Erythropoiesis and marrow stimulation

Androgen therapy has long been used clinically to stimulate erythropoiesis since the original observational study of 68 women with breast cancer which demonstrated significant, sometimes dramatic, increases in hemoglobin levels after the administration of 100 mg testosterone or dihydrotestosterone propionate injections three times weekly (Kennedy and Gilbertsen 1957). In addition, androgen therapy has smaller and less consistent effects on other bone marrow cell lineages that produce...

Erythropoiesis

Since erythropoiesis is androgen-dependant, hypogonadal patients usually present with mild anemia (with values in the female normal range) which normalizes under testosterone treatment. Therefore, hemoglobin, red blood cell count and hematocrit are good parameters for surveillance of replacement therapy. If sufficient stimulation is lacking despite adequate testosterone therapy, lack of iron should be ruled out and treated if necessary. At the beginning of therapy we check red blood values...

Potential risks

As to the risks of androgen replacement therapy in elderly men, we consider here only effects of physiological doses of testosterone and not those of massive pharmacological doses, as used by body builders. Traditionally, it has been a matter of concern that prolonged treatment with androgen may increase the risk of cardiovascular disease. The complex relationship between endogenous and exogenous androgens and cardiovascular risk is discussed in Chapter 10. With the evidence currently...

Cardiovascular risk factors

Testosterone plays an ambiguous role in relation to cardiovascular risk factors and its respective role has not been fully resolved (see Chapter 10). The interactions between the CAG repeat polymorphism, serum levels of sex hormones, lifestyle factors and endothelium-dependent and independent vessel relaxation of the brachial artery as well as lipoprotein levels, leptin and insulin concentrations and body composition were described in over 100 eugonadal men of a homogenous population. In...

Relationships between serum levels of testosterone and cardiovascular disease observational studies

At the outset, it is important to emphasize the limitations of observational studies on associations between serum levels of endogenous androgens and cardiovascular disease. The cardiovascular disease endpoints were extremely variable (mortality, morbidity such as myocardial infarction and angina, decompensated and compensated heart failure, completed stroke and transient ischemic attack, angiography, ultrasound, computer tomography, or post-mortem based diagnosis or unspecified events), study...

Testosterone and cardiovascular disease in men

Sixteen of 32 cross-sectional studies found lower levels of testosterone in patients with coronary artery disease compared with healthy controls. Sixteen showed no difference in testosterone levels between cases and controls. In none were high levels of testosterone associated with coronary artery disease. All studies which measured levels of free or bioavailable testosterone found an inverse association with coronary artery disease (reviewed in Alexandersen etal. 1996 Wu and von Eckardstein...

Testosterone and cardiovascular disease in women

By contrast to the neutral or even beneficial associations between endogenous testosterone levels and cardiovascular disease for men, the few retrospective or cross-sectional case-control studies in women revealed pro-atherogenic associations of androgens with CAD (Wu and von Eckardstein 2003). Only scanty prospective data is available on the importance of testosterone as a cardiovascular risk factor in women. Barrett-Connor and Goodman-Gruen(1995) reported a 19-year follow-up of 651...

Effects of testosterone on cardiovascular risk factors

The net effect of testosterone on cardiovascular risk is difficult to assess for at least six main reasons. First, the effects of testosterone on cardiovascular risk factors are contradictory depending on whether associations with endogenous testosterone or effects of exogenous testosterone have been investigated. Second, the associations between serum concentrations of endogenous testosterone and cardiovascular risk factors are confounded with mutual interactions between endogenous androgens,...

Associations of endogenous testosterone with cardiovascular risk factors

Several cross-sectional population studies found statistically significant correlations between plasma levels of testosterone and various risk factors, which, however, were opposite in men and women. In men testosterone plasma levels were frequently found to have positive correlations with serum levels of HDL-C as well as inverse correlations with plasma levels of triglycerides, total cholesterol, LDL-C, fibrinogen and PAI-1. However, serum levels of testosterone have even stronger inverse...

Effects of puberty on cardiovascular risk factors

Longitudinal studies of puberty were informative on the effects of endogenous sex hormones on cardiovascular risk factors in children and adolescents. Prepubertal boys and girls do not differ significantly in their serum lipid and lipoprotein levels. In contrast to girls, in whom levels of HDL-C and LDL-C change little with puberty, sexually maturingboys experience a decrease in HDL-C and increases in LDL-C and triglycerides (Bagatell and Bremner 1995). However, these changes may not reflect...

Androgen ablation therapy of prostate cancer

Androgen withdrawal induces programmed cell death (apoptosis) in prostate cells resulting in prostate tissue involution and, after some time, only a rudimentary prostate is left that is composed mainly of stromal cells (Kyprianou and Isaacs 1988 English et al. 1989). This process is reversible. Re-stimulation with androgens results in rapid proliferation and growth of the gland to its adult size. When rats are castrated one can observe massive induction of programmed cell death starting about...

Androgen receptor as a therapy target in hormoneresistant prostate cancer

Currently there is no efficient method available to treat patients who relapse during androgen ablation therapy and develop an androgen-independently growing tumor. Based on an improved understanding of AR signaling in therapy-refractory prostate cancer, novel therapies are being developed that target AR in advanced tumor cells. Specific antisense AR oligonucleotides were identified that inhibit AR expression. Treatment of such prostate cancer cells resulted in reduced androgen receptor levels,...

Conversion of paracrine to autocrine mechanism of androgen action during prostatic carcinogenesis

While it is clear that prostate cancer arises from the epithelial compartment, the identification of the specific epithelial cell subtype which the carcinogenic process initiates has only recently been the focus of study. Currently, the precursor for most peripheral zone prostatic carcinomas is thought to be high-grade prostatic intraepithelial neoplasia (HGPIN) (McNeal and Bostwick 1986). It is believed that HGPIN arises from low-grade PIN, which in turn is thought to stem from normal prostate...

