Research has investigated testosterone and its role in biological and psychological functioning. Testosterone levels decrease as men age, and aging has been associated with declines in muscle mass and strength. Decreased functional mobility can impact quality of life. Aging has also been associated with increased vulnerability to depressive symptomatology. The purpose of this study was to investigate interrelationships among testosterone, physical functioning, quality of life, and depression in the Vietnam Era Twin Study of Aging (VETSA). The mean age of the 1,237 men in VETSA was 55.4 (+2.5). Testosterone data collection began in the third year of VETSA, yielding an available sample of 778. It was hypothesized that there would be significant associations between testosterone and physical functioning, depression, and quality of life as well as between physical functioning and depression and quality of life. Contrary to expectations, when mixed models for linear regression were used, testosterone was shown to be related only to physical functioning. As predicted, however, physical functioning was significantly related to depression and quality of life. Cholesky decompositions were conducted to address the hypothesis that there were shared genetic determinants of each phenotype. Best fitting bivariate models included additive genetic and unique environmental but not common environmental influences. Significant genetic correlations were found between physical functioning and depression, and physical functioning and the mental health component score of the Short Form Health Survey (SF-36). Contrary to expectations, while testosterone and physical functioning were significantly correlated with each other phenotypically, there was no genetic correlation between the two. Trivariate models revealed genetic influences specific to depression as well as genetic influences shared with quality of life and depression. Finally, path analysis demonstrated that testosterone had a direct impact on physical functioning. Physical functioning, but not testosterone, directly impacted depression and quality of life. As there was no genetic correlation between testosterone and physical functioning, but there was a phenotypic correlation, it may be that other factors, such as cortisol, influenced the association. In sum, in this sample, physical functioning seemed to be more important than testosterone to both depressive symptomatology and quality of life.

To determine if known androgenic hormone precursors for testosterone in the androgen pathway would be readily transformed to testosterone, eight male subjects [mean age 23.8 (SEM 3) years, bodymass 83.1 (SEM 8.7) kg, height 175.6 (SEM 8.5) cm] underwent a randomized, double-blind, cross-over, placebo-controlled oral treatment with 200 mg of 4-androstene-3,17-dione (Δ4), 4-androstene-3β,17β-diol (Δ4Diol), and placebo (PL). The periods of study were separated by 7 days of washout. Blood was drawn at baseline and subsequently every 30 min for 90 min after treatment. Analysis revealed mean area-under-the-curve (AUC) serum Δ4 concentrations to be higher during Δ4 treatment [2177 (SEM 100) nmol.l-1] than Δ4Diol [900 (SEM 96) nmol.l-1] or PL [484 (SEM 82) nmol.l-1; P < 0.0001]. The Δ4 treatment also revealed a significant effect on total testosterone with a mean AUC [1632.5 (SEM 121) nmol.l-1] that was greater than PL [1418.5 (SEM 131) nmol.l-1; P < 0.05] but not significantly different from those observed after Δ4Diol treatment [1602.9 (SEM 119) nmol.l-1; P = 0.77]. Free testosterone concentrations followed a similar pattern where mean AUC for the Δ4 treatment [6114.0 (SEM 600) pmol.l-1] was greater than after PL [4974.6 (SEM 565) pmol.l-1; P < 0.06] but not significantly different from those observed after Δ4Diol [5632.0 (SEM 389) pmol.l-1; P = 0.48]. The appearance and apparent conversion to total and free testosterone over 90 min was stronger for the Δ4 treatment (r = 0.91, P < 0.045) than for Δ4Diol treatment (r = 0.69, NS) and negatively correlated for PL (r = -0.90, P < 0.02). These results would suggest that Δ4, and perhaps Δ4Diol, taken by month are capable of producing in vivo increases in testosterone concentrations in apparently healthy young men as has already been observed in women after treatment with Δ4.

