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Anabolic Running Review

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Anabolic Running Review Summary

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Rationale for the Use of Antiandrogens in Cancer Treatment

Limited to surgical removal by radical prostatectomy (if the tumour is organ-confined) or endocrine therapy (if the tumour has crossed the capsule). One major problem in the treatment of non-organ confined prostate cancer is that the currently available therapies are only palliative. For locally advanced or metastatic prostate cancer the only effective therapies are those targeting the androgen receptor (AR). As most prostate cancer cells initially grow androgen-dependently, androgen withdrawal results in the apoptosis and inhibition of tumour proliferation. Although the majority of patients (80 ) responds to endocrine therapy, almost all prostate cancer patients undergo a relapse after a median duration of 12-18 months 197 . As no effective therapies are available for such patients, there is a high medical need for better therapies. The common therapies targeting the AR can be divided into lig-and depletion by reduction of serum testosterone levels of testicular origin via...

Pharmacology of Antiandrogens

Anti-androgens competitively bind to the AR-LBD. In clinical use are CPA, flutamide, nilutamide and bicalutamide. The first steroidal anti-androgen CPA has been reviewed extensively 202 . CPA suppresses gonadotropin release and leads to a decrease of testosterone levels. Flutamide and bicalu-tamide are non-steroidal compounds widely used in prostate cancer treatment. Bicalutamide 208 has replaced flutamide and nilutamide as the anti-androgen of choice for prostate cancer treatment since it has less side effects and a longer half-life. It is therefore administered at a relatively lower dose of 50 mg day. Response rates of bicalutamide in phase II clinical trials were comparable to those of CPA and flutamide 209 . In ongoing phase III studies, bicalutamide was compared with androgen ablation or maximal androgen blockade. Interim analyses confirmed the improved tolerability of bicalutamide however, the compound failed to improve survival 210,211 .

Autonomic Nerve System

The most prominent feature of nNOS null mice is that male mice exhibit inappropriate sexual behavior, mounting females indiscriminately regardless of whether the females are in estrus or not. Furthermore, when male mice are housed together, they are markedly aggressive and do not respond to appropriate submissive postures by wild-type males nor do they elicit submissive postures in response to attack by another mouse (51). These behaviors may be a selective consequence of the loss of nNOS, because nNOS null mice have no detectable abnormalities in brain structure and have normal synaptic plasticity in the hippocampus and cerebellum (52,53). Furthermore, plasma testosterone levels, which could account for both aggression

Acute Marijuana Toxicity

Physiological effects Dose-related tachycardia, blood pressure remains stable, increased appetite, dry (cotton) mouth, conjunctival injection, reduced intra-ocular pressure, bronchodilation, weakness, muscle tremors, urinary retention, low testosterone levels impotence. Psychological effects Dose-related euphoria, relaxation, sensory alterations. Preexisting psychopathology may predispose to transient, acute psychotic reactions with paranoid delusions and hallucinations.

Sertolileydig Cell Tumors Treatment issues

This classification of tumors includes tumors comprised of Sertoli cells only, as well as tumors containing both Sertoli and Leydig cells. Tumors composed of Sertoli cells only are uniformly stage I, and only one death has been reported 64 . Sertoli-Leydig cell tumors, also called arrhenoblastomas, are rare, accounting for less than 0.2 of all ovarian tumors, and usually present in adolescents and young adults. Since stage is the most important predictor of outcome, these patients should be accurately staged (Table 13.5). Over 95 of these tumors are confined to one ovary at the time of diagnosis therefore, a normal-appearing uterus and contralateral ovary can usually be preserved. Patients with disease greater than IB, with poorly differentiated tumors, or with heterolo-gous elements present should be treated with BEP 65 or paclitaxel and carboplatin. Patients can be followed with physical examinations and with serum aFP, inhibin, and testosterone levels. Of the 18 of patients who...

Interventions To Reduce Cytokines

Testosterone levels decline with aging in both men 87 and women 88 . Testosterone replacement in men increases muscle mass 89-91 and strength 92, 93 , and decreases fat mass 90, 94, 95 . Adipocytes are a potent source of cytokines, including TNF-a and leptin. The effect of testosterone on functional status may be mediated by reducing cytokine excess through an effect on adipocytes 96-98 .

