Abdominal obesity and intra-abdominal pressure: a new paradigm for the pathogenesis of the hypogonadal-obesity-BPH-LUTS connection.

Abstract The pathogenesis of benign prostatic hyperplasia-lower urinary tract symptoms (BPH-LUTS) is complicated, multifactorial, and incompletely understood. A number of recent observations have provided for new insights and offer a better appreciation for, and the understanding of, the pathophysiological and hormonal contributions for the development and progression of prostatic enlargement. A major paradox has been the progressive increase in the prostate size at a time when the peripheral blood testosterone levels are decreasing as men age. This has been associated with the findings of increasing obesity-related states and the manifestation of BPH-LUTS. Several converging and new findings combine the mechanisms that result in an integration of the hypogonadal-obesity-increased intra-abdominal pressure (IAP)-BPH-LUTS connection. The net positive caloric balance results increased the IAP and damaged the one-way valves of the internal spermatic veins. This results in an increased venous back pressure that leads to the reflux of the high testicular testosterone concentrations and venous pressures that are transmitted to the communicating prostatic venous system. Simultaneously, increasing obesity results in an increased aromatase activity, which leads to a reduction of the testosterone levels. Consequently, there is also an increased estradiol production, which inhibits gonadotropin secretion and the production of testosterone. This hypogonadal obesity cycle eventually results in a progressive hypogonadal state, while the prostate continues to enlarge and produce increasing LUTS.

Benign prostatic hyperplasia: the hypogonadal-obesity-prostate connection.

Prostatic enlargement occurs over the course of a lifetime and is associated with many risk factors. Recent observations demonstrate that valvular damage, occurring in the internal spermatic veins results in increased hydrostatic pressures that lead to venous backflow. Two consequences of venous backflow are the prolonged exposure to hydrostatic pressure and high testosterone levels that effect the prostate directly. Furthermore, aging and obesity related states have long been associated with BPH and diminished testosterone concentrations, which by itself, predisposes and allows for the preferential deposition of abdominal/visceral fat. The increasing abdominal obesity leads to elevated intra-abdominal pressure, which over time, causes increased venous pressure. Chronically elevated intra-abdominal venous pressure eventually causes progressive failure of the one way valves in the internal spermatic veins and venous insufficiency that leads to prostate damage. All of these factors promote conditions that cause chronic progressive prostatic disease and eventually BPH.

The hypoandrogenic-anabolic deficiency state: endocrine and metabolic shifts in men.

In recent years there has been increased interest in and awareness of the consequences of the male hypogonadal state which frequently occurs as one component of the androgen deficiency complex. This is important as it allows for abnormal energy partitioning which adversely alters anabolism and the maintenance of cellular and tissue biological integrity. Accumulating evidence strongly suggests that over time all forms of diminished androgen availability, in males, leads to adverse metabolic shifts that direct energy control mechanisms towards a progressive dysfunctional anabolic state. It is now apparent that whenever hypotestosteronemia is detected other components of the androgen-anabolic deficiency complex should be evaluated. This relationship can best be viewed as the hypoandrogenic-anabolic deficiency triad: decreased gonadal, adrenal and somatotropic biosynthetic activity which requires separate evaluation of each axis. These combined deficits may provide part of the explanation for the inconsistent reports regarding the benefits of androgen and other replacement treatments. Furthermore, it suggests that these deficiencies may require simultaneous repair in order to achieve better metabolic response profiles.

Obesity in men: the hypogonadal-estrogen receptor relationship and its effect on glucose homeostasis.

Aromatase is important in men's health, obesity, the metabolic syndrome, type 2 diabetes and aging. In males with increasing obesity there is increased aromatase activity, which irreversibly converts testosterone to estradiol resulting in decreased testosterone and elevated estrogen levels. Since androgens reduce the expression of ER beta activity, decreased testosterone levels release the normally suppressed ER beta expression and results in the down regulation of GLUT4 with resultant insulin resistance. The increased estradiol concentrations influence both of the estrogen receptors, but specifically intensify the metabolic effects of ER beta because of its released suppression, a consequence of diminished testosterone concentrations. These dual actions then combine to amplify the mechanisms that lead to disordered glucose homeostasis and insulin resistance under these conditions. An appreciation of the relationships between the hormonal products of aromatase activity and their direct effects on the estrogen receptors focuses on potential innovative therapeutic interventions. These include aromatase inhibitors, which correct the dual consequences of hypotestosteronemia and hyperestrogenemia and eventually ER beta antagonists when they become available.

Estradiol induced inhibition of 11beta-hydroxysteroid dehydrogenase 1: an explanation for the postmenopausal hormone replacement therapy effects.

The adverse and beneficial effects of postmenopausal hormone replacement therapy include: ischemic heart disease, stroke, pulmonary embolism, breast cancer, an increased rate of onset of asthma as well as reductions in the incidence of diabetes in women with known coronary artery disease and osteoporotic fractures. These varied effects can be explained by the down regulation of 11beta-hydroxysteroid dehydrogenase by estradiol, which results in a reduction of tissue specific cortisol production. The reduction in local cortisol production which diminishes the endogenous anti-inflammatory effects, also allows for the progression of both vascular and pulmonary inflammation. The decrease in cortisol activation reduces insulin resistance and anti-proliferative effects thereby reducing the potential for diabetes but allowing for the emergence of malignancy. Furthermore, the decreased local tissue availability of cortisol reduces the tendency for the development of osteoporosis. New techniques and drugs are being developed to evaluate the modulation of 11beta-HSD1 activity. Further study should result in new ways to control both inflammation and metabolism.

Aromatase inhibition for the treatment of idiopathic hypogonadotropic hypogonadism in men with premature ejaculation.

BACKGROUND: Idiopathic hypogonadotropic hypogonadism (IHH) has been observed to occur in men with premature ejaculation (PE). Common IHH therapies include testosterone replacement, which increases testosterone levels but suppresses gonadotropin release; and gonadotropin-releasing hormone supplementation, which restores gonadotropin levels but is impractical for chronic use. Hormonal imbalances associated with IHH/PE are thought to be related to hyperactivity of the cytochrome P-450 enzyme aromatase. METHODS: Ten male patients with a diagnosis of IHH/PE were treated with the aromatase inhibitor anastrazole (1 mg/d orally). Levels of free and total testosterone, luteinizing hormone, follicle-stimulating hormone, prolactin, and estradiol were determined at baseline and after 2 weeks of therapy. RESULTS: After 2 weeks of therapy with anastrazole, levels of testosterone, luteinizing hormone, and estradiol had returned to normal. No effect was noted on premature ejaculation. CONCLUSION: These results suggest that aromatase inhibition with anastrazole may provide a practical and efficacious alternative for the treatment of IHH but is not effective in preventing premature ejaculation.