Magister Scientiae (Medical Bioscience) - MSc(MBS) / Obesity is a growing public health concern globally, particularly in developed countries such as the United States (US). More than 30% of Americans are considered obese. In the past 20 years in America, incidence of obesity has increased significantly (Mokdad et al., 2003). As a consequence, the Centers for Disease Control (CDC) anticipates that 1 in 3 American adults will be diabetic by 2050 (Boyle et al., 2001; Hedley et al., 2004). The most important cause of obesity is poor nutrition, absence of physical exercise and unfavourable lifestyle changes (James et al., 2001).

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.

No / Peripheral intracrine sex steroid synthesis from adrenal precursors dehydroepiandrosterone (DHEA) and DHEA-sulfate has evolved in humans. We sought to establish if there are differences in intracrine, paracrine, and endocrine regulation of sex steroids by primary cultures of human skin epidermal keratinocytes and dermal fibroblasts. Microarray analysis identified multifunctional genes modulated by steroids, quantitative RT-PCR (qRT-PCR) mRNA expression, enzymatic assay aromatase activity, scratch assay cell migration, immunocytochemistry α-smooth muscle actin (α-SMA), and collagen gel fibroblast contraction. All steroidogenic components were present, although only keratinocytes expressed the organic anion organic anion transporter protein (OATP) 2B1 transporter. Both expressed the G-protein-coupled estrogen receptor (GPER1). Steroids modulated multifunctional genes, up-regulating genes important in repair and aging [angiopoietin-like 4 (ANGPTL4), chemokine (C-X-C motif) ligand 1 (CXCL1), lamin B1 (LMNB1), and thioredoxin interacting protein (TXNIP)]. DHEA-sulfate (DHEA-S), DHEA, and 17β-estradiol stimulated keratinocyte and fibroblast migration at early (4 h) and late (24–48 h) time points, suggesting involvement of genomic and nongenomic signaling. Migration was blocked by aromatase and steroid sulfatase (STS) inhibitors confirming intracrine synthesis to estrogen. Testosterone had little effect, implying it is not an intermediate. Steroids stimulated fibroblast contraction but not α-SMA expression. Mechanical wounding reduced fibroblast aromatase activity but increased keratinocyte activity, amplifying the bioavailability of intracellular estrogen. Cultured fibroblasts and keratinocytes provide a biologically relevant model system to investigate the complex pathways of sex steroid intracrinology in human skin.—Pomari, E., Valle, L. D., Pertile, P., Colombo, L., and Thornton, M. J. Intracrine sex steroid synthesis and signaling in human epidermal keratinocytes and dermal fibroblasts.

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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