Assessment of free testosterone

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

Clinical studies with finasteride in men with benign prostatic hyperplasia

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

References

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

Randall

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

Testosterone ester combinations

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

Androgen deficiency states in women

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

Senile osteoporosis

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

Zonal and cellular organization of the prostate

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

Clinical studies with finasteride in women

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

Venous disease

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

Sex hormone binding globulin and free testosterone serum levels

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

Testosterone and erection in normal men

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

Hypoandrogenism of senescence and sexual activity

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

Regulation of pregnenolone metabolism

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

Testosterone enanthate

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

Treatment with DHEA clinical studies

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

Androgen dependence of spermatogenesis

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

Intact singers

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

Role of 5areductase in androgen physiology and pathophysiology

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

Locally produced factors

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

Clinical studies with finasteride in men with androgenetic alopecia

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

Principle of hormonal male contraception

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

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...

Effects of exogenous testosterone on cardiovascular risk factors

In the majority of studies, substitution of testosterone in hypogonadal men had no impact on total cholesterol, LDL cholesterol and triglycerides but decreased HDL-C and Lp(a) levels. Treatment with supraphysiological doses of testosterone or androgen-like anabolic steroids in normal men decreased HDL-C by about 20 and more. Conversely, castration as well as biochemical suppression of endogenous testosterone by GnRH antagonists increased HDL-C (reviewed in Wu and von Eckardstein 2003). In one...

Androgen action on spermatogenesis

5.5.1 Testicular androgen production, metabolism and transport Testosterone is produced by the interstitial Leydig cells. The details and mechanisms of testosterone synthesis and secretion are presented in chapter 1. Testicular concentrations of testosterone can exceed those found in circulating blood up to 100-fold or beyond. It was thought initially that spermatogenesis requires high local amounts of testosterone. This view could not be corroborated and spermatogenesis in the rat can proceed...

Direct effects of testosterone on erection

Androgens and a functioning androgen receptor are necessary for normal development of the human penis. In humans, the penis grows in phases, initially during early gestation and then continuing until approximately the age of five. A latency period follows until puberty, when penile size responds to the increase of testosterone levels. Growth ceases at the completion of pubertal growth despite continued high levels of circulating testosterone. The exact mechanism of penile growth cessation...

Preliminary studies with MK386 a type 1 5areductase inhibitor

Separate studies were conducted with a type 1-selective 5aR inhibitor to determine utility of this mechanism of action, which differs from that of finasteride in inhibiting the alternate isoenzyme of 5aR, in the treatment of clinical disorders. Based on the known stimulation of acne by androgens (Hamilton 1941) and tissue localization of the type 1 isoenzyme (Harris et al. 1992 Thiboutot et al. 1995), which is prominent in sebaceous glands of the skin, a potential target for intervention was in...

Physiology of erection

Erection can be regarded as a complex neurovascular process that can be initiated by recruitment of penile afferent signals (reflexogenic erection) and by visual, acoustic, tactile, olfactory and imaginary stimuli (psychogenic erection). Several brain regions have been identified that are involved in the initiation of penile erection. The effect of testosterone on these central mechanisms is described in depth in Chapter 4. At the penile level, the erection is determined by the contractile...

Generalized androgen insensitivity in humans

Partial Androgen Insensitivity Syndrome

Defective androgen action caused by cellular resistance to androgens causes the androgen insensitivity syndrome (AIS) (Hiort etal. 1996 Quigley etal. 1995). The end-organ resistance to androgens results in a wide clinical spectrum of defective virilization of the external genitalia in 46,XY individuals. Mullerian duct derivatives are usually completely absent because of the normal ability of the foetal testes to produce AMH. Since the AR gene has been cloned, it became obvious that inactivating...

Hematocrit and ischemic disease

Some men treated with testosterone respond with polycythemia, a phenomenon especially observed in older men (Drinka etal. 1995 Hajjar etal. 1997 Krauss etal. 1991 Sih etal. 1997). Especially the combination of increased red blood cell volume and decreased plasma volume results in a marked elevation of hematocrit, hence blood viscosity. In one study, three of nine patients with hematocrit > 48 (53 , 58 and 64 ) experienced central ischemic episodes such as basal ganglia stroke, brain stem...

Mechanisms of action

Three mechanisms of action have been described for DHEA as precursor for active sex steroids, as a neurosteroid interacting with neurotransmitter receptors and as a ligand for a specific DHEA receptor (for review see Allolio and Arlt 2002). As the human steroidogenic enzyme P450c17 converts almost no 17a-hydroxyprogesterone to androstenedione, the biosynthesis of virtually all sex steroids begins after the conversion of 17-hydroxypregnenolone to DHEA. Thus, only DHEA is converted to...

Outlook

Initially research in hormonal male contraception was predominantly driven by the WHO Human Reproduction Programme (Waites 2003), by the Population Council, the NIH and USAID CONRAD. While these organisations still play an important role in the development of the field, investigators initiated complementary research and tapped the national research councils and other organisations for support. When pressure from the public also increased, the pharmaceutical industry finally succumbed to the...

Sarcopenia associated with chronic illnesses

Several studies on the effects of androgen supplementation in HIV-infected men have been reported (Bhasin et al. 1998 2000 Coodley et al. 1994 Coodley and Coodley 1997 Dobs etal. 1999 Grinspoon etal. 1998 2000 Sattler etal. 1999 2002 Strawford et al. 1999a 1999b Van Loan et al. 1999). However, many of these studies were not controlled clinical trials. Most of the studies were of short duration ranging from 12-24 weeks. Several androgenic steroids have been studied in a limited fashion,...