Role of androgen in prostate cancer

Even with these hard wiring changes, activation of these pathological growth-promoting (i.e., oncogenic) pathways can still be dependent upon the binding of androgen to its receptor in the nuclei of these neoplastic cells themselves (i.e., androgen and AR-dependent), or they can be constitutive (i.e., independent of the binding of physiological androgens to the receptors), but still requiring AR functioning in the nuclei of these malignant cells to enhance the transcription of both secretory...

Grootenhuis M de Gooyer J van der Louw R Bursi and D Leysen

Synthesis of nandrolone derivatives and reference steroids Preparation of nandrolone, MENT and reference steroids Preparation of nandrolone derivatives Methods of pharmacological evaluation Androgen receptor transactivation and binding Determination of metabolic stability with human hepatocytes Aromatase susceptibility of new androgens Effects on bone, LH FSH, ventral prostate and muscle in castrated male rats Effects on plasma testosterone of intact male monkeys Pharmacokinetic evaluation in...

Action on bone marrow

Testosterone has been demonstrated to stimulate erythroid colony formation dose-dependently in vitro. Hence, androgens might have a promoting effect on erythroid colony forming units in bone marrow (Moriyama and Fisher 1975a). As trials in rabbits demonstrated, testosterone may directly act on these colony forming units to enhance their differentiation into EPO-responsive cells, causing an increase of nucleated erythroid cell numbers. Thus, EPO is required to further increase the maturation...

Additional modalities for therapy of androgenrelated bone loss

To date, testosterone substitution is the only form of therapy that has been systematically evaluated for the treatment of bone loss in male hypogonadism. However, some hypogonadal men may have contraindications to testosterone therapy, especially those with a prostate carcinoma. In addition, in some hypogonadal men, androgen therapy may not be fully sufficient to elevate bone mass into a safe range, which might be especially the case in persons receiving additional glucocorticoid therapy or...

Amino terminal domain

Steroid receptors contain activation functions 1 and 2 (AF1 and AF2) at their NH2-and COOH- terminal regions. In contrast to other steroid hormone receptors that contain a strong transactivation function at their COOH-terminus, the COOH-terminal AF2 domain in AR has a weak transactivation potential. Most of the transactivation function of the AR is carried out by the NH2-terminal domain of the receptor (Jenster etal. 1995 Poukka etal. 2000a). The mechanism of transcriptional activation by the...

Androstenedione administration in clinical studies

Effects of oral androstenedione have not been studied in women and have been largely disappointing in men. Short-term (5 days) androstenedione (100 mg day) had no anabolic effect on muscle protein metabolism in eugonadal young men (Rasmussen etal. 2000). In 30-56 year-old men androstenedione (3 x 100 mg day) for 28 days slightly reduced HDL-cholesterol without affecting prostate specific antigen (PSA), suggesting some androgenic activity (Brown et al. 2000). Serum HDL-cholesterol was also...

Animal models for SBMA

In the past few years it has been particularly difficult to generate transgenic mouse models using heterologous as well as homologous promoters to drive the expression of the AR with an expanded polyQ stretch. The mice generated showed neither neurological symptoms nor other overt pathology (Bingham etal. 1995 LaSpada etal. 1998). Recently Abel et al. (2001) generated transgenic mice in which a truncated AR was used encompassing a longer polyQ stretch. AR expression was driven by the use of...

Allolio and W Arlt

Treatment with DHEA - clinical studies Patients with impaired mood and wellbeing Patients with immunological disorders Androstenedione administration in clinical studies The emerging therapeutic profile of DHEA Effects on the central nervous system Practical approach to the patient with DHEA deficiency Man together with higher primates have adrenals secreting large amounts ofdehy-droepiandrosterone (DHEA) and its sulfate ester, DHEAS. The physiological role of these steroid hormones has long...

Biochemical evidence for defective androgen receptor

In patients with AIS, assessment of the pituitary-gonadal axis is age-dependent. In the normal male, a rise of gonadotropins and testosterone is seen during the first months of life, usually starting after the first week postnatally with a decline after six months to prepubertally low levels (Forest etal. 1973). Recently, Bouvattier described infants with CAIS and PAIS with regard to postnatal changes in testosterone and gonadotropins (Bouvattier et al. 2002). Interestingly, in CAIS...

Bone mass

Hypogonadism is associated with decreased bone density by increased bone resorption and decreased mineralization, resulting in premature osteoporosis and increased risk of fractures (see Chapter 7). Testosterone replacement in hypogonadal patients results in an increase in bone density (Behre etal. 1997b Leifke etal. 1998 Devogelaer et al. 1992 Zitzmann et al. 2002b) (Fig. 13.2). Since estrogens 10 20 30 40 50 60 70 80 90 Age (years) Fig. 13.2 Bone density as measured by phalangeal...

Bone tissue

Polymorphisms of the estrogen receptor (ER) have repeatedly been demonstrated to modulate quantity and quality of bone tissue in healthy men (e.g. Sapir-Koren et al. 2001). As androgen activity influences bone metabolism (see Chapter 7), respective observations apply to the CAG repeat polymorphism in the AR gene as well in 110 healthy younger males, a high number of CAG repeats was significantly associated with lower bone density (Zitzmann et al. 2001b). This result is corroborated by a...

Chronic obstructive lung disease

Advanced chronic airflow limitation is associatedwith weight loss and muscle depletion, possibly due to the increased energy requirements required for breathing or reduced serum testosterone concentrations (Kamischke etal. 1998). Interventions aimed at improving muscle bulk such as nutrition, exercise or androgens may therefore have an impact on the morbidity and or mortality of the underlying respiratory disease. One large well-conducted prospective study demonstrated that short-term low-dose...