Genetic Disease Models

As summarized in Table 2, disturbance of GnRH causes hypogonadism in Kallmann's syndrome by affecting the Kal-X gene, but GnRH is also affected in the Prader-Lahart-Willi syndrome and idiopathic hypogonadotrophic hypogonadism. Tumors, infiltrations, trauma, irradiation, ischemia, and surgery may cause hypothalamic or pituitary dysfunction.1,2 Isolated FSH deficiency is found with the Pasqualini syndrome. Table 2 Differential diagnosis of hypogonadotropic and hypergonadotropic hypogonadism Hypogonadotropic hypogonadism (HH) Idiopathic hypogonadotropic hypogonadism (IHH) Kallmann syndrome Adult-onset IHH Fertile eunuch syndrome Adrenal hypoplasia congenita Genetic defects of the gonadotropin subunits HH associated with other pituitary hormone deficiencies HH associated with obesity Prader-Willi syndrome Laurence-Moon-Biedl syndrome Hypergonadotropic hypogonadism Table 3 Laboratory testing of hypogonadism hypogonadism disease disease

New Research Areas

Large, long-term clinical trials are needed in males over the age of 50 years to determine the benefits and risks of androgen replacement therapy. These studies could determine if cardiovascular risk, prostate cancer, frailty, fractures, osteoporosis, cognitive function, and life expectancy are influenced by androgen replacement therapy. A critical area of uncertainty is what testosterone concentration is needed to provide adequate androgenic effects. This is an important question because it relates to the concentration of testosterone where benefits might or might not be expected. Should free, bioavailable, or total testosterone concentrations be used

Appetite Stimulants Progestational Agents

Originally used as a therapy in hormone-sensitive tumours, the observation that in a substantial number of patients appetite and weight increased led to it being studied in cancer cachexia 81 . It has been widely promoted as a therapy for cachexia and anorexia, although whether patient function or quality of life is improved is less clear. Appetite can be increased after only a short period of treatment 82 . Improvements in well-being may also occur in some patients without obvious changes in nutritional status 83 . Although it has not been assessed in all studies, there appears to be little impact on lean body mass, which is currently thought to be the most important body compartment in modulating function. In fact, a detrimental effect on muscle has been demonstrated in elderly males 84 and the weight gain seems largely secondary to increased fat and some fluid 85 . This is consistent with observations in AIDS patients 86, 87 . Megestrol acetate has...

Anabolic Agents and Testosterone

Muscle mass, but with unknown clinically meaningful changes in muscle function and disease outcome in HIV-infected men 98-102 . Morley et al. safely administered testosterone to older men with hypogonadism and noted an increase in the upper-arm strength of this population 52,103 . Dolan et al. found that testosterone administration increased muscle strength in low-weight HIV-infected women and suggested that it may be a useful adjunctive therapy to maintain muscle function in this group of patients 104,105 .

Testosterone Replacement

Data from the Baltimore Longitudinal Study on Aging (890 men), suggested that 20 of the men over 60 years of age, 30 over 70 years, and 50 over 80 years were hypogonadal, as defined by a total testosterone level 325 ng dl (11.3 nmol l), 46 . It is widely believed that total testosterone declines 1 per year after the age of 50 years 4 . Thus, the decline in testosterone follows a time course similar to the decline in muscle strength and muscle mass. Many individuals believe that it is the decline in testosterone over time that results Morley et al. 47 studied 37 men aged 69-89 years old. Twenty-six of the men had a mean total testosterone level of 272 ng dl. They were administered 200 mg of testosterone enanthate every 2 weeks for 3 months. Alternating cases was the method used to assign subjects to treatment or placebo groups. The authors reported a nine-fold increase in bioavailable testosterone and a significant increase in right-hand muscle strength. Sih et al. 48 reported that 12...

Gonadal Toxicity Following Malignancy Treatment

The loss of germ cells exerts secondary effects on the hypothalamic-pituitary-gonadal axis. Germinal apla-sia reduces the size of the testes. Consequently, testic-ular blood flow decreases, thus reducing the testosterone levels in the circulation.14 Because testosterone is a negative regulator of luteinizing hormone (LH), which is secreted by the pituitary, and LH is the primary stimulator of testosterone synthesis by the Leydig cells, LH increases to maintain constant serum testosterone levels. In addition, inhibin secretion by the Sertoli cells declines and, as inhibin limits follicle-stimulating hormone (FSH) secretion by the pituitary, serum FSH levels tend to rise.

