Andropauze & testosteron replacement therapy (engels)

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ANDROPAUSE: CLINICAL FEATURES AND THERAPEUTIC OPTIONS

INTRODUCTION:

In men and women there is a consortium of physiologic and psychologic symptoms as well as biochemical changes that are attributed to an aging-related decline in gonadal hormones. Menopause in women is based on the end of the reproductive cycle associated with ovarian failure and is characterized by the relatively abrupt onset of well-recognized symptoms. In contrast, the term andropause has been used to describe the slow, steady decline of testosteron in men as they age. This process is not universal in men, is more insidious in its onset and its clinical presentation more subtle and varied. For these reasons it has been suggested that androgen decline in the aging male (ADAM) is a more appropriate designation for this syndrome.

1 Recently there has been considerable interest in both male health and the topic of andropause. This paper will discuss the physiologic and clinical manifestations of this syndrome and provide an approach to the treatment of men with these symptoms.

CHANGES IN THE AGING MALE

Clinical Manifestations The andropause syndrome can be difficult to detect clinically as the symptoms are often attributed to the natural aging process. The characteristic symptoms include weakness, depression, fatigue, changes in body hair and skin, loss of libido, lean body mass and bone mass as well as decreases in intellectual activity and spatial orientation ability. The severity and frequency of each symptom are variable.
Erectile Function Male aging is associated with a decline in coïtusual interest and activity and an increase in erectile dysfunction. In men between the age of 40 and 70, 52% reported some degree of impotence.2 This aging related impaired coïtusual function is multi-factorial with testosteron likely playing only a minor, if any role. The Massachusetts Male Aging Study, which surveyed over 1,100 men, was unable to find any relationship between impotence and testosteron levels.3 testosteron appears more important in maintaining desire and nocturnal erections2 rather than directly improving erectile function.
For most men with coïtusual dysfunction there are other therapies more effective for treating erectile dysfunction including sildenafil (Viagra), penile injections, vacuum-suction devices and penile prostheses.
Mood and Cognition It has been frequently described that testosteron replacement improves one's sense of over-all well-being.4 Improvements in energy and mood and a decline in anxiety have been described in hypogonadal men receiving testosteron.5,6 In a double blinded crossover trial of elderly men, 92% were able to correctly identify which period they had been on testosteron rather than placebo based on improved libido, aggressiveness in business transactions and a general improvement in sense of well being.7 Similarly it has been suggested that testosteron administration can improve the decline in spatial cognition that is associated with aging.8
Body Composition Male aging is associated with a decrease in both muscle tissue mass and some aspects of muscle strength.5 A role for testosteron in these changes is supported by the fact that testosteron replacement in young, healthy, hypogonadal men increases fat-free mass, muscle size and strength.9 Similarly in young, healthy, eugonadal men supraphysiologic doses of testosteron increases fat-free mass, muscle size and strength.10 Exercise, and in particular, weight or resistance training appears to augment the effect.10
testosteron also appears to play a role in the increase in adipose tissue and redistribution of body fat associated with aging.11 Leptin is a protein produced in adipose tissue that is believed to play a role in regulating body weight and adipose tissue mass by stimulating satiety or hunger. Leptin levels are strongly correlated with testosteron in men12 and replacement of testosteron in elderly men reduces leptin levels.11 These findings suggest that testosteron has an effect on obesity.
Bone Density Osteoporosis is a significant, but under recognized cause of morbidity and mortality in elderly men. As in women bone density decreases and osteoporotic fractures increase with age.8,13 Hypogonadism is associated with a significant decrease in bone density and increased risk of fractures. Testosterone is thought to play a role in this process although the mechanism is unclear. Testosterone replacement has been shown to significantly improve bone mineral density in hypogonadal men.14 A reduction in fractures following normalization of bone mineral density has not been established.
Androgen Levels Only 1-2% of the testosteron in the circulation is free or unbound to plasma proteins. The remainder is bound either tightly to coïtus-hormone-binding-globulin (SHBG, 60%) or weakly to albumin (40%). Hypogonadal men are best identified through measurement of bioavailable testosteron that includes only the free and albumin bound components.15 The SHBG-bound-testosteron is not available for tissue uptake.
Total serum testosteron, free testosteron and non-SHBG-bound testosteron all decline with increasing age.15 In contrast, SHBG-bound testosteron increases with increasing age. The net result is that bioavailable testosteron decreases disproportionately more than total testosteron.15 In addition there is also a flattening of the normal circadian rhythm of testosteron release leading to low steady levels of testosteron throughout the day.3
The clinical significance of the age-related decline in testosteron is unclear. There is great variation in serum testosteron among men of all ages, such that many healthy elderly men have levels within the normal range.4 Total testosteron levels below the normal reference level are reported in 7% of men age 40-60, 20% of men age 60-80 and 35% of men over 8016. In some older men with total testosteron values in the low normal range the clinical significance of this may be better established by measuring the bioavailable non SHBG bound fraction. Unfortunately normal values for bioavailable testosteron are not unequivocally established thus any result must be correlated with the clinical scenario.