Correlational studies demonstrating the relationship of serum testosterone concentrations and muscle mass and function

Healthy, hypogonadal men have lower fat free mass (FFM) and higher fat mass when compared to age-matched eugonadal men (Katznelson et al. 1996 1998). The age-associated decline in serum testosterone levels correlates with decreased appendicular muscle mass and reduced lower extremity strength in Caucasian as well as African-American men (Baumgartner etal. 1999 Melton etal. 2000 Morley et al. 1997 Roy et al. 2002). Similarly, epidemiological studies have demonstrated an inverse correlation...

Critical illness trauma and surgery

Critical illness, trauma, burns, surgery and malnutrition all result in a catabolic state characterised by acute muscle breakdown which is reversed during recovery. These catabolic states are characteristically accompanied by functional hypogo-nadotrophic, androgen deficiency. This is due to functional partial GnRH deficiency as pulsatile GnRH administration can rescue LH pulsatility and hypoandrogenemia (Aloi et al. 1997 van den Berghe et al. 2001). This has long led to the hypothesis that...

Depression

Testosterone has long been considered effective for treatment of depression (Altschule and Tillotson 1948). Recent studies have shown that blood testosterone concentrations are lower in older men with dysthymia or major depression compared with non-depressed controls (Seidman et al. 2002). This effect may also be modulated by androgen receptor polymorphisms, since blood testosterone concentrations predict depression, but only in the subgroup of men with shorter CAG repeats (Seidman etal....

Detection of misuse of anabolic androgenic steroid hormones

Doping control is organized by national and international sport federations and by the WADA for the different types of sports. Increasingly national anti-doping programs are organizing dope control by one overall organization. This strategy seems to be the most effective testing action as any possible intention by individual sport federations to hide positive cases and to protect their athletes can be excluded. The IOC only performed doping tests during the Olympic winter and summer games and...

Early studies with finasteride a type 2 5areductase inhibitor

Initial studies with finasteride were conducted in normal volunteers to determine the biochemical efficacy and safety profile of the drug after single doses or with multiple daily dosing. 18.3.1 Effects on serum androgens and gonadotropins Administration of finasteride markedly reduces circulating DHT levels in adult men ( 70 below baseline), and inhibition of DHT formation is maintainedwith chronic dosing (Gormley 1995 Gormley etal. 1990 Stoner et al. 1994). Because finasteride is a selective...

Effects of testosterone on vascular reactivity

An early hallmark of atherosclerosis is decreased vascular responsiveness to various physiological stimuli due either to endothelial or to endothelium-independent disturbances in the vascular smooth muscle cell (Bonetti et al. 2003). As a result, decreased vasodilation and enhanced vasoconstriction can lead to vasospasm and angina pectoris. Moreover, endothelial dysfunction also contributes to coronary events by promoting plaque rupture and thrombosis (Libby 2002 Ross 1999). Testosterone can...

Endocrine control of spermatogenesis

5.7.1 Synergistic and differential action of androgens and FSH on testicular functions It can be stated safely that the combination of androgen and FSH consistently produced a better stimulatory effect on spermatogenesis than either factor alone. What might represent a functional distinction between testosterone and FSH is the fact that testosterone induces differentiation of somatic cells in the immature primate testis (Schlatt etal. 1993). This does not seem to be the case for FSH. Hence,...

Folliclestimulating hormone FSH and spermatogenesis

5.6.1 FSH receptor and sites of FSH action Remarkably, the expression of the FSH receptor appears to be restricted to Sertoli cells only. Previous reports on spermatogonial expression of FSH receptor have not been confirmed to date. In all likelihood, FSH also acts on spermatogenesis indirectly via a single somatic cell type. Testicular FSH receptor expression in the ratis highest in stages XII-II (Heckertand Griswold 2002 Rannikko etal. 1996),e.g. when A-type spermatogonia develop further,...

Genetic aspects of the androgen receptor in human androgen insensitivity

The AR is a ligand-activated transcription factor of androgen-regulated genes. It is commonly assumed - though not experimentally proven to date - that a controlled temporal and spatial expression of androgen-regulated genes during early embryogenesis provokes a distinct spectrum of functional and structural alterations of the internal and external genitalia, ultimately resulting in the irreversible formation of the normal male phenotype (Holterhus etal. 2003). The ARbelongs to the...

GF Weinbauer M Niehaus and E Nieschlag

Organisation and kinetics of spermatogenesis The hypothalamo-hypophyseal-testicular circuit Androgen dependence of spermatogenesis Pubertal initiation of spermatogenesis Adult spermatogenesis maintenance and reinitiation Testicular androgen production, metabolism and transport Testicular androgen concentrations and spermatogenesis Testicular androgen receptor and sites of androgen action Follicle-stimulating hormone (FSH) and spermatogenesis FSH receptor and sites of FSH action Endocrine...

Historical development of testosterone therapy

The first experimental proof that the testes produce a substance responsible for virility was provided by Berthold (1849). He transplanted testes from roosters into the abdomen of capons and recognized that the animals with the transplanted testes behaved like normal roosters They crowed quite considerably, often fought among themselves and with other young roosters and showed a normal inclination toward hens. Berthold concluded that the virilizing effects were exerted by testicular secretions...

Immune system

Based on data from animal experiments (Svec and Porter 1998) and from in vitro studies (Meikle etal. 1992 Okabe etal. 1995) DHEA has been suggested asasteroid with immune-regulatory activity. This view is supported by the clinical studies in patients with SLE demonstrating glucocorticoid-sparing activity of DHEA and clinical improvement (Chang et al. 2002 Petri et al. 2002 Van Vollenhoven et al. 1995). However, in these studies DHEA was given at a clearly supraphysiological dose (200 mg day)...

