Urologic Endocrinology

Urology is a specialist discipline having both medical and surgical aspects. In recent years, a growing interest in medical urological diseases of mainly endocrinological origin has emerged. Within this context, age-related male hypogonadism is of paramount importance. Recent preclinical and clinical data has demonstrated the critical consequences of hypogonadism not only on sexual behavior, but also on the entire psychophysical health of men as testosterone regulates the functional properties of multiple body tissues.

The Testis

Normal Androgen Metabolism

Testosterone, mainly secreted by Leydig’s cells into the testes, is the major active sex hormone circulating in the blood of males. Its production is regulated by a negative feedback system involving a gonadotropin-releasing hormone (GnRH) and a luteinizing hormone (LH).1 Testes produce 0.24 mmol/day of testosterone. The adrenal cortex contributes to circulating androgen levels by producing 0.002 mmol/day of androgens, mainly as androstenedione. In males, testosterone secretion begins in fetal life with peak concentrations seen at 12 weeks of gestation.A second testosterone secretion peak is observed at birth. Then, up until puberty, testosterone levels in males are low and similar to those in females. Pulsatile secretion of gonadotropin-releasing hormones and

luteinizing hormones begins at the onset of puberty and results in the maturity of the Leydig cells. Testosterone is metabolized into dihydrotestosterone by 5-alpha reductase and to estradiol by aromatase. In young men, there is a diurnal variation in serum testosterone concentration, with the highest values seen at 8 AM and the lowest in late afternoon.2 Total testosterone circulates mostly in the blood and is 98% bound to serum proteins, primarily a sex hormonebinding globulin (SHBG) and albumin; only 1–2% of serum testosterone is free of bound protein.The combination of albumin-bound (weakly bound) testosterone and free testosterone is referred to as bioavailable testosterone, which is available to target tissues for androgenic action.3

Hypogonadism: Definition and

Classification

Hypogonadism represents a state of impaired testosterone secretion, which may occur if the hypothalamic-pituitary-gonadal axis is interrupted at any level.Primary (hypergonadotropic) hypogonadism refers to testicular disorders and is characterized by low serum testosterone levels despite high levels of the follicle-stimulating hormone (FSH) and the luteinizing hormone (LH). Secondary (hypogonadotropic) hypogonadism is characterized by failure of gonadal function

Aging, Hypogonadism and Sexual

Function: New Concepts

Testosterone levels start declining in the fifth decade of life, with the lowest levels seen in men 70 years of age and older.11,12 The rate of decrease in total testosterone levels is approximately 110 ng/dL per decade (Fig. 17.1). The development of age-related hypogonadism appears to involve deficits at multiple levels of the hypotha- lamic–pituitary–testicular axis13-16 (Fig. 17.2). With aging, there is a decrease in the number and volume of the Leydig cells, impaired steroid hormone biosynthesis, impaired blood supply to the gonads and decreased steroid output after administration of human chorionic gonadotropin.In addition,the number,volume and function of Leydig cells decrease with aging and are affected by several medications, including glucocorticoids, spironolactone, opiates, and ketoconazole.17-20 Alterations in the hypotha- lamic-pituitary compartment include loss of diurnal variations in gonadotropin levels,blunted luteinizing-hormone response to gonadotropinreleasing hormone stimulation, decreased or absent response of luteinizing-hormone levels to naloxone or tamoxifen, and increased gonadotrophic sensitivity to testosterone feedback.21,22 Neuroleptic drugs that cause hyperprolactinemia can inhibit the release of gonadotropinreleasinghormones,leadingtohypogonadotropic hypogonadism. Longitudinal studies on aging reported an average annual decrease of total serum testosterone of 3.2 ng/dL in men older than 53 years, i.e., about 1% per year based on a low limit of normal 325 ng/dL. According to

recommendations of the International Society of Andrology (ISA), the International Society for the Study of the Aging Male (ISSAM) and the European Association of Urology (EAU), TDS is defined as “a clinical and biochemical syndrome associated with advancing age and characterized by typical symptoms and deficiency in serum testosterone levels.”These associations also clarified that TDS may result in a significant decline in the quality of life and adversely affects the functioning of multiple organ systems.23,24 Testosterone plays a key role in the regulation of erectile function at both the central and peripheral levels. In the brain, low testosterone levels are associated with a reduction in erectile signaling. Studies in hypogonadal patients have shown that testosterone replacement results in a significant increase in brain activity in response to sexual stimulation at levels similar to those seen in men with normal testosterone.25 At the peripheral level, testosterone promotes biochemical and structural homeostasis of penile tissues. In animal experimental models, hypogonadism has been reported to be associated with cavernous smooth muscle cell apoptosis,abnormal collagen deposition within corpora cavernosa, adypocite accumulation in the subtunical region, penile dorsal nerve atrophy and penile tunica albuginea fibrosis. These structural alterations were partially reverted after testosterone replacement therapy. Another vital role for testosterone is in the regulation of PDE5 expression. The castration of rats has shown a significant reduction in the PDE5 gene and protein expression in the corpus cavernosum as well as an erectile response to electrostimulation.These effects were completely reversed with testosterone substitution. In addition, an ever-increasing number of reports indicate that T deficiency interferes not only with normal function but also with the response to treatments specifically aimed at correcting the inadequate mechanisms of erection.26 A number of studies have indeed confirmed that testosterone replacement therapy can improve libido and erectile function in a significant proportion of men with testosterone deficiency syndrome.27

Epidemiological Aspects

Hypogonadism affects an estimated two to four million men in the United States and its

Hypothalamus

Pituitary

Hypothalamus

Dmphragma sella

BI

Estradiol

Aromatase 0,3%

Androgen receptor

Tissue (Bio) available

prevalence increases with age.12,28,29 In North America, several cross-sectional and longitudinal studies have confirmed the decline in androgen production associated with age.12,28,29 It has been estimated that only 5% of affected men currently receive treatment.

Physiological Actions and Tissue

Targets of Sexual Hormones

Testosteroneregulatesmorpho-functionalhomeo- stasis in multiple organs and body systems.