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Summary of research on the effects of castration (GDX) and sex steroid manipulations on cell survival and proliferation in the dentate gyrus of male rodents relative to relevant control groups. Numerous experiments, involving a wide range of testosterone doses, have also demonstrated that testosterone replacement or supplementation have no effect on cell proliferation in the dentate gyrus of castrated or intact adult male rodents 93,94,95,96,97,98. Among adult male rats, castration had no effect on cell proliferation within the dentate gyrus but caused a significant decrease in the survival of new neurons, as measured 24–30 days after BrdU injection 88,89. However, a more recent field study demonstrated that cell proliferation and neurogenesis decline in both male and female voles during the breeding season relative to the non-breeding season . In contrast, reproductively active and reproductively inactive males did not differ in the amount of cell proliferation occurring within the dentate gyrus 85,87, suggesting that seasonal fluctuations in androgens may enhance cell survival but not cell proliferation. Summary of research on the effects of castration (GDX) and sex steroid manipulations on cell survival and proliferation in the subventricular zone and olfactory bulbs of male rodents relative to relevant control groups.
The effects of sex steroids upon the brain are commonly divided into early developmental effects (organizational) and effects that occur in the adult brain (activational). Additionally, a number of studies have shown that performance on a variety of spatial memory tasks results in increased adult neurogenesis. There is, however, considerable evidence that estradiol regulates hippocampal neurogenesis in females , demonstrating a clear sex difference in the regulation of adult neurogenesis by sex steroids. It is therefore unlikely that the effects of testosterone upon neurogenesis in male rodents involve an estrogen-dependent pathway. Thus, there is some evidence that acute doses of estradiol increase cell proliferation and possibly early neuronal development, but these effects do not correspond with the timing of the neurogenesis-enhancing effects of prolonged testosterone exposure.
Additional larger and longer-term randomized studies are necessary to further investigate the effects of combination therapy in individuals with muscular dystrophy. In the investigator-initiated, single-center, single-arm, proof-of-concept study, rHGH combined with testosterone (combination therapy) was found to be safe and well tolerated in a well-defined sample of participants with FSHD. In addition, laboratory study response (e.g., increases in IGF-1 levels and testosterone levels) was serially monitored as a marker of study medication compliance. Thyroid studies, fasting insulin levels, creatine kinase, C-reactive protein, luteinizing hormone, and follicle stimulating hormone levels were also monitored throughout the study. Elevations of IGF-1 higher than 400 ng/mL, total testosterone levels higher than 1,100 ng/dL, or a hematocrit level ≥54% were predetermined as criteria for mandatory study drug dosage reduction.
Similarly, exposure to either testosterone or estradiol had no effect on cell proliferation of mouse SVZ cells grown in culture . However, there is no sex difference in hippocampus size or caching behavior in chickadees and so it seems unlikely that sex steroids regulate seasonal changes in hippocampal neurogenesis in this species. Specifically, Alvarez-Buylla and Kim (1997) noted that pyknosis within the HVC is highest during periods of seasonal decline in testosterone, and they suggested that low testosterone induces cell death, providing vacancies for newly proliferated cells to grow into. Estradiol acts through two known intracellular receptors (ERα and ERβ) to have genomic effects as well as through a G-protein coupled receptor (GPER) to have more rapid non-genomic effects . DHT has been shown to have an approximately two-fold higher binding affinity to androgen receptors and a five-fold slower dissociation constant from these receptors compared to testosterone .
This is postulated to contribute to the higher incidence of certain neurodevelopmental disorders as well as increased aggressive behaviors and diminished executive functioning in males with ASD as compared to females. Research has indicated individuals with autism spectrum disorder (ASD) have elevated androgen levels when compared to their peers. Thus, it is hypothesized that androgens negatively impact cognitive functions regulated through these structures . Although the exact location and function of ARs in the adult brain remain under investigation, animal models have demonstrated the presence of ARs at multiple CNS locations. These hormones not only play an important role in the development of secondary sexual characteristics and fertility but are increasingly recognized for their role in the development and function of the CNS.