In foetal sexual differentiation

Normal male sexual development is dependent both on genetic events of gonadal development as well as on endocrine pathways initiated by hormones secreted from the testes (Fig. 3.2). Gonadal differentiation is initiated with the development of the bipotent gonad during early embryonal life (Hiort and Holterhus 2000). Several genes are known to be involved in this process leading to the creation of the undifferentiated gonad. Abnormalities in the Wilms tumour 1 (WT1) gene are associated with...

In puberty and adulthood

Increasing androgenic steroid secretion from the adrenals is defined as adrenarche and precedes puberty. Adrenarche is associated with increased growth of pubic and axillary hair independent of gonadal androgen secretion. Adrenal androgens include mainly dehydroepiandrostendione, its sulfate, and androstendione, but also other adrenal steroids have androgenic potential. Adrenocorticotropic hormone (ACTH) is a potent stimulator of adrenal androgen secretion however, its potency relative to...

Iron incorporation

Early results in patients with iron-deficient anemia demonstrated the beneficial and synergistic effects of additional androgen administration (Victor etal. 1967). In the following, testosterone has been demonstrated to enhance iron (Fe) incorporation in red blood cells (Naets and Wittek 1968) and administration of testosterone propionate can increase the incorporation of 59Fe by erythrocytes in mice after a delay of three to four days (Molinari 1970 1982 Molinari and Rosenkrantz 1971)....

Isotope dilutionmass spectrometry

Unlike protein hormones, which are heterogeneous, steroids can be quantified very accurately in biological samples by means of isotope dilution-mass spectrometry. This procedure allows the absolute identification and quantification oftestosterone inblood and other specimens. The procedure is based on the highly specific recognition of the steroid by mass spectrometry coupled to an exact estimation of recovery by addition of labeled testosterone (isotope dilution). According to a well validated...

Kennedy syndrome a pathological expansion of the AR gene CAG repeats

X-linked spinobulbar muscular atrophy (X-SBMA) or Kennedy syndrome, is a rare inherited neurodegenerative disease characterized by progressive neuromuscular weakness being caused by a loss of motor neurons in the brain stem and spinal cord. Disease onset developing in the third to fifth decade of life is likely to be preceded by muscular cramps on exertion, tremor of the hands and elevated muscle creatine kinase. The initial description of one of the individuals affected with Kennedy syndrome...

Kennedy syndrome spinobulbar muscular atrophy SBMA

A rare inherited neurodegenerative disease, Kennedy syndrome or spinobulbar muscular atrophy (SBMA), is characterized by progressive neuromuscular weakness resulting from a loss of motor neurons in the spinal cord and brain stem. The onset of this disease occurs in the third to fifth decades of life and is often preceded by muscular cramps on exertion, tremor of the hands and elevated muscle creatine kinase (Kennedy etal. 1968). The initial description of Kennedy syndrome also contains one case...

Lessons from genetic studies on the role of testosterone in atherosclerosis

In the absence of controlled intervention studies and in view of the conflicting data presented above, it is difficult to predict the net effects of testosterone on cardiovascular disease. Further difficulties arise from the fact that associations found in observational studies do not prove causal relationships and that in theory several effects of testosterone on intermediate phenotypes can be exerted via either non-genomic or genomic mechanisms, the latter being mediated either directly via...

Metabolism of androgens in different tissues

In adult men testosterone itself is the hormone governing libido, gonadotropin feedback regulation, and growth and function of extragenital tissues, such as muscle, kidney, liver, and bone. When testosterone diffuses from the outside into the cytosol of cells, it binds either to AR directly, or is converted into DHT with higher affinity to the receptor, or, after it is aromatised to estradiol (E2) it can interact with ERa or ERp. In addition, it is feasible that the androgen is metabolised to...

Methods of pharmacological evaluation

22.3.1 Androgen receptor transactivation and binding Steroid receptor activity is dependent on three factors the concentration of the ligand, the receptor, and co-regulatory proteins. The composition and presence of steroid receptors in the cell determine the response of the ligand and the transactivation of target genes by ligand-occupied receptors is modulated by the presence of nuclear co-activators and co-repressors (Katzenellenbogen et al. 1996). For the determination of the androgenic...

Muscle protein synthesis as the target of androgen action

Induction of androgen deficiency by administration of a long acting GnRH agonist in healthy, young men is associated with decreased rates of 13C-leucine appearance, a measure of proteolysis (Mauras etal. 1998). Lowering of testosterone concentrations in this study (Mauras etal. 1998) is also associated with a significant decrease in nonoxidative leucine disappearance, a marker for whole body protein synthesis. Conversely, testosterone supplementation stimulates the synthesis of mixed skeletal...

Organisation and kinetics of spermatogenesis

Spermatogenesis comprises the development of sperm from stem spermatogonia. This process encompasses the multiplication and differentiation of stem cells into differentiated and proliferating germ cells, the redistribution of genetic information during meiosis and the maturation and differentiation of haploid germ cells. Following proliferation of A-type spermatogonia into B-type spermatogonia, these cells enter meiosis and are termed spermatocytes and after completion of reduction divisions,...

Other approaches for selective actions

Modifications of the AR such as splice variants, isoforms or postranslational modifications may effect the interaction of the androgen with the receptor and determine tissue selectivity, but not much is known yet. Recent publications (Kousteni et al. 2001 Migliaccio et al. 2000) stress the importance of transcription-independent, nongenomic actions of steroids, reflecting the observation of rapid effects, mediated by hormones and their hormone receptors within minutes, thereby excluding...

Other influences

Although LH appears to be the most important hormone, Leydig cells are also target cells for other hormones. In addition, the neural network must be considered. For a long time the importance of neuronal connections between the brain and the testis was neglected, but recent data show that the neural network can regulate the sensitivity of the Leydig cells towards LH (Csaba et al. 1998 Selvage and Rivier 2003). The relative importance of this neuronal network under normal physiological...