Adult testosterone levels

A number of studies provide evidence for an influence of circulating levels of androgens on aggression in males and females after puberty (Table 4.2). The hormonal effect is now referred to as activational as opposed to organizational effects in early life. In the beginning, several pertinent studies were carried out in prison where usually some ofthe inmates are highly aggressive. Here, the researchers expected a significant relationship between current testosterone levels and aggression, a...

Androgen dynamics in women

In women, androgens have been both celebrated and cursed as the hormones of aggression and anger and as fuel for passion. In reality, while the effects of testosterone in men have been widely studied and a clear testosterone deficiency state identified, investigation into the role of testosterone in women is a far more recent venture that is only now yielding fruit. Until recently, circulating androgens in women have simply been considered either by-products of adrenal cortical or ovarian...

Hereditary angioedema

The efficacy of oral 17a-alkylated androgens in hereditary angioedema was established by a small, double-blind, placebo-controlled randomised cross-over study (Spaulding 1960) in which six members of a single family received multiple periods of treatment or placebo. This study clearly demonstrated the efficacy of oral methyltestosterone in reducing the frequency of attacks well before the disease pathogenesis was understood. Subsequent studies confirmed these observations showing that androgen...

Transdermal application

The skin easily absorbs steroids and other drugs and transdermal drug delivery has become a widely used therapeutic modality. The scrotum shows the highest rate of steroid absorption, about 40-fold higher than the forearm (Feldmann and Maibach 1967). This difference in absorption rates has been exploited for the development of a transdermal therapeutic system (TTS) to deliver testosterone. 40 and 60 cm2 large polymeric membranes loaded with 10 or 15 mg testosterone when attached to the scrotal...

Testosterone buciclate

The disadvantage of all esters described so far is that they produce initially supra-physiological testosterone levels which may exceed normal levels severalfold and then slowly decline, so that before the next injection pathologically low levels may be reached. Some patients recognize these ups and downs of testosterone levels in parallel variations of general well-being, sexual activity and emotional stability. Despite these disadvantages testosterone enanthate and cypionate are still the...

Anemia of endstage renal failure

The anemia of end-stage renal failure has multiple contributory factors including EPO deficiency, toxic inhibitors of EPO action, androgen deficiency, micronutrient deficiency (iron, folate, pyridoxine), blood loss and hemolysis (Neff et al. 1985). The effect of androgen therapy on hemoglobin involves both increased circulating EPO concentration (Buchwald etal. 1977) and augmentation of EPO action (Ballal etal. 1991). EPO deficiency is a major factor (Winearls 1995) and androgen therapy...

The mechanism of androgen action in the hair follicle

6.4.1 Hair growth in androgen insufficiency syndromes As described in Chapters 1 and 2 of this book, androgens from the blood stream enter the cell and bind to specific, intracellular androgen receptors, usually in the form of testosterone or its more potent metabolite, 5a-dihydrotestosterone. The hormone-receptor complex, generally in combination with transcriptional regulators then activates the appropriate gene transcription for that cell type. Androgen insufficiency patients without...

Androgen treatment in hypogonadism and effects on erythropoiesis

As mentioned above, early studies in artificially hypogonadal rats demonstrated the positive effects of testosterone on erythropoiesis by withdrawal and substitution trials androgen administration to healthy men can cause a marked increment in erythropoiesis (Kamischke et al. 2002 Palacios et al. 1983 Wu et al. 1996). Correspondingly, hypogonadal men very often present with markedly lowered concentrations of erythrocytes and or hemoglobin, hence anemia. Indeed, anemia can be used as a...

Ligand independent activation of the androgen receptor

In the absence of ligand, several molecules or signal transduction cascades have been shown to activate the transcriptional activity of the AR. For example the protein kinase C (PKC) activator 12-O-tetradecanoylphorbol-13 acetate enhanced AR activity 10-12-fold in the absence of androgen (Darne etal. 1998). In androgen depleted LNCaP prostate cells, stimulation of the transactivation by the protein kinase A activator forskolin was shown to require the N-terminal region of the receptor (Nazareth...

Sjogrens disease chronic urticaria

Few well-controlled studies of androgen therapy have been reported in other rheumatological disorders. This is not just due to paucity of cases in the female-preponderant autoimmune diseases as there are no controlled studies of androgen therapy even in ankylosing spondylitis or gout, the male preponderant rheumato-logical diseases. In systemic lupus erythematosus (SLE), only two small uncontrolled studies (including together five men among 17 patients) using androgen therapy (nandrolone...

Thrombocytopenia

A beneficial effect of androgen therapy in thrombocytopenia due to marrow failure has been suggested by a study in myelodysplasia associated with thrombocytopenia in which 20 patients were randomised to receive either danazol (600 mg daily) or fluoxymesterone (1 mg kg day). Althoughboth groups had an impressive response in termination of clinical bleeding (6 6) and increasing platelet count (11 20), the lack of a placebo group means that the contribution of natural remission could not be...

Physical exercise

A great deal of research on the effects of exercise upon the male and female reproductive system has taken place, and it has been demonstrated that some similarities, especially with regard to testosterone, exist between the sexes in the physiological outcomes of physical training when intrinsic gender differences in the endocrine system are acknowledged (Hackney 1989 Shangold 1984). Despite their athletic appearance male athletes have lower androgen levels than untrained men in a resting...