TREATMENT

Treatment of androgen deficiency should be aimed at restoring libido and a sense of well-being. Other benefits may include prevention of osteoporosis, maintenance of muscle strength and prevention of frailty and improved mental acuity.
The evidence for testosteron replacement in elderly men is based on two short term and one long-term study. Sih et al11 assessed upper extremity strength and side effects over 12 months in 32 hypogonadal men (bioavailable testosteron (60 ng/dL) over the age of 50, randomized to either placebo or 200 mg testosteron cypionate by intramuscular injections (Level 2 evidence). Their treatment group showed improvements in grip strength, increased hemoglobin and decreased leptin. There were no changes in cognitive ability, body composition, serum PSA or prostate abnormalities on digital rectal examination between the two groups. Unfortunately there was no assessment of more clinically relevant physical parameters, such as lower extremity strength, which could reflect abnormalities of gait or falls. Similarly there lacked any quantitative quality of life assessment. Polycythemia developed in 4 men (24%) receiving testosteron, three were withdrawn from the study, and one received therapeutic phlebotomy.
Tenover et al7 performed a six-month crossover trial of IM testosteron replacement or placebo in 13 men (ages 57-76) with low to borderline low levels of testosteron (<400 ng/dL) (Level 2 evidence). Testosterone produced an increase in body weight and lean body mass but no difference in grip strength. Testosterone also produced a significant decrease in urine hydroxyproline, implying a suppression of bone resorption but there was no change in other markers of bone metabolism. Testosterone also resulted in an increase in PSA from baseline; however, there were no abnormalities detected by DRE or ultrasonography. Two patients receiving testosteron developed polycythemia.
Morley et al17 examined the effects of IM testosteron replacement in 8 elderly (mean age 78), hypogonadal men compared to 6 age matched controls over 3 months (Level 3 evidence). The treatment group had significant increases in grip strength, serum osteocalcin and hemoglobin and decreased total serum cholesterol.

COMPLICATIONS

Prostate growth, whether malignant or benign, is highly dependent on steroid hormones. A major concern is that testosteron replacement will stimulate the onset or hasten the development of prostatic carcinoma. Removing androgens by androgen blockade has a well recognized inhibitory effect on clinically diagnosed prostate cancer. Whether replacing testosteron in hypogonadal promotes development of de novo malignancies or progression of sub-clinical carcinomas is not known. To date, the small and short term studies have not demonstrated an increased risk.1 However, the level of experience at this time is insufficient to conclusively rule out a causal relationship.1 For this reason careful monitoring of these patients with serum PSA and digital rectal exams is recommended.
The effect of testosteron on benign prostatic hypertrophy has also been a concern. The most recent data from placebo controlled trials of testosteron replacement in hypogonadal men suggests that the changes in PSA, prostate volume and lower urinary tract symptoms are clinically insignificant.18 Current recommendations suggest serum PSA and digital rectal exam before instituting testosteron replacement then yearly thereafter.
Lipids The effects of hypogonadism and testosteron replacement on lipid profiles and risk of cardiovascular disease is unclear. Interestingly, low serum testosteron levels appear to be associated with increased triglycerides and decreased levels of high-density lipoprotein cholesterols; testosteron replacement appears to restore these to more favorable levels.19 Several recent studies have suggested that hypogonadism may be a risk factor for coronary artery disease although this remains to be fully explained.20,21 The impact of testosteron therapy on cardiovascular risk is not entirely clear, however, most current data suggests it does not induce an atherogenic profile.16 Careful lipid monitoring should be provided for patients on testosteron replacement particularly those with risk factors for CAD.
Hepato-toxicity Reports of liver toxicity and development of hepato-cellular carcinoma have been almost exclusively limited to methylated forms of testosteron, which have fallen into disuse. Current injectable, oral and transdermal preparations (available in U.S. only) without methyltestosterone are believed to be safe from these effects.1
Hematologic Testosterone has a stimulatory effect on erythropoiesis through an unclear mechanism and can result in increased hematocrit, increased hemoglobin and hypercoagulability. Two studies have shown an incidence of polycythemia or increased hematocrit in as many as 24% of patients.22,23 This is a relatively common and undesirable side-effect of injectable testosteron replacement and hematocrit assessment on a 3 monthly basis has been recommended.