Overall effect of testosterone

Testosterone has many biological functions and, as demonstrated in this chapter, testosterone is a safe medication. There are only very few reasons why testosterone should be withheld from a hypogonadal patient (see 13.6). Nevertheless, to date many hypogonadal men do still not receive the benefit of testosterone therapy because they are not properly diagnosed and the therapeutic consequences are not drawn (e.g. Bojesen et al. 2003). Some physicians even believe that the shorter life expectancy...

Patients with immunological disorders

In a number of studies DHEA supplementation has been used to modify immune functions and alter the course of immunopathies. Most studies have been performed in patients with systemic lupus erythematosus (SLE), a chronic autoimmune inflammatory disease of unknown etiology (Chang et al. 2002 Petri et al. 2002 Van Vollenhoven et al. 1995). The concept to use DHEA in the treatment of SLE was based on the observation that women are more often affected and that androgens and DHEA concentrations are...

Pharmacogenetic aspects of testosterone therapy

Considering observations in eugonadal men, one can assume that testosterone therapy in hypogonadal men should have a differential impact on androgen target tissue, depending on the number of CAG repeats. In a longitudinal pharmaco-gentic study in 131 hypogonadal men, prostate volume was assessed before and during androgen substitution. Considered were the length of CAG repeats, sex hormone levels and anthropometric measures. Initial prostate size of hypogonadal men was dependent on age and...

Pharmacological profile

22.4.1 Androgen receptor binding and transactivation Table 22.1 summarizes the results for androgen receptor binding and agonistic activity. The binding activity shows that introduction of a 7a-methyl or ethyl group to nandrolone increases the relative binding affinity (RBA) while a 7a-vinyl or ethynyl did not increase the RBA. Org X has a RBA that is 3-fold higher than nandrolone and 9-fold higher than testosterone. The relative agonistic activity (RAA), however, of all the 7a- derivatives of...

Prohormones of androgens

17B-hydroxy-5a-androst-1-en-3-one 5a-Androst-1-ene-3B,17B-diol ( 1-Testosterone ) 17B-hydroxy-5a-androst-1-en-3-one 5a-Androst-1-ene-3B,17B-diol ( 1-Testosterone ) Fig. 24.3 Structure formula of prohormones of dihydrotestosterone and prohormones with 1-ene structure. Fig. 24.3 Structure formula of prohormones of dihydrotestosterone and prohormones with 1-ene structure. Fig. 24.4 Structure formula of prohormones of nortestosterone. sublingual or buccal application. In contrast to such incorrect...

Prostate and seminal vesicles

The prostate and seminal vesicles are androgen-sensitive organs and are small in hypogonadal patients. Their volumes increase under testosterone therapy. Testosterone induces their normal functions, as indicated by the appearance of seminal fluid. Well-substituted patients should have ejaculate volumes in the normal range (i.e. > 2 ml). There is much concern about the effects oftestosterone with regard to the development of benign prostatic hyperplasia (BPH) and carcinoma of the prostate and...

Prostate development

The prostate is the prototype of a hormone-dependent organ. During embryogenesis dihydrotestosterone triggers its development from the urogenital sinus. In this process, the interaction of the stromal and the epithelial compartments of the prostate gland are of crucial importance. The AR is first expressed in the stromal cells, which makes the cells responsive to dihydrotestosterone to stimulate proliferation and determine differentiation of the epithelial cells in a paracrine manner through...

Proteinprotein interaction of the AR

The AR is able to perform interactions with proteins. The AR monomer can build an intermolecular interaction bridge and makes contact with a variety of other proteins. These interactions are vital for the AR-mediated transcriptional transac-tivation of target genes as they modulate the activity of the receptor. Direct contact between the amino-terminal and the carboxyl-terminal regions (N C-interaction) of the AR was found using a two-hybrid system and glutathione-S-transferase fusion protein...

Psychological implications

Testosterone substitution in hypogonadal men improves lethargic or depressive aspects of mood significantly (Burris etal. 1992). Studies exploring the relationship between gonadal function anddepressive episodes demonstrated testosterone levels to be markedly decreased in respective patients (Unden et al. 1988 Schweiger et al. 1999 Barrett-Connor etal. 1999). Accordingly, treatment with testosterone gel may improve symptoms in men with refractory depression (Pope etal. 2003). The age-dependent...

Rheumatoid arthritis RA

The rationale for androgen therapy in RA is that (a) the lower prevalence in men suggests a protective role for androgens, (b) active disease is associated with reduction in endogenous testosterone production, (c) androgen effects on muscle and bone may improve morbidity in RA and (d) androgen effects (e.g. fibrinolysis) may reduce disease activity. The best designed and conducted studyofandrogen therapy involved 107 women with active RA according to American College of Rheumatology (ACR)...

Sexuality

It is widely acknowledged that sexual behaviour in humans is multifactorial. Although no attempt will be made to deal with these issues here, it should be pointed out that intrapsychic, social, somatic and cultural factors can profoundly influence sexuality. The evidence presented here serves primarily to underline the contribution of sex hormones as a determinant of sexual behaviour. It has long been recognized that androgens play a critical role in human male sexual behaviour. Prepubescent...

Stress

Activation of the hypothalamic-pituitary-adrenal axis and the subsequent release of cortisol is considered one of the major components of the physiological stress response in humans (Rose 1984). Stress responses of the pituitary-gonadal axis are not as well known although their sensibility and specifity are impressive. Earliest studies investigated young military trainees in extremely stressful situations during combat training (Kreuz et al. 1972 Rose et al. 1969) and observed a significant...

Testosterone cypionate and testosterone cyclohexanecarboxylate

Testosterone cypionate (cyclopentylpropionate) pharmacokinetics were compared with those of testosterone enanthate in a cross-over study involving six healthy men aged 20-29 years. Three subjects received 194 mg of testosterone enanthate, followed seven weeks later by 200 mg of testosterone cypionate and vice versa (amount of unesterified testosterone 140 mg in both preparations). The serum testosterone profiles were identical after injection of both preparations in equivalent doses, both in...

