# Testosterone Replacement Therapy



## Arnold (May 29, 2010)

*Testosterone Replacement Therapy*
Wayne J.G. Hellstrom, M.D.

*Introduction*

Testosterone is responsible for normal growth and development of male sex organs and maintenance of secondary sex 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 testosterone by the Leydig cells of the testes, and FSH stimulates spermatogenesis.

When the testes fail to produce normal levels of testosterone, testosterone  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 testosterone 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  testosterone levels.3 

Men with primary hypogonadism (congenital or  acquired) or hypogonadotropic hypogonadism are candidates for testosterone  replacement therapy, and there are now a variety of products available to treat  these disorders. Successful management of testosterone 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 testosterone 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 sexual function and secondary sexual  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 sexual thoughts, feelings of desire, and sexual 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 testosterone, which is  obtained in the morning. When the total testosterone 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 testosterone  level is low and LH is elevated, testosterone 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 testosterone 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 testosterone 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 sexual characteristics,  libido and erectile function 


*Types of Testosterone Replacement  Therapy* 

Ideal testosterone 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 testosterone 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 testosterone,10  these preparations still constitute roughly a third of the testosterone  prescriptions filled in the United States. Both modified and unmodified oral  testosterone preparations are available. Unmodified testosterone 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 testosterone enanthate is generally  sufficient to produce serum testosterone levels that are supranormal initially  and fall into the normal ranges over the next 14 days. Fluctuations in  testosterone levels may yield variations in libido, sexual function, energy, and  mood. Some patients may be inconvenienced by the need for frequent testosterone  injections.11 Increasing the dose to 300 to 400 mg may allow for maintenance of  eugonadal levels of serum testosterone for up to three weeks, but higher doses  will not lengthen the eugonadal period.12 


*Transdermal systems* 

Currently, three testosterone 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 testosterone 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 testosterone  replacement therapy should be monitored to ensure that testosterone levels are  within normal levels. The physician prescribing testosterone replacement should  evaluate any changes in the clinical symptoms and signs of testosterone  deficiency and should assess for other concerns, such as acne and increase in  breast size and tenderness. Serum testosterone levels should be checked three to  12 hours after application of a transdermal delivery system. For patients on  injectable testosterone, nadir testosterone 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 sextant 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 testosterone 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  testosterone replacement therapy have been demonstrated, including effects on  mood, energy levels, and libido. Long-term follow-up of testosterone replacement  in hypogonadal males and a control group indicates that self-assessment of  libido was significantly higher (p< 0.0001) in the testosterone-treated  group.18 Testosterone replacement has also been shown to enhance libido and the  frequency of sexual acts and sleep-related erections.19 Transdermal testosterone  replacement therapy, in particular, has been linked to positive effects on  fatigue, mood, and sexual function, as well as significant increases in sexual  activity.20 More specifically, testosterone 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 testosterone replacement therapy.23 

Testosterone replacement  therapy is also associated with potentially positive changes in body  composition. In hypogonadal men, testosterone 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 testosterone replacement in hypogonadal men resulted in improved  strength and increased hemoglobin compared to controls.27 In another study by  Urban and colleagues,28 testosterone administration also increased skeletal  muscle protein synthesis and strength in elderly men. Testosterone replacement  with transdermal testosterone delivery systems in HIV-infected men with low  testosterone 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 testosterone 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  testosterone 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  testosterone 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 testosterone 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  testosterone 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 testosterone 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 testosterone  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  testosterone 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 testosterone 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 testosterone replacement  therapy. 


*Polycythemia and Sleep Apnea* 

Polycythemia  has been associated with testosterone replacement therapy24 and is correlated  with elevated bioavailable testosterone and estradiol levels.40 Physiologic  replacement with transdermal testosterone, however, resulted in fewer cases of  polycythemia than replacement with testosterone enanthate injections.40 Although  the mechanism is unclear, testosterone 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  testosterone-treated men, PSA rose to normal levels but no higher than in the  controls, leading the authors to conclude that testosterone-induced prostate  growth should not preclude hypogonadal men from testosterone replacement  therapy.41 Indeed, another study indicates that even men who achieved  supraphysiologic levels of serum testosterone 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  testosterone 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 testosterone replacement therapy and  should be evaluated. The effects of transdermal testosterone replacement on  prostate size and PSA levels in hypogonadal men have also been evaluated.44  Prostate size during therapy with transdermal testosterone 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 testosterone 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  testosterone 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 sex organs and maintenance of secondary sex 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 testosterone replacement therapy  should include a complete medical history and hormonal screening. Total serum  testosterone should be measured in the morning. When the serum testosterone  level is low and LH is elevated, testosterone replacement therapy is warranted.  Patients with low serum LH and testosterone 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 testosterone 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 sexual characteristics, libido, and  erectile function. 

Several different types of testosterone replacement  are currently marketed, including tablets, injectables, and transdermal systems.  Oral testosterone is associated with elevations in liver function tests and  abnormalities at liver scan and biopsy. While injectable testosterone is  considered safe, fluctuations in testosterone levels may yield variations in  libido, sexual function, energy, and mood, and patients may be inconvenienced by  the need for frequent testosterone injections. Transdermal systems offer a  convenient, though more costly, means of testosterone replacement and have  demonstrated safety and efficacy in a number of clinical trials. 

The  physician prescribing testosterone replacement should evaluate any changes in  the clinical symptoms and signs of testosterone deficiency and should assess the  patient by performing a DRE and checking serum testosterone levels, PSA, and  hematocrit at baseline and at prescribed intervals during treatment. Although  testosterone 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 testosterone replacement therapy and the development of  prostate cancer. The administration of exogenous testosterone is not a means of  reversing the aging process in men with normal testosterone levels, but it may  offer considerable benefit for men suffering from hypogonadism.  


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## proffrank (May 29, 2010)

Wow, NICE THREAD!!!! Its helping me, although not a complete replacement!!! MAYBE, sooooon!@!!!


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