Biochemical Features Of The Recq4 Helicase

To determine if each helicase can be expressed in specified tissues or organs, we analyzed the expression of all five RecQ helicase genes in various human organs and tissues by Northern blotting (Fig. 6). The data show that RECQL4, WRN, and BLM are expressed in a tissue specific-fashion, and support the idea that a close correlation exists between the site of gene expression and the site (tissue or organ) of disease phenotypes. For example, WRN is expressed highly in pancreas, testis, and ovary, and WS patients often show clinical symptoms of diabetes and hypogonadism. Also, BLM is highly expressed in the thymus

Pharmacology of 5aReductase Inhibitors

It reduces human serum DHT levels by 65-70 and prostatic DHT levels by 85-90 130 . The efficacy, safety and ability to reverse the natural progression of benign prostatic hyperplasia have convincingly been demonstrated. Since serum testosterone levels are unaffected, side effects such as decreased libido, fertility and sexual function are rare. Treatment with finas-teride results in shrinkage of the prostate gland by inducing apoptosis and atrophy of the epithelial cells with little effect on the stroma 130 . As fi-nasterides selectively inhibit the 5aR-2, the prostate still receives androgenic stimuli from the residual 30 of serum DHT and 10 of intraprostatic DHT, which has been generated by the 5aR-1.

Hormonal regulation of bone remodeling

Sex hormones are major regulators of bone turnover and remodeling in both genders. Estrogens reduce bone loss by inhibiting the generation of new osteoclasts, reducing the activation frequency of the BMU and promoting apoptosis of mature osteoclasts via mechanisms that are not well understood. Some of the effects of estrogen seem to be mediated via the modulation of growth factors and cytokines, while others are associated with binding to at least two different estrogen receptors (ERa, ERb). A reduction in circulating endogenous estrogen levels, as occurs during and after menopause, has been shown to prolong osteoclast survival and stimulate the recruitment and hence generation of osteoclasts. The result is an increase in the activation frequency of the BMU, reflected in a high bone turnover state.14 While there is no doubt that androgens (i.e., testosterone, dihydrotestosterone) play a dominant role in male bone health, it also appears that circulating estradiol levels are important...

Ataxiatelangiectasia

Many female AT patients have congenital hypoplasia of the ovaries and menarche may be delayed or absent (4,18). Male patients have been shown to have histological abnormalities of their testes, and incomplete spermatogenesis has been reported (19,20), although hypogonadism is less frequent and milder than in affected females.

Selective Androgen Receptor Modulators

The development of selective androgen receptor modulators (SARMs) that have anabolic effects on the muscle but that do not have adverse effects on the prostate and cardiovascular system has been of considerable interest for the treatment of older men with testosterone deficiency.51-54 The nonsteroidal SARMs differ from testosterone in that they are not converted to active metabolites, such as estradiol and DHT, but they act as agonists in muscle and bone and only partial agonists in prostate and seminal vesicles. More favorable pharmacokinetics and androgen receptor specificity of nonsteroidal SARMs compared to testosterone provide promise for unique pharmacological interactions with the androgen receptor and actions that may allow more specific indications for their clinical use. The proposed mechanisms to explain the tissue selectivity of SARMs as nuclear receptor modulators include ligand binding specific conformational changes in the ligand-binding domain and modulation of surface...

Pathogenesis of posttransplantation bone disease

The pathogenesis of post-transplantation bone disease is multifactorial (Table 46.1). Many patients have low bone mass prior to transplantation. Other pathoge-netic factors include glucocorticoid therapy, cyclosporin and other immunosup-pressive agents, hypogonadism, calcium and vitamin D deficiency and reduced physical activity, some of which may also contribute to bone disease prior to transplantation. Several studies have documented a high prevalence of osteoporosis prior to transplantation in 243 consecutive patients with chronic liver disease undergoing assessment prior to transplantation, 37 were shown to have osteoporosis, defined by World Health Organization criteria, at the hip and or spine and only 15 had normal BMD, i.e. a T score 1 at both sites 5 . Regression analysis demonstrated that age was a significant predictor of low BMD in women but not men the only other independent risk factor, again in women, was low body weight. Other groups have reported a similar or even...