TYPES OF REPLACEMENT THERAPY

Options for replacement include oral tablets and capsules, trans-dermal patches (scrotal and non-scrotal), and intramuscular injections.
Older methyltestosterone oral formulations are undesirable because of their significant first-pass metabolism in the liver. The methylated forms also have significant hepatotoxicity. Testosterone undecanoate is absorbed through lymphatics and is thought to be free of liver toxicity.24 Oral bid or tid dosing can reduce serum testosteron fluctuations and may have a lower incidence of polycythemia and increased hematocrit.
Parenteral testosteron can be administered as aqueous testosteron, which is rapidly degraded and generally unsatisfactory for chronic replacement, or as a slow release oil based preparation (testosteron enanthate or cypionate). Most preparations achieve a supraphysiologic maximum concentration approximately 72 hours after injection then slowly decline over the next 10-14 days to a hypogonadal range. The wide fluctuation in levels during the dosing interval can produce gynecomastia, breast tenderness, significant mood swings and changes in libido and coïtusual function.
Transdermal patches have recently become available that provide a more physiologic approach to testosteron replacement by mimicking the normal diurnal variation in testosteron levels. The original patches were scrotal, more recently non-scrotal patches have become available (neither is currently available in Canada). Patches are applied at bedtime so peak testosteron levels occur in the morning then decline during the day.3,24 These patches appear to have most of the benefits of parenteral testosteron replacement including improved coïtusual function and libido with maintenance of normal hematocrit, lipid profile, PSA and prostate volumes. In addition there appears to be less aggressiveness, although these effects have not been studied in long-term trials.1 Complications include the inconvenience of the patch, local dermatitis as well as higher costs.

CONCLUSIONS

Current evidence supports the existence of progressive hypogonadism affecting many older men, which has been labeled andropause or ADAM syndrome. The diagnostic criteria are imprecise as many of the symptoms of this condition such as mood and energy level are difficult to measure and separate from "normal" aging. As well, possible changes in the androgen receptors with aging leave us unsure of the exact level of androgen required for optimum health. In addition, many other hormone changes and disease states affect the aging man.
Nonetheless, testosteron appears to be a prominent hormone involved in this syndrome and testosteron replacement in this population is used with increasing frequency. Androgen replacement should be instituted based on the combination of low bone density or patient symptoms and low testosteron levels and in the absence of other causes. A DRE and PSA should be performed on all men prior to instituting testosteron replacement. Patients with known prostate or breast cancer (due to conversion to estrogen), abnormal DRE or elevated PSA or severe lower urinary tract symptoms are not suitable for testosteron replacement. It has been suggested that for the first year after institution of testosteron replacement men be followed with quarterly DRE and PSA, lipid profile and hematocrit. The DRE, PSA, and lipid profile can be increased to yearly after the first year.