Both testosterone and DHT bind to an androgen receptor; however, DHT has a stronger binding affinity than testosterone and may have more androgenic effect in certain tissues at lower levels. In general, androgens such as testosterone promote protein synthesis and thus growth of tissues with androgen receptors. Insufficient levels of testosterone in men may lead to abnormalities including frailty, accumulation of adipose fat tissue within the body, anxiety and depression, sexual performance issues, and bone loss. Some evidence indicates that BDNF is activated by androgens, but there is currently little evidence that testosterone upregulates BDNF in the dentate gyrus through a direct pathway. This enhanced survival involves an androgen-dependent pathway in males, distinct from the estrogen-dependent pathway that can increase or decrease neurogenesis in females. The experiments summarized here clearly demonstrate that testosterone influences adult neurogenesis, as specifically demonstrated within the HVC of birds and within the olfactory bulbs and dentate gyrus of rodents. However, testosterone replacement had no effect on a stress-induced decrease in cell proliferation or the number of DCX-expressing cells in the dentate gyrus among male mice .
Testosterone is a naturally occurring androgen that is produced in both men and women. Participants experienced improvements in ambulation, strength, muscle mass, and disease burden after receiving this study intervention. As such, combination therapy has the potential to limit disease progression and functional decline in individuals with muscular dystrophy. 5α-Reductase is highly expressed in the male reproductive organs (including the prostate gland, seminal vesicles, and epididymides), skin, hair follicles, and brain and aromatase is highly expressed in adipose tissue, bone, and the brain. Approximately 5 to 7% of testosterone is converted by 5α-reductase into 5α-DHT, with circulating levels of 5α-DHT about 10% of those of testosterone, and approximately 0.3% of testosterone is converted into estradiol by aromatase. Finally, increasing levels of testosterone through a negative feedback loop act on the hypothalamus and pituitary to inhibit the release of GnRH and FSH/LH, respectively. When testosterone levels are low, gonadotropin-releasing hormone (GnRH) is released by the hypothalamus, which in turn stimulates the pituitary gland to release FSH and LH.
In women, correlations may exist between positive orgasm experience and testosterone levels. Current clinical guidelines recommend comprehensive baseline evaluation including complete blood count, lipid panel, prostate-specific antigen, and cardiovascular risk assessment before initiating testosterone replacement therapy. Serious side effects may include liver toxicity, heart disease (though a randomized trial found no evidence of major adverse cardiac events compared to placebo in men with low testosterone), and behavioral changes. Common side effects from testosterone medication include acne, swelling, and breast enlargement in males. Decline of testosterone production with age has led to interest in androgen replacement therapy. This is known as hormone replacement therapy (HRT) or testosterone replacement therapy (TRT), which maintains serum testosterone levels in the normal range. In androgen-deficient men with concomitant autoimmune thyroiditis, substitution therapy with testosterone leads to a decrease in thyroid autoantibody titres and an increase in thyroid's secretory capacity (SPINA-GT).
In this study, we report the findings of a 36-week single-arm Study of Testosterone and rHGH in FSHD (STARFiSH). Facioscapulohumeral muscular dystrophy (FSHD) is the second most common form of adult-onset muscular dystrophy in the world.1,2 Clinically, FSHD is characterized by progressive weakness and atrophy of the face, shoulders, arms, and hip girdle muscles; impaired ambulation; and functional impairment related to muscle weakness. Combination therapy was safe and well tolerated in men with FSHD. The most common adverse event was mild injection site reaction at the rHGH and/or testosterone injection site. Nineteen of 20 participants completed the study, with no participants experiencing a serious adverse event. Participants were also evaluated for changes from baseline in lean body mass (LBM) and fat mass, measured by dual-energy X-ray absorptiometry; ambulation, measured by 6-minute walk distance; strength; clinical function, measured using the FSHD-Composite Outcome Measure (FSHD-COM); and patient-reported disease burden, measured by the FSHD Health Index (FSHD-HI). - http://35.207.205.18:3000/nellefortin98
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