Alcohol Induced Sexual Dysfunction

Chronic male alcoholics, even without liver dysfunction, commonly demonstrate primary hypogonadism, as evidenced by decreased sperm count and motility, and altered sperm morphology. Increases in luteinizing hormone and a decrease in the free androgen index were reported in noncirrhotic males and related to lifetime quantity of ethanol intake (Villalta et al., 1977).

Clinical Trial Issues

Most clinical trials with testosterone replacement treatment have been done in postpubertal males with hypogonadism from various causes. With few exceptions, they have been open-label double-blind studies would be a challenge, although preferable. Total testosterone concentrations have generally been used for the diagnosis of androgen deficiency and for adequacy of replacement testosterone therapy. Free or bioavailable testosterone concentrations may provide a better basis for diagnosis of deficiency and for adequate replacement therapy. Intrinsic potency, bioavailability, and rate of clearance from the circulation are determinants of the biological actions of androgens. A 5 mg delivery dose of a patch or gel system or 200 mg of either testosterone enanthate or cypionate intramuscularly (IM) every 2 weeks is administered for androgen replacement therapy in males with hypogonadism. If IM testosterone enanthate or cypionate is used, an injection of 100 mg produces a better pattern of...

Leptin and Congenital Leptin Deficiency

Total leptin deficiency or insensitivity is associated with hypothalamic hypogonadism in humans and rodents. Leptin treatment restored luteinising hormone secretion and pubertal development in leptin-deficient patients, confirming its critical role in reproduction. It was proposed that high levels of leptin observed in children might reflect leptin resistance, as seen in obesity, serving to maintain sufficient food intake and growth and prevent the onset of premature puberty. Central leptin administration decreases the expression of

Discussion

This patient was typical, in that she presented with symptoms and signs of hyperthyroidism, which were quite mild. There is usually a goiter present, but the findings characteristic of Graves' disease (orbitopathy, dermopathy) are not seen. Features of a pituitary mass lesion (headache, visual field abnormalities) may occur in a minority of patients, and were not observed in this patient. Acromegaly is present in about 15 of cases, and amenorrhea galactorrhea in about 10 (1). Hypopituitarism, especially hypogonadism, may also be a presenting feature. In this patient, FSH and luteinizing hormone (LH) were appropriately elevated for her postmenopausal status. It should be stressed that this ratio is not valid in postmenopausal women, as was the case here, or in men with primary hypogonadism, because they will have high serum a concentrations resulting from high serum gonadotropin levels. Of course, pituitary MRI will show a mass lesion in 95 of TSHoma patients, and should be normal in...

Acromegaly

The subjects ranged in age from 21 to 77 years with a median age of 43 years. Twenty-five individuals were Caucasian and 20 were Black. Twenty percent of the individuals had age-matched z-scores in the spine of -1 or poorer, whereas only 8.8 had similar age-matched z-scores in the proximal femur. Osteopenia in the spine was correlated with duration of disease and hypogonadism. Total body calcium was increased even in osteopenic patients suggesting that excess growth hormone insulinlike growth factor-1 (GH IGF-1) caused a positive bone balance except in the spine. Thirteen percent of subjects in this study had BMD values in the spine that were two or more SDs above the age-matched mean BMD value.

Insulinoma

Deficiency of GnRH with a resulting decrease in FSH and LH levels, producing an isolated hypogonadotropic hypogonadism. It is typically associated with agenesis or hypoplasia of the olfactory bulbs, producing anosmia or hyposmia (lack of stintiulus for GnRH production due to absent olfactory bulb catecholamine synthesis). More common in men.

Thalassemia Major

2 were hormone deficient and not receiving sex-steroid replacement. A control group consisting of 20 healthy subjects was matched for age, sex, height, and weight. Bone density was measured by DXA (SOPHOS L-XR-A) at the PA lumbar spine and proximal femur. In this cross-sectional study, bone density at the PA lumbar spine was reduced in groups 1 and 2 compared to the control group. The reduction was greater in group 2 than in group 1. Proximal femoral bone density was reduced in group 2 only in comparison to the control group. The authors suggested that the treatment of hypogonadism with sex hormone replacement therapy was beneficial in the prevention and treatment of osteoporosis in thalassemics.