- [Link niet meer beschikbaar] and [Link niet meer beschikbaar]​

Thanks to Dr. Gary McIsaac, Consultant urologist at Trillium Health Center, Mississauga Ontario, for reviewing the draft copy of his article.
References:

1. Morales A, Heaton J, Carson CR. Andropause: a misnomer for a true clinical entity. J Urol 2000; 163(3):705-12.
2. Gooren L. The age related decline in androgen levels in men: clinically significant. Br J Urol 1996; 78:763-8.
3. Schow D, Redmon B, Pryor J. Male menopause: how to define it, how to treat it. Postgrad Med 1997; 101:62-79.
4. Vermeulen A. The male climacterium. Ann Med 1993; 25:531-534.
5. Tenover J. Androgen administration to aging men. Endocrinol Metab Clin North Am 1994; 23:877-92.
6. Wang C, Alexander G, Berman N, et al. Testosterone replacement therapy improves mood in hypogonadal men - a clinical research center study. J Clin Endocrinol Metab 1996; 81:3578-3583.
7. Tenover J. Effects of androgen supplementation in the aging male. J Clin Endocrinol Metab 1992; 75:1092-1098.
8. Swerdloff R, Wang C. Androgen deficiency and aging in men. West J Med 1993; 159:579-585.
9. Bhasin S, Storer T, Berman N, et al. A replacement dose of testosteron increases fat-free mass and muscle size in hypogonadal men. J Clin Endocrinol Metab 1997; 82:407-413.
10. Bhasin S, Storer T, Berman N, et al. The effects of supraphysiologic doses of testosteron on muscle size and strength in men. N Engl J Med 1996; 335:1-7.
11. Sih R, Morley J, Kaiser F, al e. Testosterone replacement in older hypogonadal men: a 12 month randomized controlled trial. J Clin Endocrinol Metab 1997; 82:1661-1667.
12. Behre H, Simoni M, Neischlag E. Strong association between leptin and testosteron. Clin Endocrinol 1997; 47:237-240.
13. Abu E, Horner A, Kusec V, et al. The localization of androgen receptors in human bone. J Clin Endocrinol Metab 1997; 82:3493-3495.
14. Behre H, Kliesch S, Liefke E, et al. Long-term effect of testosteron therapy on bone mineral density in hypogonadal men. J Clin Endocrinol Metab 1997; 82:2386-2390.
15. Gray A, Feldham H, McKinlay J. Age, disease and changing coïtus hormone levels in middle-aged men: Results of the Massachusetts Male Aging Study. J Clin Endocrinol Metab 1991; 73:1016-1025.
16. Vermeulen A, Kaufman J. Ageing of the hypothalamus-pituitary-testicular axis in men. Horm Res 1995; 43:25-28.
17. Morley J, Perry M, Kaiser F, et al. Effects of testosteron replacement therapy in old hypogonadal males: a preliminary study. J Am Ger Soc 1993; 41(149-152).
18. Tenover J. Androgen deficiency in the aging male. Aging Male, suppl 1998; 1:16.
19. Zmuda J, Cauley J, Kriska A, et al. Longitudinal relation between endogenous testosteron and cardiovascular disease risk factors in middle aged men. A 13 year follow-up of former Multiple Risk Factor Intervention Trial participants. Am J Epidemiol 1997; 146:609-613.
20. Philips G, Pinkernell B, Jing T. The association of hypotestosteronemia with coronary artery disease in men. Arterioscler Thromb 1994; 14:701-704.
21. Uyanik B, Ari Z, Gumus B, et al. Beneficial effects of testosteron undecenoate on the lipoprotein profiles in healthy elderly men. A placebo controlled study. Jpn Heart J 1997; 38:73-78.
22. Winkler U. Effects of androgens on hemostasis. Maturitas 1996; 24:147-153.
23. Jockenhovel F, Vogel E, Reinhardt W, et al. Effects of various modes of androgen substitution therapy on erythropoiesis. Eur J Med Res 1997; 2:293-297.
24. Nieschlag E. Testosterone replacement therapy: something old, something new. Clin Endocrinol 1996; 45:261-2.

Bron: Andropause - Clinical features and Therapeutic Options

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testosteron Replacement Therapy

Wayne J.G. Hellstrom, M.D.

