nearly a century to elucidate the complex chemistry, metabolism, mode and spectrum of activity of the vitamin D endocrine system. Nutritional rickets, whether due to simple vitamin D or calcium deficiency or both, remains widely ravaging many infants and children around the world. Asian countries and the Middle East are mainly confronted with vitamin D deficiency whereas many African and some Asian countries face calcium deficiency rickets. Immigrants and refugees or in general people with a darker skin living in moderate climate zone are also confronted with this disease. There is great consensus how this disease could be prevented or cured. In collaboration with most international professional societies, we prepare a memorandum, in line with the successful battle against iodine deficiency disorders, to convince the World Health Organization and its member states to start an implementation program to eradicate nutritional rickets by 2030.