Case Description

A DEXA scan to assess bone mineral density showed severe osteoporosis with a bone mineral density (BMD) at the spine (L1-L5) of 0.774 gm cm2, T score (in relation to peak BMD) of -2.89 and Z score (age matched normal) -2.83 and BMD at the hip of 0.713 gm cm2, T score of -2.59 and Z score of -2.30. His total testosterone was 363 ng dL (normal range 300-1200 ng dL) and free testosterone 30 pg mL (normal 50-240 pg mL).

Sarcopenia

With aging, testosterone levels decrease because of failure of the hypothalamic-pituitary-gonadal axis 33 . The decline in testosterone occurs at the rate of about 1 per year, beginning at 30 years of age. Loss of testosterone leads to an increase in adipocyte precursors and a decrease in satellite precursors. In addition, it is associated with a decline in muscle-protein synthesis. Testosterone replacement in older persons increases muscle mass and, to a lesser degree, muscle strength 34 . Decreased creatine intake Peripheral vascular disease Hypogonadism Cytokine excess Myostatin excess

Laboratory Features

Endocrine abnormalities were found in two-thirds of our patients at presentation. Hypogonadism was the most common abnormality, and 71 of males had erectile dysfunction. Twenty-four of 28 patients who had serum testosterone levels measured had a reduction. Gynecomastia was found in 17 men. Prolactin levels were not increased. Hypothyroidism was found in 14 of patients. An additional 12 had a mild increase in the thyroid-stimulating hormone level but had normal thyroxin levels. Abnormalities of the adrenal-pituitary axis were present in 16 . In five additional patients, adrenal insufficiency developed during follow-up.

Gonadal Function

In the male there are two aspects of testicular function to consider in those undergoing treatment for malignant disease the germinal epithelium responsible for production of spermatozoa under the control of FSH, and the Leydig cells responsible for testosterone production under the control of LH. Chemotherapy, particularly alkylating agents such as cyclophospha-mide and procarbazine, can cause failure of the germinal epithelium, resulting in oligospermia or azoosper-mia. Although Leydig cell function may be impaired, with testosterone levels in the low-normal range associated with an elevated LH level, testosterone deficiency is rarely seen following chemotherapy. Radiation to the testes can cause germinal epithelium failure at doses as low as 2 Gy. Doses in excess of 20 Gy result in Leydig cell failure and testosterone deficiency 87 . Men undergoing treatment known to cause azoospermia should be counseled and offered sperm banking, for use later in life when considering fertility....

Androstenedione

However, clinical studies do not support its claimed benefits. Androstenedione does not increase muscle strength or muscle size. Androstenedione does not appear to increase testosterone levels on a long-term basis. It does increase estrogen levels, which may increase the risk of conditions and cancers that are sensitive to this hormone, including endometriosis, uterine fibroids, and cancers of the breast, uterus, ovaries, and prostate. Androstenedione decreases levels of HDL, the good form of cholesterol, and may thereby increase the risk of heart disease and stroke. Multiple other possible side effects may occur with androstenedione.

Diet Infertility

In men, poor nutrition - a diet high in refined carbohydrates, saturated fat, and processed foods and low in important micronutrients -may reduce sperm number and motility. To help increase sperm quality, the diet should emphasize high-quality protein, whole grains, and fresh fruits and vegetables. Heavy alcohol consumption (more than 3 drinks per day) can impair fertility.6 Overweight men are more likely to have low testosterone levels and lower numbers of sperm.

Endocrine System

Alcohol interferes with gonadal function even in the absence of cirrhosis by inhibiting normal testicular, pituitary, and hypothalamic function. Testicular atrophy, low testosterone levels, decreased beard growth, diminished sperm count, and a loss of libido result. However, testicular atrophy does not occur in all male alcoholics but is associated with alcohol dehydrogenase polymorphism in the testes, as reflected by the genetic variant of an increased frequency of the ADH21 allele (Yanauchi et al., 2001).

Treatment Strategies

If hypogonadism is identified as the underlying cause of fatigue, exogenous testosterone or synthetic anabolic steroids may be administered (Dufour et al., 2005). However, patients receiving this treatment are susceptible to anabolic and androgenic effects such as increased heart rate, increased blood pressure, and hirsutism. Testosterone therapy may take the form of injections, pills, patches, gels, or creams. This treatment has been shown to have a beneficial effect on not only fatigue but also sexual interest, appetite, wasting, energy levels, and even concomitant depression. It Anemia Hypogonadism Adrenal insufficiency Hypothyroidism Infections Malnutrition Depression Inactivity

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