Tulane University Medical CenterNew Orleans, LA

Introduction

testosteron is responsible for normal growth and development of male coïtus organs and maintenance of secondary coïtus characteristics. It is the primary androgenic hormone, and its production and secretion are the end product of a series of hormonal interactions. Gonadotropin-releasing hormone (GnRH) is secreted by the hypothalamus and controls the pulsatile secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the anterior pituitary. Luteinizing hormone regulates the production and secretion of testosteron by the Leydig cells of the testes, and FSH stimulates spermatogenesis.
When the testes fail to produce normal levels of testosteron, testosteron deficiency results. Hypergonadotropic hypogonadism is caused by primary testicular failure. Testosterone levels are low and pituitary gonadotropins are elevated. In secondary, or hypogonadotropic hypogonadism, there is inadequate secretion of pituitary gonadotropins. In addition to a low testosteron level, LH and FSH levels are low or low-normal.1, 2 While pre-pubertal hypogonadism is generally characterized by infantile genitalia and lack of virilization, the development of hypogonadism after puberty frequently results in complaints such as diminished libido, erectile dysfunction, infertility, gynecomastia, impaired masculinization, changes in body composition, reductions in body and facial hair, and osteoporosis.1 In addition to these complaints, mood inventory scores indicate that hypogonadal men report levels of anger, confusion, depression, and fatigue that are significantly higher than those reported by men with normal testosteron levels.3
Men with primary hypogonadism (congenital or acquired) or hypogonadotropic hypogonadism are candidates for testosteron replacement therapy, and there are now a variety of products available to treat these disorders. Successful management of testosteron replacement therapy requires appropriate evaluation and an understanding of the benefits and risks of treatment.

Diagnosis of Testosterone Deficiency

Given the variety of causes of testosteron deficiency, a medical and medication history, physical exam, and directed laboratory evaluation are imperative. The medical history should include questions regarding developmental abnormalities at birth, the rate and extent of virilization at the time of puberty, and the current status of coïtusual function and secondary coïtusual characteristics, such as beard growth, muscular strength, and energy level. Hypogonadal men have statistically significant reductions in the incidence of nocturnal erections, the degree of penile rigidity during erection, and the frequency of coïtusual thoughts, feelings of desire, and coïtusual fantasies.3 Alterations in body composition, including increases in percent body fat, changes in adipose tissue distribution, and reduction in muscle mass, are frequently seen in hypogonadal men.4,5 Spinal trabecular bone density is also decreased in men with hypogonadotropic hypogonadism,6 and hip fractures are more common in hypogonadal men than in normal men.7
Initially, hormonal screening is limited to measurement of total serum testosteron, which is obtained in the morning. When the total testosteron level is low and/or the patient complains of reduced libido, a serum prolactin level should also be measured. A high serum prolactin level may indicate pituitary dysfunction and may require consultation with an endocrinologist. Serum LH levels are measured when serum prolactin levels are normal or low to help differentiate intrinsic testicular failure from a pituitary or hypothalamic abnormality. LH is usually high in patients with primary testicular disease. When the serum testosteron level is low and LH is elevated, testosteron replacement therapy is warranted.

Testosterone Replacement Therapy

Testosterone replacement should in theory approximate the natural, endogenous production of the hormone. The average male produces 4-7 mg of testosteron per day in a circadian pattern, with maximal plasma levels attained in early morning and minimal levels in the evening.8 However, the subtleties of pulsatile and diurnal rhythms are potentially difficult to imitate, and evidence suggests that different dose response curves exist for different androgen-dependent functions.9 The clinical rationale for treatment of testosteron deficiency may include:
-stabilizing or increasing bone density
-enhancing body composition by increasing muscle strength and reducing adipose
-improving energy and mood
-maintaining or restoring secondary coïtusual characteristics, libido and erectile function

Types of Testosterone Replacement Therapy

Ideal testosteron replacement therapy produces and maintains physiologic serum concentrations of the hormone and its active metabolites without significant side effects or safety concerns. Several different types of testosteron replacement are currently marketed, including tablets, injectables, and transdermal systems.

Oral agents

Although elevations in liver function tests and abnormalities at liver scan and biopsy are relatively common in patients receiving oral testosteron,10 these preparations still constitute roughly a third of the testosteron prescriptions filled in the United States. Both modified and unmodified oral testosteron preparations are available. Unmodified testosteron is rapidly absorbed by the liver, making satisfactory serum concentrations difficult to achieve. Modified 17-alpha alkyltestosterones, such as methyltestosterone or fluoxymesterone, also require relatively large doses that must be taken several times a day.