The effects of lowering endogenous testosterone concentrations on body composition

Experimental suppression ofserum testosterone levels by administration of a GnRH agonist analog in healthy young men is associated with a significant reduction in fat-free mass and an increase in fat mass, and a decrease in fractional muscle protein synthesis (Mauras etal. 1998). In this study, gonadal suppression was also associated with a decrease in whole body leucine oxidation as well as non-oxidative leucine disappearance rates. Rates of lipid oxidation decreased after treatment, with...

Tim days

Fig. 14.12 Serum concentrations (mean SEM) of testosterone after single-dose intramuscular injections of 1000 mg testosterone undecanoate in tea seed oil in 7 hypogonadal men (squares) or castor oil in 14 hypogonadal men (circles). Broken lines indicate normal range of testosterone (adapted from Behre etal. 1999a, reproduced by permission of the European Journal of Endocrinology). patients (Behre etal. 1999a). Follow-up examinations were performed 1,2,3,5 and 7 days after injection and then...

Treatment of delayed puberty in boys

Androgen replacement therapy in male adolescents with constitutional delay of growth and adolescence has been shown to be beneficial psychologically as well as physiologically, and should be initiated promptly on diagnosis (Albanese and Stanhope 1995 de Lange etal. 1979 Kaplan et al. 1973 Rosenfeld et al. 1982). Boys with delayed puberty are at risk for not obtaining adequate peak bone mass and for having deficiencies in developing social skills, an impaired body image, and low self-esteem....

Metabolism of testosterone

The steady state level of biologically active steroids in the body as a whole is determined by the rate of synthesis and the rate of degradation. To maintain a steady state concentration of active steroids in a target cell a similar balance between the supply and removal must be maintained. The supply side of the balance is determined by the rate of inward transport of active steroid, sometimes in combination with activation through metabolism of the precursor. Similarly, factors that control...

Variation in the androgen receptor

A variable number of CAG repeats in exon 1 of the androgen receptor gene on the X-chromosome, which normally ranges between 9 and 35 encodes for a variable number of glutamine residues in the aminoterminal domain of the receptor and is inversely associated with the transcriptional activity of testosterone-responsive target genes. Abnormal expansion of the CAG repeats beyond the number of 36 leads to Kennedy disease, which is accompanied by signs of hypoandrogenism (see Chapter 2 for details)....

Clinical implications

Current evidence indicates that the gender difference in the incidence ofcardiovas-cular diseases cannot be explained on the basis of ambient testosterone exposure. It has therefore been speculated that exposure to testosterone in pre- or perinatal life is responsible or contributes to the male gender disadvantage in cardiovascular disease (Liu etal. 2003). In adults, androgens can exert both beneficial and deleterious actions on a multitude of factors implicated in the pathogenesis of...

Altered neuroendocrine regulation

Although the combined observations of a diminished testicular reserve for testosterone secretion and increased basal gonadotropin levels may seem in line with the view that the age-related decline of Leydig cell function results from primary testicular dysfunction, closer examination of the data suggests that other mechanisms must also be involved. Indeed, the observed responses to hCG challenges in elderly men indicate that the secretory reserve of the Leydig cells, albeit diminished, should...

Summary and future directions

Androgens circulate in appreciable amounts in women. Female serum testosterone levels rely on a complex interplay of hormonal secretion and bioconversion of peripheral prehormones. Testosterone levels are proportional to ovarian and adrenal secretion and peripheral bioconversion of the adrenal androgens DHEAS and DHEA, the predominant circulating androgens. Adrenal androgen secretion attenuates with age in a cortisol-independent fashion due to involution of the reticularis zone of the adrenal...

DHEA secretion and age

In humans and in some non-human primates the secretion of DHEA(S) shows a characteristic pattern throughout the life cycle (Orentreich etal. 1984 Palmert etal. 2001 Reiter et al. 1977) (Fig. 19.1). DHEA(S) is secreted in high quantities by the fetal zone of the adrenal cortex, leading to high circulating DHEAS levels at birth. As the fetal zone involutes, a sharp fall in serum DHEA(S) concentrations is observed post partum to almost undetectable levels after the first months of life. Levels...

Coactivators and corepressors

Activation of transcription by AR is regulated by a number of cellular proteins that interact with the receptor. The best characterized are the p160 SRC (steroid receptor co-activator) family members SRC-1 NCoA-1 (Alen et al. 1999 Bevan et al. 1999), SRC2 GRIP1 (glucocorticoid receptor-interacting protein 1) TIF2 (transcription intermediary factor 2) (Berrevoets et al. 1998 Kotaja et al. 2002a Shang etal. 2002), and SRC3 ACTR (activator ofthe thyroid and retinoic receptor) AIB1 (amplified in...

The treatment of androgenpotentiated hair disorders

Currently, the most effective treatment for male pattern baldness is the transplant of follicles from non-balding sites into the balding region, capitalising on the retention ofthe different intrinsic responses to androgen discussed earlier. This has significant disadvantages not only is it very invasive and heavily reliant on the skill of the operator for a good cosmetic result, but the alopecia continues to progress behind the transplanted area so that further transplants are often required....

General prospects

23.1.1 Why male contraception at all The invention of the pill for women was undoubtedly one of the most significant medical and cultural events of the twentieth century. Nature has sweetened procreation with the pleasures of sex to guarantee human reproduction. The pill was the culmination of a millennial-long development of methods to disentangle procreation from sex, and has had a substantial impact on society - e.g. on family planning, morality and demography, not to mention economic and...

