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...

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...

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...

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...

Contamination of nutritional supplements with prohormones

Since 1999, the same time when prohormones were entering the market, nutritional supplements became sporadically contaminated with prohormones. Contamination in this context signifies that a supplement contains substances which are not declared on the label. As the amount of contamination is low, less than 1 per mill of the product, it is assumed that the prohormones are not intentionally added to the supplements but contamination may occur due to poor quality control during the production of...

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...

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...

Endogenous androgen deprivation

Hamilton and Mestler (1969) investigated mentally handicapped castrated and non-castrated inmates of a psychiatric institution and found that castrated patients lived longer. Nieschlag and colleagues compared the life span of castrated and intact singers and did not reveal any differences in total or cardiovascular mortality (Nieschlag et al. 1993). In agreement with a neutral or beneficial effect of endogenous androgens in men, bassos tended to live longer than tenors. By contrast and in...

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...

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...

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....

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...

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...

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

In industrialized countries, the average life expectancy is some eight years less in males than in females. Since cardiovascular disease is the most frequent cause of death and male gender is one of the classic risk factors for premature coronary artery disease (threefold excess in men before the age of 55 years), stroke (up to twofold excess in men), peripheral vascular disease (two to threefold excess in men) and heart failure, the lack of estrogens and the abundance of androgens have often...

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...

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...

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...

Overtall stature

The effect of testosterone on epiphysial closure may be used to treat boys who are dissatisfied with their prospective final overtall body height (for review Drop etal. 1998). Treatment has to start before the age of 14. Doses of 500 mg testosterone enanthate have to be administered every two weeks for at least a year to produce effects (Bettendorf etal. 1997). This treatment should be reserved for special cases since tall stature is not a disease but rather a cosmetic and psychological...

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...

Practical approach to the patient with DHEA deficiency

At present there is no established indication and no generally accepted pharmacological preparation of DHEA for treatment. However, there is growing acceptance (Achermann and Silverman 2001 Arlt and Allolio 2003a Oelkers 1999) of the view that DHEA replacement in patients with adrenal insufficiency may be beneficial in a substantial percentage of cases. In these patients not only very low or absent circulating DHEA(S) is demonstrated, but there is evidence of impaired wellbeing, reduced...

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...

Prenatal hormones and aggression

Animal studies generally indicate that the presence of androgens in early life is important in establishing a biological readiness for future aggressive behaviour (Archer 1988). Much of the pertinent research on psychological effects of sex hormones in human studies consists of naturally occurring syndromes which result either from spontaneous endocrine excess or deficiency during fetal and early postnatal life (e.g., congenital adrenal hyperplasia) or prenatal sex hormone treatment of the...

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...

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...

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...

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...

Structure of the androgen receptor gene and its mRNA

The AR gene consists of 8 exons (Fig. 2.1) (Lubahn etal. 1989) it shares this gene structure with the other steroid receptors which form a subfamily of the nuclear receptors. Besides the steroid receptors this superfamily also includes the retinoid and thyroid hormone receptors, vitamin D receptors, peroxisome proliferator-activated receptors and a number of orphan receptors (Hager 2000 Owen and Zelent 2000 Whitfield et al. 1999). All the members have a unique molecular structure comprising a...

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...

Testosterone in blood

Testosterone circulates in serum largely bound to transport proteins. Like other steroids and thyroid hormones, both albumin and specific binding globulins are involved in testosterone binding. Testosterone binds to albumin with low affinity but, due to its high concentration, albumin displays a very high binding capacity. The specific transport protein for testosterone, some other androgens and estradiol is SHBG. A systematic analysis of serum transport of steroid hormones and their...

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....

Wasting

Many older studies examined the role of androgen therapy to augment body weight in patients with wasting or cachexia from a variety of underlying medical diseases as well as for cosmetic reasons in otherwise healthy people. For example, one doubleblind study treated 28 healthy men and women and 26 male patients with wasting associatedwith chronic diseases (e.g. tuberculosis, chronic degenerative disorders) with placebo or one of two doses (25 mg or 50 mg daily) of norethandrolone for 12 weeks...