Intramuscular injection

Testosterone cypionate and enanthate are frequently used parenteral preparations that provide a safe means of hormone replacement in hypogonadal men. Testosterone is esterified to inhibit degradation and to make it soluble in oil-based injection vehicles that retain the drug in muscle tissue. In men 20-50 years of age, an intramuscular injection of 200 to 300 mg testosteron enanthate is generally sufficient to produce serum testosteron levels that are supranormal initially and fall into the normal ranges over the next 14 days. Fluctuations in testosteron levels may yield variations in libido, coïtusual function, energy, and mood. Some patients may be inconvenienced by the need for frequent testosteron injections.11 Increasing the dose to 300 to 400 mg may allow for maintenance of eugonadal levels of serum testosteron for up to three weeks, but higher doses will not lengthen the eugonadal period.12

Transdermal systems

Currently, three testosteron transdermal systems are marketed: a system applied to the scrotum that has no permeation enhancers [Testoderm, 6 mg, ALZA Corporation, Palo Alto, CA] and two systems that contain permeation enhancers for application to appendage or torso skin [Androderm 2.5 mg and 5 mg, SmithKline Beecham Pharmaceuticals, Philadelphia, PA; Testoderm TTS, 5 mg, ALZA Corporation, Palo Alto, CA]. Scrotal patches produce high levels of circulating dihydrotestosterone (DHT) due to the high 5-alpha-reductase enzyme activity of scrotal skin.
Clinical studies of transdermal systems demonstrate their efficacy in providing adequate testosteron replacement therapy.13-15 Skin irritation may be associated with the use of transdermal systems; however, Testoderm and Testoderm TTS caused significantly less topical skin irritation than Androderm in two separate clinical studies.16,17

Monitoring Patients on Testosterone Replacement

Patients on testosteron replacement therapy should be monitored to ensure that testosteron levels are within normal levels. The physician prescribing testosteron replacement should evaluate any changes in the clinical symptoms and signs of testosteron deficiency and should assess for other concerns, such as acne and increase in breast size and tenderness. Serum testosteron levels should be checked three to 12 hours after application of a transdermal delivery system. For patients on injectable testosteron, nadir testosteron levels should normally be obtained at three to four months prior to the next injection. Levels that exceed 500 ng/dL or are less than 200 ng/dL require adjustment of the dose or frequency.
A digital rectal examination (DRE) should be performed and prostate specific antigen (PSA) checked in all men before initiating treatment. These should be repeated at approximately three to six months, and then annually in men >40 years of age. An abnormal DRE, a confirmed increase in PSA >2 ng/mL, or a total PSA >4.0 ng/mL requires urologic evaluation that usually consists of transrectal ultrasonography and coïtustant prostate biopsies. The hematocrit level should also be checked at baseline, at three to six months, and then annually. A hematocrit >55% warrants evaluation for hypoxia and sleep apnea and/or a reduction in the dose of testosteron therapy. Measurement of bone mineral density of the lumbar spine and/or the femoral necks at one year may be considered in hypogonadal men with osteopenia.

