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...

A von Eckardstein and FCW Wu

Relationships between serum levels of testosterone and cardiovascular Testosterone and cardiovascular disease in men Testosterone and cardiovascular disease in women Effects of testosterone on cardiovascular disease - interventional Androgen excess from anabolic steroid abuse Exogenous testosterone treatment in men with cardiovascular disease Exogenous androgen treatment in women Cardiovascular effects of testosterone in animal studies Myocardial function and heart failure Effects of...

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...

Adaptation of Leydig cells

Most of the initial effects of LH or hCG on steroid production are stimulatory, as can be seen from the rapid increase of the testosterone concentration in plasma. In rats this response is much faster and more pronounced than in man (Huhtaniemi et al. 1983 Saez 1989). Although studies with isolated cells from human testis have shown that a small proportion of the human cells can respond more or less similarly to those in rats, it is unknown why the magnitude of the steroido-genic response of...

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...

Aidshiv wasting

A number of randomised placebo-controlled studies of androgen therapy in HIVpositive men with AIDS wasting have reported increased lean mass, but minimal effects on total body weight, possibly due to concomitantly reduced fat mass. In the most comprehensive study (Grinspoon etal. 1998 Grinspoon etal. 2000), 51 men selected for both weight loss and low serum testosterone concentration were randomised to receive testosterone enanthate 300 mg or oil-based placebo intramuscularly every three weeks...

Amino and carboxylterminal interaction

A unique property of the AR in the regulation of gene expression is its ability to provide intra-domain interaction and communication between the amino- and the carboxyl-terminal domains of the receptor (Langley etal. 1995 1998 He etal. 1999). This interaction is mediated through a FXXLF and WXXLF motifs at amino acids 23-27 and 429-439 in the NH2-terminus of the receptor with distinct regions in the HBD of the AR (He et al. 2000). Interaction between NH2- and COOH-termini of the AR was shown...

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...

Androgen replacement in women the present state of the art

Another parallel between androgen replacement in men and in women is seen in the evolving technology of testosterone replacement. Hypogonadal men were initially replaced with potent oral anabolic steroids, then by substantial doses of oral MT. In high doses, however, this preparation has significant hepatic problems, including liver dysfunction (Westabay etal. 1977), hepatic adenomas (Farrell etal. 1975), and possible induction ofhepatic carcinoma (Goldfarb 1976) (see also Chapter 14). The...

Androgen response elements

Upon hormone binding, the AR is translocated from the cytoplasm into the nucleus where it uses its DNA binding domain to interact as a homodimer to specific DNA sequences termed androgen response elements (AREs). These elements are generally located at the promoter or enhancer regions of AR target genes such as probasin (Rennie etal. 1993), prostate binding protein (PBP) (Claessens etal. 1989 1993), glandular kallikrein-2 (hKLK2) (Murtha etal. 1993), prostate specific antigen (PSA) (Riegman...

Androgeninduced liver disorders

A consistent adverse feature of pharmacological androgen therapy, regardless of indication, is the risk of androgen-induced liver disorders (Ishak and Zimmerman 1987). These involve biochemical effects on hepatic function, hepatotoxicity (hepatitic or cholestatic) and liver tumor development (benign or malignant) and peliosis hepatis. These risks are a class-specific adverse effect of 17a-alkylated androgens, especially when used orally but no reliable estimates of the incidence or prevalence...

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...

Bioassay

While immunological methods measure the mass of circulating testosterone, the overall androgenic bioactivity in serum and peripheral tissues results frombioavail-able testosterone and other androgens. An in vitro androgen bioassay has been recently developed, based on the androgen-dependent interaction between the ligand-binding domain and the N-terminal region of the androgen receptor, which were fused to Gal4 DNA-binding domain of Saccharomyces cerevisiae and to the transcriptional activation...

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 disease

The role of androgens in bone development and disorders is discussed in Chapter 7. Androgen therapy to treat osteoporosis has the advantage for fracture prevention of not only increasing bone mass but possessing potentially synergistic beneficial effects on muscular strength and mental function to prevent falls due to frailty, an independent contributor to osteoporotic fractures. The evidence supporting androgen therapy, however, is limited. For treatment of idiopathic osteoporosis, the largest...

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...

Chaperones and cochaperones in androgen receptor action

In the absence of ligand, the AR exists in an inactive complex with molecular chaperones (Hsp90, Hsp70, Hsp56 and immunophilins). These proteins help in maintaining the correct conformation of the receptor necessary for efficient ligand binding (Pratt and Toft 1997). Fig. 2.3 Hsp70 and its co-chaperones Schematic diagram of the Hsp70 showing the NH2-terminal ATPase domain of the protein and the COOH-terminal substrate binding domain (SBD) responsible for interaction with unfolded proteins....

