Archive for August, 2014

General Concepts

Androgens are defined by their ability to specifically bind to the androgen receptor. A number of androgens are present in men. Testosterone (T) is the dominant circulating androgen. It is synthesized primarily by the Leydig cells in the testis, with a small portion (5%) produced by the adrenals. The adrenals also produce dehydroepi­ androsterone (DHEA), and androstenedione.

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In men, approximately 40–68% of T circulates in the bloodstream loosely bound to albumin, approximately 30–60% is bound tightly to sex hormone-binding globulin (SHBG), and approximately 0.5–3% circulates unbound, termed free T. Bioavailable T consists of the free and albumin-bound fractions, since it appears that the tight binding of T to SHBG renders it biologically unavailable.

Testosterone’s effect may be direct, or mediated via local conversion to dihydrotestosterone (DHT) or estradiol. Testosterone is converted to DHT peripherally by the enzyme 5a-reductase, and to estradiol by the enzyme aromatase. Adrenal androgens may be converted to testosterone and to DHT in target tissues.

Androgens in Physiology and Pathophysiology of Erectile Dysfunction

In animals models there is strong evidence that the penile erectile response is androgen-dependent. Testosterone is directly involved in erectile physiology and pathophysiology, and may exert its effect on erection at various loci, including the central nervous system, peripheral nerves, penile vasculature, and structural components of the penis itself.

Testosterone in the Brain

There is evidence that testosterone may mediate the libido and erectile response via a central nervous mechanism. Androgen receptor-linked brain sites are present in the hypothalamus, pituitary gland and medial preoptic area (MPOA). In the lizard, used as a model for the primitive brain, castration eliminates the male sexual response, and direct implantation of T into the preoptic area and hypothalamus restored the full range of sexual behaviors, including mounting and successful erection, although circulating levels of T were undetectable. In the rat, direct electrical stimulation of MPOA induces an erection. Castration greatly attenuates this response, and testosterone substitution restores full erection with sildenafil citrate Australia.

The brain effect of androgens on the sexual response in men is demonstrated also by functional brain imaging. Men with TD showed decreased activation in regions of the brain that are typically activated in healthy controls and in androgendeficient men after testosterone replacement.

Curiously, erections associated with visual stimulation in men appear to be unaffected by TD, suggesting that these types of erections are largely androgenindependent.

Natural History

Contrary to popular belief, Peyronie’s disease is frequently a progressive disorder, as nearly half of untreated men have worsened curvature or increased plaque size. Among 246 men newly diagnosed with PD and followed for 1 year without treatment, 12% improved, 40% remained stable, and 48% worsened. Clinicians often separate the disease into an active and a quiescent phase based upon the clinical and diagnostic evaluation.

The quiescent, or chronic, phase is generally considered to be a time of disease stability without further progression in plaque size, penile deformity, or curvature. In contrast, the active phase is characterized by increasing plaque size or penile curvature and penile pain. While it may be true in many men that the active phase lasts from 12–18 months from the onset of disease, a significant proportion of men experience continued progression after this time point. Medical therapy in online Australia Pharmacy offers the promise of shortening the acute phase of disease by stabilizing the underlying penile lesion and minimizing progression of disease.

Etiology of Peyronie’s Disease

Inflammation is a characteristic finding within Peyronie’s plaques. Because of this finding, sources of inflammation, such as that resulting from penile injury, have been implicated as causal factors underlying the development of PD. These findings also underlie the search for anti-inflammatory treatments ed – viagra australia pills  (e.g., vitamin E) that may minimize inflammation and treat penile lesions. Further support for this hypothesis comes from pathologic studies that have demonstrated tunica albuginea scarring secondary to vascular inflammation between the tunica albuginea and the corpora cavernosa. Anatomically, an outer, longitudinally oriented layer of connective tissue overlies an inner, circularly oriented layer. Fibers from the inner layer radiate outward to serve as a support structure to reinforce the corporal septum. Insertions of these fibers may separate with minimal trauma leading to bleeding and inflammation.

If this model of trauma is indeed correct, why are younger men much less likely to develop PD, when they are more likely to have sex more often and more vigorously than older men? It has been suggested that in older men, even mild diminution of erectile rigidity may increase susceptibility to buckling forces. The subsequent trauma to the tunica albuginea may be more likely to result in injury given that an older man’s tissues are less elastic and more prone to disruption. Once a traumatic event has occurred, edema may limit the dispersion of cytokines and related inflammatory mediators, thus perpetuating the local injury. A combination of inflammation and less effective wound healing among some men may lead to fibrosis, a loss of elasticity, and excessive collagen deposition. PD lesions have a higher ratio of collagen type III to type I than in healthy tunica albuginea, a loss of elastic fibers, and increased fibrin deposits. Furthermore, early in the disease process, fibroblasts are found in greater concentration along with inflammatory cells. Calcified ossification of these lesions can occur in up to one-third of these cases. These pathophysiological factors may explain the initial pain experienced by many men with PD that is followed by subsequent penile deformity, curvature, and plaque.

In general, tunical plaques are found on the dorsal aspect of the penis; however, the abnormal tissue may extend beyond the palpable lesion, or even into the corporal tissue or intercavernosal septum. Among the minority of men with PD who do not have palpable plaques, penile ultrasound often demonstrates septal defects, intracorporal fibrosis, or subtunical calcifications. When the normally elastic tunica albuginea fibers are replaced by relatively non-compliant collagen rich tissue, this relative inelasticity and contracture of the tunica albuginea leads to decreased penile length/girth and ipsilateral penile deviation. Further, this inelasticity of the tunica albuginea may impede the normal vasoocclusive mechanism of erection and thus lead to venous leak. This hypothesis would provide an explanation for the erectile dysfunction treatment in Canadian pharmacy viagra seen in some men with PD.