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

Injections 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

Estrogen And Androgen Over Time 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

Testosterone Enanthate Pharmacokinetics

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...

The paradoxical effects of androgens on human hair growth

Normal Man Body

6.3.1 Human hair growth before and after puberty In utero the humanbodyiscoveredwith quite long, colourless lanugo hairs. These are shed before birth and at birth, or shortly after, babies normally exhibit pigmented, quite thick protective hairs on the eyebrows and eyelashes and variable amounts on the scalp by the age of three or four the scalp hair is usually quite well developed, though it will not yet have reached its maximum length. These readily visible pigmented hairs are known as...

Contraindications to testosterone treatment

Effects and side-effects of testosterone therapy have been described in detail above. Here the major reasons for not initiating or for interrupting testosterone therapy are briefly summarized. The major contraindication to testosterone therapy is a prostate carcinoma. A patient with an existing prostate carcinoma should not receive testosterone. A carcinoma has to be excluded before starting therapy and the patient on testosterone should be checked regularly for prostate cancer (digital...

Factors affecting serum testosterone levels in elderly men

16.2.4.1 Influence of physiological factors and lifestyle The physiological basis underlying the large inter-individual variation in serum testosterone levels seen at any age is not yet fully elucidated, but several physiological variables and factors related to lifestyle have been identified accounting for part of the wide range of normal values observed in healthy men (Kaufman and Vermeulen 1999). The apparent inter-individual variability of testosterone levels is not merely artefactual as a...

Interpretation of results

For androgen replacement therapy and male hormonal contraception there is a need for orally active androgens which can substitute the total spectrum of physiological effects of testosterone, preferably at a lower dose. In the search for new orally active androgens, a combination of in vitro and in vivo assays has been used with the aim to select androgens with higher androgen receptor affinity and less metabolic instability than the reference androgen, testosterone. Additional prerequisites of...

Exogenous testosterone treatment in men with cardiovascular disease

The longterm effects of exogenous testosterone on coronary event rates has not been investigated. However, in several small studies therapeutic doses of testosterone reduced the severity and frequency of angina pectoris events and improved electrocardiographic signs of myocardial ischemia. Webb and colleagues (Webb etal. 1999) showed that a single i.v. bolus of 2.3 mg of testosterone increased time to 1-mm ST segment depression by 66 sec in 14 men with coronary artery disease and low plasma...

Subdermal application

Subdermal testosterone pellet implantation was among the earliest effective modalities employed for clinical application of testosterone which became an established form of androgen replacement therapy by 1940 (Deansley and Parks 1938 Vest and Howard 1939). With the advent of other modalities, e.g. intramuscular testosterone ester injections, they went out of general use. However, investigations in the 1990s redefined the favourable pharmacokinetic profiles and clinical pharmacology of...

Initiation of substitution therapy and choice of preparation

Testosterone substitution is started when the diagnosis is established and serum testosterone levels below the normal range are found, taking into account the various influences on serum testosterone levels including diurnal variations. In order to establish a diagnosis by documenting low serum testosterone levels, usually determination of testosterone in a serum sample taken between 08.00 and 10.00 in the morning is sufficient (Vermeulen and Verdonck 1992). Pooled sera will not improve...

H6 Prevalence of testosterone deficiency in patients with erectile dysfunction

Various studies have estimated the prevalence of testosterone deficiency in patients with erectile dysfunction. A systematic multidisciplinary assessment of 256 men with erectile dysfunction showed a prevalence of hypothalamic-pituitary-gonadal axis abnormalities of 17.5 . In only 12.1 did the testosterone deficiency clearly contribute to erectile dysfunction (Nickel et al. 1984). Another routine hormonal screening in 300 men presenting with a primary complaint of erectile dysfunction showed a...