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This study examined effects of carbohydrate (C), carbohydrate-protein (CP), or placebo (P) beverages following eccentric resistance exercise on muscle damage by serum creatine kinase (CK), muscle protein breakdown by urinary 3-methylhistidine (3MH), muscle soreness, isokinetic muscle strength, muscle glycogen resynthesis, and serum hormones. Untrained males (N=26) underwent a 9-day controlled meat-free diet and 24 hr urine collections. To reduce glycogen, subjects cycled for 40 min at 70% of VO_2peakfollowed by 5 cycling sprints on day 4 evening. On day 5, fasted subjects performed 100 eccentric leg flexions at 120% of 1-RM and drank C (n=8, 1.25 g C/kg), CP (n=9, 0.875 g C/kg, 0.375 g protein/kg), or P (n=9) beverages immediate post-exercise (IPE) and 2 hr later. Muscle biopsies were taken IPE on day 5, and days 6 and 8 mornings. Blood was obtained days 4-10 fasted plus IPE, 3 hr, and 6 hr post-exercise on day 5. At 3 hr on day 5, insulin was higher for CP (24.6 ( 15.5 &amp;#181;IU/ml) and C (17.2 +/- 10.9 &amp;#181;IU/ml) than P (5.3 +/- 0.4 &amp;#181;IU/ml, p<.05). Glycogen was low on day 5, partially recovered on day 6, and normal by day 8 (p<.01) with no difference among groups. Isokinetic quadriceps peak torque at 60^o/s decreased 24% on day 6 and remained depressed by 21% on d 8 (p<.01) for all groups. Soreness peaked on day 7 and CK on day 8 (p<.01) with no differences by group. CK increased (p<.01) over day 5 (delta CP 24.6 +/- 19.1, delta P 39.2 +/- 71.6, delta C 70.8 +/- 60.4 U/L) and was highest for C (p<.05). On day 5, CP had lowest 3MH (193.0 +/- 13.8 &amp;#181;mol/d) versus C (251.1 +/- 22.5 &amp;#181;mol/d, p<.05). Testosterone at 3 hr on day 5 was lower for C (4.2 +/- 0.3 ng/ml) and CP (4.3 +/- 0.3 ng/ml) versus P (5.1 +/- 0.2 ng/ml, p<.05). In summary, glycogen, muscle strength and soreness were unaffected by beverage. However, a CP beverage may be beneficial for reducing muscle damage and protein breakdown on the day of eccentric resistance exercise. / Ph. D.

The side effects of testosterone for transgender men are often overlooked and under-researched. Urinary incontinence in the form of overactive bladder disorder, stress incontinence, and mixed incontinence may arise or be exacerbated by use of testosterone. Using menopause and other similar hormonal transitions such as pregnancy as a reference, the purpose of this thesis is to fully understand the effects of testosterone replacement therapy on transgender people assigned female at birth, and to fully understand the effect of testosterone replacement therapy on the pelvic floor and why there is a potential increased incidence of urinary incontinence. Menopause and pregnancy are used as reference because these are hormonal transitions associated with a decrease in estrogen levels. The decrease in estrogen causes a looseness in the connective tissue structures, which leads to a lack of support in the pelvic floor muscles, causing a urinary incontinence. With a comparison between menopause, pregnancy, and testosterone replacement therapy established, potential solutions to stress urinary incontinence and overactive bladder disorder will be explored.

For many years, the role of testosterone has been perceived to play a role in the development of prostate cancer and certain cardiovascular diseases (Jones et al., 2013); with its general therapeutic roles being much overlooked. Much of this unprecedented assumption was based upon clinical observations showing the benefit of androgen deprivation in prostate cancer patients, and the perceived reports of higher cardiovascular death amongst people abusing steroid therapies (Jones et al., 2013; Basaria et al., 2010). However, there has been compelling evidence that suggests that testosterone administration within physiological ranges does not contribute to prostate cancer or the pathogenesis of cardiovascular disease (Morgentaler et al., 2009; Jones et al., 2013; Traish et al., 2009). Recent evidence actually suggests the protective role of androgens in the management of metabolic conditions, such as: obesity, metabolic syndrome, and type-2 diabetes mellitus, all of which are known to increase the risk of cardiovascular disease (Traish et al., 2009; Morgentaler et al., 2009; Wang et al., 2000). Erectile dysfunction, which is a type of endothelial dysfunction disorder, is defined as the persistent inability to achieve or maintain an erection for satisfactory sexual performance, and it affects an estimated 30 million American men between the ages of 40 to 70 years old, and this prevalence increases with age (Nehra A, 2007; Barkin J, 2011; Guay A, 2007). The male human erection involves a multifactorial interplay between various mechanisms within the body; encompassing psychological, vascular, neural and endocrine factors (Dean et al., 2005; Castela et al, 2011). The human erection involves the increased inflow of blood into the penile arteries, and the subsequent veno-occlusion, all of which occurs at a perfectly orchestrated hormonal environment (Bivalacqua et al, 1998; Castela et al., 2011). Nitric oxide is released from the endothelium, which dilates penile arteries and relaxes the penile smooth muscles, causing the corpora cavernosa of the penis to fill with blood; the ischiocavernosus and bulbospongiosus muscles then compress the veins, which restricts the egress of blood (Bivalacqua et al, 1998; Castela et al., 2011). Nitric oxide increases cGMP, which decreases intracellular calcium uptake, and increases K+ efflux; these all cause a smooth muscle cell relaxation. The decreased venous outflow from the penis helps maintain erection. In addition to nitric oxide, several other mechanisms are involved in the erectile response. The endothelium, which regulates vascular tone and blood flow, is responsible for the cholinergic smooth muscle relaxation observed by the addition of acetylcholine (Furchgott et al., 1983). Chamness et al. (1995) have shown that androgen differentially affects nitric oxide synthase activity in the male reproductive tract endothelium. Thus, the role of androgens, namely testosterone, is of importance in maintaining erectile function. In addition to affecting nitric oxide synthase activity, testosterone is also shown to affect erectile physiology in many more ways, including its role in activating K+ channels to increase the efflux or inhibit calcium channels via hyperpolarization (Yildiz et al., 2009), and even increasing arterial blood flow to the penis (Aversa et al., 2000). Interestingly, testosterone also modulates endothelial function. Endothelial progenitor cells are responsible for the regeneration of the endothelium. The area of study of these progenitor cells is relatively new, thus, it is important to evaluate how they affect endothelial function. Since erectile dysfunction is a form of endothelial dysfunction, it has been found that patients with erectile dysfunction had significantly lower levels of circulating progenitor cells than patients with a normal erectile function (Baumhäkel et al., 2006). Endothelial cells in the penile arteries play a critical role in regulating the physiological function of the erectile response in humans. Modulation of the endothelium in the penis by androgens, thus, is a critical area of research that must be further addressed.