Choice of the kit and assay validation

Presently most laboratories choose to measure serum testosterone and DHT by commercially available kits. In all cases the final adoption of a kit for routine determination should depend on an in-house re-validation of the candidate assay. This re-validation includes an assessment of the sensitivity, specificity, accuracy and intra-assay precision of the kit. The specificity and the accuracy of the assay are checked by performing cross-reactivity, parallelism and recovery tests. These tests are...

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 macrophage functions

Monocytes which have immigrated into the vascular wall differentiate to macrophages and bind lipoproteins which have permeated the endothelium and become modified within the arterial wall, for example by oxidation. Unregulated uptake of oxidatively modified lipoproteins via type A scavenger receptors leads to the intracellular accumulation of cholesteryl esters in macrophages and thereby to foam cell formation. Foam cells together with T-lymphocytes, release inflammatory mediators which...

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...

Elderly subjects

The age-related decline in circulating DHEA(S) has led to a number of randomized trials to assess the effect of oral DHEA in otherwise healthy elderly subjects. In a first double blind placebo-controlled trial using a cross-over design 13 men and 17 women aged 40-70 years received either 50 mg DHEA or placebo for three months (and vice versa) (Morales et al. 1994). The subjects reported an improvement in wellbeing using a non-validated questionnaire for self-assessment of wellbeing. No change...

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,...

Enuresis

Following suggestions from the 1940s that androgen therapy might improve childhood enuresis, a recent controlled clinical trial involving 30 boys aged 6-10 years has claimed a benefit for oral mesterolone treatment compared with placebo (El-Sadr etal. 1990). This study may have been flawed as the method of randomisation leading to 20 being treated with mesterolone (20 mg daily for 2 weeks) compared with 10 on placebo (vitamin C) was not explained. The statistically significant increase in...

Exogenous androgen treatment in women

There is increasing interest in the use of testosterone as part of postmenopausal hormone replacement therapy, in particular to improve reportedly impaired sexual function (Davis and Tran 2001). Whether the concurrent use of testosterone will impact on the perceived benefits of estrogen hormone replacement therapy on the cardiovascular system is currently unknown. In a 20-year (1975-1994) retrospective survey ofthe Amsterdam Gender Dysphoria Clinic (vanKesteren 1997),293 female-to-male...

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,...

Frequency of steroid hormone misuse

Considering this misuse of AAS, the question arises to what extent AAS are really misused Is it restricted to a few high-level performing athletes in sports or is it so extensive as to be regarded as a social drug problem Available data derive 1. from positive findings resulting from checking AAS doping in competition sports and 2. from results of questionnaires concerning the use of AAS in non-competitive sports. 24.2.1 Androgen misuse in controlled competition sports Androgen misuse in...

Future research

As indicated by the trial involving MENT as a synthetic androgen, the future lies with substances which have a prostate-sparing effect but can exert the beneficial effects of androgens. This could be facilitated by selective androgen receptor modulators (SARMS), which are currently under development (see Chapter 20). It will be crucial for the efficacy of these substances that their aromatization-endproducts exert sufficient effects at the estrogen receptor. This is especially the case in...

General

In the human male, testosterone is the major circulating androgen. More than 95 is secreted by the testis, which produces approximately 6-7 mg per day (Coffey 1988). The metabolic steps required for the conversion of cholesterol into androgens take place in approximately 500 million Leydig cells that constitute only a few percent of the total testicular volume. Although Leydig cells are of major importance for the generation of circulating androgenic hormones, the adrenal cortex also...

General background

Many of the clinical features of aging in men are reminiscent of the clinical changes seen in hypogonadism in young men. It seems a reasonable working hypothesis that some of these clinical changes are causally related to declining Leydig cell function. Unfortunately, this possibility has not been fully explored and it is equally plausible that many of the observed changes and the age-related decrease in serum testosterone levels are coincident and independent consequences of aging....

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...

Gonadotropins

The determination of LH and FSH plays a key role in establishing the diagnosis of hypogonadotropic (i.e. secondary) or hypergonadotropic (i.e. primary) hypo-gonadism. However, during surveillance of testosterone therapy they are of less importance. Negative feedback regulation between hypothalamus, pituitary and testes causes negative correlation between serum testosterone and LH, as well as to some extent to FSH levels in normal men. In cases with primary hypogonadism (e.g. intact hypothalamic...

Hair growth

Male pattern baldness is described by a loss of scalp hair and affects up to 80 of males by the age of 80 years. Abalding scalp is caused by androgens and expression of the AR in the respective hair follicle and is thus known as androgenetic alopecia (see Chapter 6). One can assume that the influence of the CAG repeat polymorphism on androgenicity causes a variation of androgenetic alopecia. In men with such a clinical condition, significantly shorter CAG repeats were described in comparison to...