Benefits of Testosterone Replacement Therapy

A number of benefits of testosteron replacement therapy have been demonstrated, including effects on mood, energy levels, and libido. Long-term follow-up of testosteron replacement in hypogonadal males and a control group indicates that self-assessment of libido was significantly higher (p<0.0001) in the testosteron-treated group.18 Testosterone replacement has also been shown to enhance libido and the frequency of coïtusual acts and sleep-related erections.19 Transdermal testosteron replacement therapy, in particular, has been linked to positive effects on fatigue, mood, and coïtusual function, as well as significant increases in coïtusual activity.20 More specifically, testosteron replacement therapy has been shown to improve positive mood parameters, such as feelings of wellness and friendliness, while reducing negative mood parameters, such as anger, nervousness, and irritability.21 Testosterone replacement is an effective treatment for some depressive symptoms in hypogonadal men and may effectively augment treatment in selective serotonin reuptake inhibitor (SSRI)-refractory major depression.22 Relative to eugonadal men, hypogonadal men in one study were impaired in their verbal fluency and showed improvement in verbal fluency following testosteron replacement therapy.23
Testosterone replacement therapy is also associated with potentially positive changes in body composition. In hypogonadal men, testosteron replacement therapy has demonstrated a number of effects, including an increase in lean body mass and decrease in body fat,24 an increase in weight,25 and increases in muscle size.26 Parenteral testosteron replacement in hypogonadal men resulted in improved strength and increased hemoglobin compared to controls.27 In another study by Urban and colleagues,28 testosteron administration also increased skeletal muscle protein synthesis and strength in elderly men. Testosterone replacement with transdermal testosteron delivery systems in HIV-infected men with low testosteron levels has been associated with statistically significant gains in lean body mass (p=0.02), increased red cell counts, and improvements in emotional distress.29 Transdermal testosteron has also been administered to HIV-positive women, yielding positive trends in weight gain and quality of life.30
Improvements in bone density have also been shown with testosteron replacement therapy. Increases in spinal bone density have been realized in hypogonadal men,31 with most treated men maintaining bone density above the fracture threshold.32 Testosterone replacement in hypogonadal men improves both trabecular and cortical bone mineral density of the spine, independent of age and type of hypogonadism.33 In addition, a significant increase in paraspinal muscle area has been observed, emphasizing the clinical benefit of adequate replacement therapy for the physical fitness of hypogonadal men. 33

Contraindications to Testosterone Replacement Therapy

Testosterone replacement is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate, as it may cause rapid growth of these tumors. Hormone therapy is also inappropriate in men with severe benign prostatic hypertrophy (BPH)-related bladder outlet obstruction. Use of testosteron to improve athletic performance or correct short stature is potentially dangerous and inappropriate. In addition, the hormone does not correct ambiguous genitalia resulting from androgen deficiency during fetal development34,35 and should not be administered at dosages high enough to inhibit spermatogenesis.

Safety Issues with Testosterone Replacement

Although testosteron replacement may be indicated in the aging male with documented hypogonadism, this hormone should not be administered with the intent of reversing the aging process in men with normal testosteron levels. Testosterone replacement therapy may be associated with azoospermia, lipid abnormalities, polycythemia, sleep apnea, and the potential for prostate changes.

Azoospermia

The administration of exogenous testosteron as a means of male contraception is under study.36 In these men, azoospermia usually results within approximately 10 weeks of beginning therapy. Rebound of the sperm count to baseline levels occurs within six to 18 months of cessation, and subsequent fertility has been demonstrated.37

Lipid Abnormalities

Physiologic testosteron replacement is known to reduce total cholesterol, low density lipoprotein (LDL), and high density lipoprotein (HDL) levels,24 but the extent to which these parameters are affected by treatment varies considerably between studies. While reductions in HDL did not reach significance in a study by Tenover24 and testosteron replacement was not associated with unfavorable changes in lipid profiles in a separate study by Tan and colleagues,38 research by Anderson and colleagues39 suggests testosteron replacement therapy may result in significant reductions in HDL and elevations in blood viscosity. Some authorities recommend that lipid values be followed closely in men receiving testosteron replacement therapy.

Polycythemia and Sleep Apnea

Polycythemia has been associated with testosteron replacement therapy24 and is correlated with elevated bioavailable testosteron and estradiol levels.40 Physiologic replacement with transdermal testosteron, however, resulted in fewer cases of polycythemia than replacement with testosteron enanthate injections.40 Although the mechanism is unclear, testosteron replacement therapy may also cause or worsen obstructive sleep apnea.

Prostate Changes

Although PSA is not specific for prostate cancer, it is a good surrogate for judging the effects of androgens on the prostate. In one study of testosteron-treated men, PSA rose to normal levels but no higher than in the controls, leading the authors to conclude that testosteron-induced prostate growth should not preclude hypogonadal men from testosteron replacement therapy.41 Indeed, another study indicates that even men who achieved supraphysiologic levels of serum testosteron had no significant changes in PSA levels.42
In a different evaluation, hypogonadal men with normal pretreatment DRE and serum PSA levels who were treated with parenteral testosteron replacement showed no abnormal alterations in PSA or PSA velocity.43 The authors concluded that any significant increases in these parameters should not be attributed to testosteron replacement therapy and should be evaluated. The effects of transdermal testosteron replacement on prostate size and PSA levels in hypogonadal men have also been evaluated.44 Prostate size during therapy with transdermal testosteron was comparable to that reported in normal men, and PSA levels were within the normal range.