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<p> The present thesis reports an experiment that investigated the phenomenon of asymmetric paw elevation in the tripedal stance of the Mongolian gerbil, and tested the Geschwind-Galaburda extra-genetic theory of human handedness. Neonate gerbils of both sexes were injected with testosterone propionate during the "critical" period of brain development. They were then assessed for asymmetry in eye opening, for anogenital distance, and for paw elevation and scent marking before and after puberty. Eye opening asymmetry was not affected by treatment. Paw elevation was affected by treatment, with treated gerbils of both sexes displaying more right elevations before and after puberty than untreated gerbils. Control females displayed systematic patterns in paw elevation before and after puberty. Adult gerbils in all conditions displayed more consistency in paw elevation than young gerbils. Anogenital distance was increased with treatment, but only in the females. Adult scent marking behavior was marginally reduced with treatment, but only in the males. Results are interpreted within the Geschwind-Galaburda theory of handedness, and the hormonal basis of paw elevation is discussed. </p> / Thesis / Master of Science (MSc)

Resistance exercise training (RET) can lead to muscle hypertrophy; however, the relative contribution that exogenous (protein supplementation and specific training variables) versus endogenous (biology inherent to the individual) factors have on RET-induced muscle hypertrophy is controversial. In Study 1, we provided an evidence-based conclusion that protein supplementation during periods of RET results in a small but statistically significant increase in RET-induced muscle hypertrophy. In Study 2, we corroborate previous research and observed that the amount of mass lifted per repetition (load) did not determine RET-induced muscle hypertrophy in resistance-trained men when RET was performed to volitional fatigue. In Study 4, we observed similar muscle fibre activation following resistance exercise with lighter versus heavier loads when both were lifted until volitional fatigue. In Studies 2 and 3, we observed no relationship between circulating anabolic hormones (e.g., testosterone) and RET-induced muscle hypertrophy. Nonetheless, in Study 3, we found significantly greater muscle androgen receptor content in the top versus the bottom quintile of respondents for muscle hypertrophy following 12 weeks of RET indicating that androgen receptor content, and not circulating androgen concentration, may be an important determinant of hypertrophy. Finally, in Study 5, we observed that RET-induced muscle hypertrophy was an consistent within an individual (independent of load and limb) but considerably different between participants. Together, these data suggest that the exogenous factors we studied – protein supplementation and load (when RET was performed to volitional fatigue) – had a relatively small influence on RET-induced muscle hypertrophy. In contrast, we found that endogenous variables, such as intramuscular androgen receptor content and likely other genetic influences, appear to contribute more to the significant heterogeneity seen in RET-induced muscle hypertrophy. Future research in this area should prioritize understanding the biology that underpins the individual variability in RET-induced muscle hypertrophy. / Thesis / Doctor of Philosophy (PhD) / Resistance exercise training (RET) increases muscle size (hypertrophy); however, the relative influence that protein supplementation, specific training variables, and individual (genetic) variation have on the RET-induced hypertrophy is controversial and largely unknown. Broadly, data in this thesis show that protein supplementation slightly augments RET-induced hypertrophy, and that the magnitude of RET-induced hypertrophy may be related to the number of androgen (e.g., testosterone) receptors inside an individual’s muscle. In contrast, we found that neither load nor hormones affect RET-induced hypertrophy. Interestingly, data in this thesis also show that RET-induced hypertrophy is consistent within an individual but varies considerably between people, which illustrates the greater influence that individual variation has on RET-induced hypertrophy. We conclude that when RET is performed with a high degree of effort, protein supplementation and specific training variables confer a relatively small benefit on RET-induced hypertrophy compared to the influence of biological variability between people.