Hepatitis

Short-term controlled studies of androgen therapy in men with alcoholic hepatitis do not provide convincing evidence of any benefit. A prospective randomised multicentre Veterans Administration study claimed a mortality benefit after 30 days of oxandrolone treatment (80 mg daily), compared with placebo in 263 men presenting with alcoholic hepatitis (Mendenhall et al. 1984). The poorly defined entry and end-point definitions have been criticised (Maddrey 1986) and the benefits, if any, appeared...

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...

In vitro studies

Growth and resorption of bone tissue are mediated by osteoblasts and osteoclasts, respectively. Both types of cells exert mutual influence on each other and equilibrium between the activity ofboth cell lines maintains net bone mass during constant renewal and turnover, while decreased osteoblast activity as well as enhanced osteoclast activity will result in loss of bone mass. Androgen receptors have been located on normal human osteoblasts (Colvard et al. 1989) and both aromatizable and...

Influence of sexual behaviour on testosterone

The general concept that behaviour can feed back to hormone levels was first described with regard to sexual behaviour in an often cited publication (Anonymous 1970). A man working on an island attributed his increased beard growth immediately prior and during his visits to his girlfriend on the mainland to elevated androgen levels induced by sexual anticipation and sexual activity. Since then, numerous empirical studies dealt with effects of sexual behaviour (e.g., sexual stimulation,...

Introduction

Androgens are key regulators of male sexual differentiation and development of a normal male phenotype. In the adult they are required for maintenance and function of male genital organs and spermatogenesis. In addition, they are involved in a large number of physiological processes such as stimulating muscle and hair growth, bone development, erythropoiesis as well as controlling male psychosocial behavior. The two main androgens in the human body are testosterone and dihydrotestosterone, the...

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)....

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...

Ligand binding domain

The main function of the ligand-binding domain (LBD) is to bind ligand and it is helped in this task by molecular chaperones. Genetic and biochemical studies have shown that the chaperones Hsp90 and Hsp70 participate in the activation process of the receptor. They maintain the apoAR (AR in the absence of hormone) in a high affinity ligand-binding conformation which is important for efficient response to hormone (Caplan etal. 1995 Fang etal. 1996). To understand the specific recognition of...

Liver function

The testosterone preparations proposed for testosterone replacement do not have negative side-effects on liver function (e.g. Gooren 1994). Nevertheless, many physicians believe that testosterone may disturb liver function. This impression derives from 17a-methyltestosterone and other 17a-alkylated anabolic steroids which are indeed liver toxic and which should no longer be used in the clinic (see Chapter 14). However, there maybe ethnic differences since the weekly application of200 mg...

Lot40110

Results obtained measuring a certified control serum over one year by enzyme immuno assay (EIA). Shortly after introduction of this control serum it became evident that the assay had the tendency to overestimate the target value of this lot (17.9 nmol l). After servicing of the pipettor plate reader equipment and re-validation (August 2002) the results improved. to the scheme organizer. The results are then evaluated and the laboratory receives an assessment...

Mechanisms of androgen action within the erythropoietic system

First intervention trials concerning androgens and erythropoiesis were performed in intact rats which exhibited a marked increase of hemoglobin concentrations and bone marrow activity upon testosterone administration (Vollmer and Gordon 1941). These results were confirmed in orchiectomized or hypophysectomized animals in which the resulting anemia could be successfully treated by injections with testosterone propionate (Crafts 1946 Steinglass etal. 1941). These results led to clinical...

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...

Mixed agonistsantagonists

The development of therapeutically useful mixed AR agonists antagonists, like the clinically available SERMs for ER, may offer unique therapeutic advantages over their only agonistic counterparts. The steroidal compound mifepristone (RU38486) has partial agonistic and antagonistic actions (Berrevoets etal. 2002). Recently non-steroidal ligands known for better receptor selectivity than steroidal ligands were developed for estrogen, gestagen and androgen receptors. It was shown previously that...

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...

Muscular dystrophies

The effects of androgen therapy on neuromuscular disorders have been best studied by Griggs et al. in a series of careful studies of myotonic dystrophy (MD), a genetic myopathy due to a trinucleotide (CTG) repeat mutation in the myotonin (protein kinase) gene. MD is associated with testicular atrophy and biochemical androgen deficiency compared with age-matched healthy men or men with other neuromuscular wasting diseases (Griggs etal. 1985), although serum testosterone does not correlate with...

N Burger and P Casson

Do androgens have physiologic relevance in women Possible benefits of androgen replacement in women Testosterone replacement and sexual function Testosterone and insulin sensitivity in women Is testosterone cardioprotective in women Testosterone replacement and body morphology in women Testosterone replacement and bone mass in women Androgen replacement in women the present state of the art

Nongenomic effects of androgens

Most androgenic hormone action is thought to go through direct activation of DNA transcription via high affinity interactions with the androgen receptor. Information on the physiology and pathophysiology of these receptor actions will be given in the next chapters. In this section, complementary non-genomic effects of androgens will be discussed shortly. In recent years, a variety of rapid non-genomic effects of sex steroids has been documented for these nuclear-oriented ligands (reviewed by...