Testosterone propionate

Single-dose pharmacokinetics of 50 mg testosterone propionate after intramuscular injection to seven hypogonadal patients and the best-fitted pharmacokinetic profile are shown in Fig. 14.4 (Nieschlag et al. 1976). Maximal testosterone levels in the supraphysiological range were seen shortly after injection (40.2 nmol l, tmax 14 h). Testosterone levels below the normal range were observed following day 2 (57 h) after injection. The calculated values for AUC were 1843 nmol * h l, forMRT 1.5 d and...

Use of testosterone in male hypogonadism

The primary clinical use of testosterone is substitution therapy of male hypogo-nadism. Hypogonadism may be caused by hypothalamic, pituitary, testicular or Table 13.1 Overview of disorders with male hypogonadism classified according to localisation of cause Hypothalamic-pituitary origin (hypogonadotropic syndromes secondary hypogonadism) Idiopathic hypogonadotropic hypogonadism (IHH) including Kallmann syndrome Congenital adrenal hypoplasia Prader-Labhart-WiHi syndrome Laurence-Moon-Biedl...

Clinical relevance of animal models for the study of androgen actions

A comprehensive set of data is available to indicate that the cynomolgus monkey model is highly representative for preclinical studies on the endocrine regulation of spermatogenesis. Unlike the rhesus monkey, bonnet monkey or Japanese macaque, this nonhuman primate species does not show annual variations of testicular activity. A series of experimental studies is available and has been reviewed above. The findings obtained clearly prove that the data collected in the cynomolgus monkey on the LH...

Assessment of free testosterone

The direct measurement of free testosterone in serum is based on the same principles governing the assay of free thyroid hormones and has been extensively considered and reviewed by R. Ekins in the past (Ekins 1990). As indicated above, serum testosterone exists in an equilibrium between free and protein-bound fractions, an equilibrium which is invariably disturbed by all methods of free hormone measurement, a factor that should be kept in mind when choosing a method and analyzing the data. The...

Clinical studies with finasteride in men with benign prostatic hyperplasia

Early studies with finasteride in men with benign prostatic hyperplasia (BPH) were designed to confirm the biochemical efficacy of the drug. Prior studies had identified the predominance of DHT, compared to testosterone, within the prostate due to intraprostatic type 2 5aR activity (Bruchovsky and Wilson 1968). In several studies evaluating the ability of finasteride to reduce DHT formation within the prostate, suppression of intraprostatic DHT levels up to 95 , exceeding the maximal...

References

Aasebo U, Gyltnes A, Bremnes RM, Aakvaag, A Slordal L (1993) Reversal of sexual impotence in male patients with chronic obstructive pulmonary disease and hypoxemia with long term oxygen therapy. J Steroid Biochem Mol Biol 46 799-803 Adams GE, Dische S, Fowler JF, Thomlinson RH (1976) Hypoxic cell sensitisers in radiotherapy. Lancet 1 186-188 Ahn YS, Harrington WJ, Simon SR, Mylvaganam R, Pall LM, So AG (1983) Danazol for the treatment of idiopathic thrombocytopenic purpura. N Engl J Med 308...

Randall

Structure and function of the hair follicle The paradoxical effects of androgens on human hair growth Human hair growth before and after puberty Androgen-dependent hair growth conditions The mechanism of androgen action in the hair follicle Hair growth in androgen insufficiency syndromes The current model for androgen action in the hair follicle Paracrine factors implicated in mesenchyme-epithelial interactions in the hair follicle The treatment of androgen-potentiated hair disorders Hair...

Testosterone ester combinations

Testosterone ester mixtures have been widely used for substitution therapy of male hypogonadism (e.g. TestovironRDepot 50 20 mg testosterone propionate and 55 mg testosterone enanthate TestovironRDepot 100 25 mg testosterone propionate and 100 mg testosterone enanthate SustanonR 250 30 mg testosterone propionate, 60 mg testosterone phenylpropionate, 60 mg testosterone isocaproate and 100 mg testosterone decanoate). These combinations are used following the postulate that the so-called...

Androgen deficiency states in women

A core precept of endocrinology is that of an endocrinopathy, defined as a hormonal deficiency state with clearly defined adverse sequelae. This paradigm is best illustrated by hypothyroidism and subsequent replacement, or by male hypogonadism with testosterone replacement. In the previous section, we have hypothesized that a clear androgen deficiency state does not exist in women undergoing natural menopause, but there are several conditions that are associated with decreased levels of...

Senile osteoporosis

Aging of men is accompanied by progressive bone loss, which persists and may even accelerate in old age. Osteoporosis in men is increasingly being recognized as a significant problem of public health. The age-specific incidence of both hip and vertebral fracture is about half that in women (Van Der Klift et al. 2002), and occurring with a delay of five to six years. One out of four patients suffering a hip fracture is a male and the prognosis of hip fracture, as well as of other major...

Zonal and cellular organization of the prostate

Fig. 12.5 Cellular heterogeneity within the normal prostate Histological architecture of the prostate is comprised of blood vessels that provide nutrients, including androgen, to the fibrous stromal layer which consists primarily of fibroblasts and smooth muscle cells, and to the epithelial layer. Epithelium can be subdivided into a basal epithelium, which contains AR negative proliferating cells, and secretory luminal epithelium, which consists of fully differentiated AR and p27Kip1 positive,...

Clinical studies with finasteride in women

Finasteride is not indicated for use in women. Due to its mechanism of action (type 2 5aR inhibition), finasteride use is contraindicated in women when they are or may be pregnant because of the risk of undervirilization of a developing male fetus. However, several studies have been published testing finasteride in women with a variety of disorders, including female pattern hair loss and hirsutism. 18.7.1 Study in postmenopausal women with androgenetic alopecia To determine whether finasteride...