Prostate Cancer

There appears to be little association between testosteron replacement therapy and the development of prostate cancer. The etiology of prostate cancer is apparently multifactorial, and dietary, geographic, genetic, and other influences are all thought to play a role in the development of the disease. Recent studies indicate that testosteron levels have no apparent systematic relationship to the incidence of prostate cancer.45,46


Summary

Testosterone is the primary androgenic hormone and is responsible for normal growth and development of male coïtus organs and maintenance of secondary coïtus characteristics. Pre-pubertal hypogonadism is generally characterized by infantile genitalia and lack of virilization, while the development of hypogonadism after puberty frequently results in complaints such as diminished libido, erectile dysfunction, infertility, gynecomastia, impaired masculinization, changes in body composition, reductions in body and facial hair, and osteoporosis. Hypogonadal men also report levels of anger, confusion, depression, and fatigue that are significantly higher than those reported in eugonadal men.
Evaluation of potential candidates for testosteron replacement therapy should include a complete medical history and hormonal screening. Total serum testosteron should be measured in the morning. When the serum testosteron level is low and LH is elevated, testosteron replacement therapy is warranted. Patients with low serum LH and testosteron levels need an imaging study of their pituitary and may need endocrinologic consultation.
Testosterone replacement should in theory approximate natural, endogenous production of the hormone. The clinical rationale for treatment of testosteron deficiency may include: stabilizing or increasing bone density; enhancing body composition by increasing muscle strength and reducing adipose tissue; improving energy and mood; and maintaining or restoring secondary coïtusual characteristics, libido, and erectile function.
Several different types of testosteron replacement are currently marketed, including tablets, injectables, and transdermal systems. Oral testosteron is associated with elevations in liver function tests and abnormalities at liver scan and biopsy. While injectable testosteron is considered safe, fluctuations in testosteron levels may yield variations in libido, coïtusual function, energy, and mood, and patients may be inconvenienced by the need for frequent testosteron injections. Transdermal systems offer a convenient, though more costly, means of testosteron replacement and have demonstrated safety and efficacy in a number of clinical trials.
The physician prescribing testosteron replacement should evaluate any changes in the clinical symptoms and signs of testosteron deficiency and should assess the patient by performing a DRE and checking serum testosteron levels, PSA, and hematocrit at baseline and at prescribed intervals during treatment. Although testosteron replacement is contraindicated in men with carcinoma of the breast or known or suspected carcinoma of the prostate, in general, therapy appears to be safe for the vast majority of hypogonadal men. There is no apparent association between testosteron replacement therapy and the development of prostate cancer. The administration of exogenous testosteron is not a means of reversing the aging process in men with normal testosteron levels, but it may offer considerable benefit for men suffering from hypogonadism.

References

1. Ghusn, H.F. and Cunningham, G.R.: Evaluation and treatment of androgen deficiency in males. The Endocrinologist, 1(6):399, 1991.

2. American Association of Clinical Endocrinologists and the American College of Endocrinology. AACE Clinical Practice Guidelines for the Evaluation and Treatment of Hypogonadism in Adult Male Patients. ED8143, 1996.

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Bron: Testosterone Replacement Therapy

 

[jacky den bels]

oei allemaal in het Engelands moet ik eens rustig voor gaan zitten

 

[koen85]

Engelands??

Eerst Nederlands maar eens onder de knie krijgen

 

[NightStalker]

oei allemaal in het Engelands moet ik eens rustig voor gaan zitten

Klik om te verkleinen...

 

[jacky den bels]

hahahaha

 

[Gorill0r]

oei allemaal in het Engelands moet ik eens rustig voor gaan zitten

Klik om te verkleinen...

Typisch een belgenlander