Nuclear localization and hinge region

A signal responsible for nuclear import is encoded by amino acid residues 608-625 (RkcyeagmtlgaRKlKKl) in the hinge region and is functionally similar to the bipartite nucleoplasmin nuclear localization signal (NLS). Mutational analysis showed that both basic parts of this nucleoplasmin-like sequence (shown in bold letters) contribute to the nuclear targeting of the AR (Jenster et al. 1993). It is possible that these portions of the AR are hidden but become exposed to mediate nuclear transport...

O Hiort and M Zitzmann

Generalized androgen insensitivity in humans Biochemical evidence for defective androgen receptor Genetic aspects of the androgen receptor in human androgen insensitivity The role of CAG repeat polymorphisms of the androgen receptor Kennedy syndrome a pathological expansion of the AR gene CAG repeats Pharmacogenetic aspects of testosterone therapy A hypothetical model of androgen action Treatment options in androgen insensitivity syndromes

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...

Outlook

Further decoding of the molecular and biochemical pathways is necessary for a comprehensive understanding of normal and abnormal sexual determination and differentiation. Based on the known molecular defects of impaired human sexual development, recent achievements in the field of functional genomics and proteomics offer unique opportunities to identify the genetic programs downstream of these pathways, which are ultimately responsible for structure and function of a normal or abnormal genital...

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...

Pluripotent stem cells as the target of androgen action

Because testosterone administration has reciprocal effects on muscle mass and fat mass, and increases satellite cell number, we considered the possibility that the target of androgen action might be a precursor cell from which muscle and fat cells are derived. We hypothesized that testosterone regulates body composition by promoting the commitment of mesenchymal pluripotent cells into myogenic lineage and inhibiting their differentiation into adipogenic lineage. To test this hypothesis, we...

Potential benefits

From the discussion in the preceding sections of this chapter and from literature reviews (Bhasin and Buckwalter 2001 Gruenewald and Matsumoto 2003), it emerges that testosterone administration to elderly men can induce potentially beneficial effects, but the results are often mitigated and there usually is no demonstrated impact on endpoints that are directly relevant for the clinic. Several studies have shown improvement of lean body mass and sometimes also of muscle strength, but whether...

Preface

Testosterone, the hormone that turns males into men, has enjoyed continually growing interest among clinicians and scientists and has gained public attention over the past decades. This heightened interest is matched by a similarly increasing body of research and knowledge about male physiology and testosterone's biological and molecular action, about clinical symptoms and syndromes caused by testosterone deficiency and about the modalities for its use. The number of preparations available for...

Principles of immunological testosterone assays

The principles of hormone measurement in general also apply to testosterone and good chapters on hormone assays are available in various textbooks of endocrinology (e.g. Segre and Brown 1998). As for all other hormones, the accurate measurement of testosterone in blood was made possible by the advent of radioimmunoassays (RIA). In immunological assays the hormone being measured (i.e. the antigen) competes with the labeled hormone (i.e. the tracer) forbindingto an antiserum (the antibody). Since...

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...

Red cell glycolysis

Erythrocyte-uptake of glucose subsequently results in glycolysis providing energy via phosphorylation products to enhance the activity of the general transcription machinery. This process is a prerequisite for red blood cell proliferation and is effective after 8-12 hours of glucose utilization (Molinari et al. 1976). Androgens can enhance the uptake of glucose (Molinari et al. 1976) once they have permeated the cell membrane, a process which is independent of various types ofhemoglobin...

Regulation of cholesterol side chain cleavage activity

The cholesterol side chain cleavage enzyme (P450scc) responsible for the initiation of the steroidogenic process is located in the inner membrane of the mitochondria. This inner mitochondrial membrane contains small amounts of cholesterol. The availability of cholesterol in the inner membrane is thus at least one of the rate-limiting factors for the generation of pregnenolone from cholesterol. Other factors that are of importance are the amount of oxygen, the activity of the P450scc enzyme and...

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)...

S Bhasin TW Storer AB Singh L Woodhouse R Singh J Artaza WE Taylor I Sinha Hikim R Jasuja and N Gonzalez Cadavid

Historical aspects of the anabolic steroid controversy Evidence that testosterone has direct anabolic effects on the mammalian Correlational studies demonstrating the relationship of serum testosterone concentrations and The effects of lowering endogenous testosterone concentrations on body composition The effects of physiologic testosterone replacement in healthy, young hypogonadal men The effect of supraphysiologic doses of testosterone on body composition Testosterone dose-response...

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...