Venous disease

The use of androgen therapy in acute or chronic venous disease arises from their fibrinolytic effect, which may reduce venous fibrin plugging. One study of chronic venous insufficiency aiming to test whether androgen therapy would reduce the rate of venous ulceration involved 60 patients with venous skin changes but no ulceration being treated with below-knee compression stockings as standard therapy (McMullin et al. 1991). They were randomised to receive either stanozolol (10 mg daily) or...

Sex hormone binding globulin and free testosterone serum levels

Sex Hormone Binding Globulin Molecule

Whereas some authors may still argue that total testosterone concentrations are not reduced in perfectly healthy elderly men, all authors agree that the free and non-specifically bound serum testosterone, generally considered to represent the serum testosterone fractions readily available for biological activity, do indeed decrease with age (for review Vermeulen 1991). In healthy ambulatory men, mean serum levels of free testosterone (FT) and of non SHBG-bound or so called bioavailable...

Testosterone and erection in normal men

So far, only small-scale studies have been performed testing the effects of testosterone on erection in normal men. In addition, these studies do not allow exact differentiation between effects on sexual behaviour and direct effects on the penis. Fig. 11.1 Effects of treatment of hypogonadal men (n 227) with testosterone gel (squares, 50 mg d circles, 100 mg d) and non-scrotal testosterone patches (triangles, 5 mg d) on erection as assessed by a questionnaire on percentage of full erection...

Hypoandrogenism of senescence and sexual activity

Aging in men is accompanied by a decrease in libido and sexual activity. Mean coital frequency was reported to be about four times a week at age 20-25 years and decreases to less than twice a month between 75 and 80 years (Masters 1986 Tsitouras-Bulat 1995). Nevertheless, only 15 of men over 60 years old deny any sexual interest (Verwoerdt et al. 1969) and 80 of men over 60 years old remain sexually active (Kaiser 1992). Whereas normal libido requires adequate testosterone levels, as shown by...

Regulation of pregnenolone metabolism

The first product of the cholesterol side chain process, pregnenolone, which is biologically inactive, is further metabolised by enzymes present in the endoplasmic reticulum. Much has been learned about the primary structure and the biosynthesis of various P450 enzymes after application of new techniques such as protein chemistry and molecular biology (reviewed by Miller 1988). This can be illustrated for enzyme activities that convert C21-pregnenolone to C19-steroids. It was previously thought...

Testosterone enanthate

Single-dose pharmacokinetics oftestosterone enanthate after intramuscular administration of 250 mg testosterone enanthate to seven hypogonadal patients and the best-fitted pharmacokinetic profile are shown in Fig. 14.6 (Nieschlag etal. 1976). Maximal testosterone levels in the supraphysiological range were seen shortly after injection (39.4 nmol l, tmax 10 h). Testosterone levels below the normal range were observed following day 12 after injection. The calculated values were 9911 nmol * h l...

Treatment with DHEA clinical studies

19.5.1 Patients with adrenal insufficiency The classical approach to study the physiological role of a hormone in humans is to analyze the effect of a hormonal deficit and the changes induced by replacement of the missing hormone. Thus adrenal insufficiency is the most useful model disease to understand the clinical activity of DHEA. As in adrenal insufficiency (AI) not only DHEA but also cortisol and (in primary AI) aldosterone is lacking, one might speculate that replacement of cortisol and...

Androgen dependence of spermatogenesis

5.4.1 Neonatal androgen secretion A distinct peak of testosterone synthesis and secretion occurs perinatally and -depending on the species - is of variable duration during the neonatal period. The physiological significance of this activation of testosterone production is not entirely clear. In the rat model, blockade of the neonatal androgen secretion by a GnRH antagonist provoked a delay of puberty and infertility in the adult animals (Kolho and Huhtaniemi 1989a 1989b). Surprisingly,...

Intact singers

Fig. 13.3 Longevity of intact and castrated singers (50 in each group) born between 1580 and 1859 (matched pairs of intact and castrated singers with similar birth dates were formed) (Nieschlag etal. 1993). of testosterone, possibly mediated through changes in lipid metabolism. Hence it may be asked whether testosterone may have a life-shortening effect on patients with hypogonadism under testosterone treatment. Appropriate controlled studies to answer this question directly are not available...

Role of 5areductase in androgen physiology and pathophysiology

18.1.1 Normal androgen metabolism During the last century, the identification and characterization of the major sex steroids, which include androgens, estrogens, and progestins, helped define their biologic functions. Androgens were demonstrated to be essential for normal male sexual differentiation in utero and for development and maintenance of male secondary sexual characteristics, including terminal body hair growth, muscle mass, sexual behavior and fertility. Androgens are steroid hormones...

Locally produced factors

Leydig cells in the testis are surrounded by other cells belonging either to the seminiferous tubules, such as Sertoli cells, or by cells in the interstitial tissue, such as macrophages. Many observations indicate that these neighbouring cells can potentially influence the function of Leydig cells in a paracrine fashion. FSH stimulates development of Leydig cells, probably via Sertoli cell products. Disturbances in the spermatogenic epithelium also affect Leydig cells. Moreover, conditioned...

Clinical studies with finasteride in men with androgenetic alopecia

As in the development program in men with BPH, initial clinical studies with finasteride in men with male pattern hair loss (androgenetic alopecia, AGA) were directed toward demonstration ofbiochemical efficacy (Kaufman 1996). Androgen receptor number, DHT content and 5aR activity were all reported to be higher in balding than non-balding scalp from subjects with AGA, lending further support to the hypothesis that lowering DHT content in the scalp would be useful in the treatment of patients...

Principle of hormonal male contraception

The testes have an endocrine and an exocrine function the production of androgens and of male gametes. Suppression of gamete production or interference with gamete function without affecting the endocrine function is the goal of endocrine approaches to male fertility regulation. However, since the two functions ofthe testes are interdependent, it has remained impossible so far to suppress spermatogenesis exclusively and reversibly without significantly affecting androgen synthesis. FSH and LH...