A Guide to Men's Health, Reproductive Medicine, and Microsurgery
Hypogonadism refers to any condition resulting from decreased testicular function. It has also become synonymous with low testosterone levels and can be associated with a variety of symptoms including a decrease in sex drive (libido), energy, mental activity, bone density, and muscle mass along with an increased body fat percentage.
Testosterone is important in maintaining normal sexual and reproductive function, skeletal growth, and muscle development. It is converted to dihydrotestosterone (DHT), which is important for facial/body hair growth, acne, and prostate development. Testosterone can also be converted by aromatase to estradiol (E2), which plays a role in bone formation and breast tissue development.
Hypogonadism can be classified as primary or secondary, or it can be a combination of the two. Primary hypogonadism refers to failure of the testicles to produce testosterone despite an adequate stimulus from the pituitary gland and is characterized by a low testosterone level, elevated follicle stimulating hormone (FSH) and luteinizing hormone (LH), and impaired sperm production. Secondary hypogonadism is caused by failure of the hypothalamus or pituitary gland to produce an adequate stimulus for testosterone production and is characterized by low testosterone, low or normal FSH/LH, and impaired spermatogenesis.
Although the definitions of low testosterone vary, the 2nd Andropause Consensus Panel stated that a total testosterone level of less than 200 ng/dL is diagnostic of hypogonadism. When the level is between 200 and 400 ng/dL, clinical considerations and symptomotology as well as a free testosterone should be considered prior to starting therapy. A level greater than 400 ng/dL usually excludes hypogonadism from the diagnosis. More recently, the Endocrine Society reported that normal testosterone levels should be greater than 300 ng/dL, taking into account variations in individual laboratory reference ranges.
Hypogonadism affects 4% to 5% of the general male population and approximately 20% of men older than 60 years of age. A man’s total testosterone diminishes by about 1-2% per year starting in his 30's.
Despite the prevalence of this disease in the United States, the Food and Drug Administration reports that only 5% of hypogonadal men are currently receiving treatment.
There are several concomitant illnesses and conditions, as well as several medications that have been associated with hypogonadism including:
Additionally, hypogonadism is associated with osteoporosis as a risk factor for degenerative bone conditions.
It has been reported that approximately 60% of Americans are overweight and one third are considered obese. Obesity is associated with decreased lean muscle mass and increased visceral and peripheral fat. Testosterone is converted into estradiol in fat, causing further changes in testosterone and estradiol ratios. Hypogonadism is also associated with abnormalities in cortisol secretion which causes truncal deposition of fat, further compounding the problem of obesity and complicating weight loss. Treatment with testosterone has been shown to increase lean body muscle mass, decrease percent fat composition, increase insulin sensitivity, decrease fasting blood glucose, improve plasma cholesterol levels, and decrease diastolic blood pressure.
Another common disease in our society is diabetes. Twenty percent of diabetic men have a low serum testosterone level and 55% are reported having a low serum free testosterone level. This problem is compounded with aging, with 36% of diabetic men older than 70 years of age having low testosterone levels. The association between hypogonadism and the development of insulin resistance is supported by epidemiologic studies showing a 2.7 times greater risk of developing diabetes in this population. Further evidence from Finland has shown that the risk of metabolic syndrome (the presence of 2 or more metabolic risk factors such as abdominal obesity, elevated blood pressure, dyslipidemia and insulin resistance) is 2.5 times greater in hypogonadal men with total testosterone levels in the lowest quartile. Testosterone replacement has been shown to decrease blood glucose values and mean glycated hemoglobin (HbA1C).
Men infected with HIV represent a growing population of men diagnosed with hypogonadism. Approximately 20% to 40% of HIV positive men and 50% of men with acquired immune deficiency syndrome (AIDS) are diagnosed with hypogonadism. The etiology of hypogonadism in this subset of patients is multifactorial and related to direct viral infection of the testes causing testicular failure in some instances. Diminished hypothalamic pituitary function along with the side effects from antiretroviral medications are also implicated in hypogonadism in these patients. Double-blind, placebo-controlled studies have demonstrated the effectiveness of treatment of hypogonadal symptoms in HIV- and AIDS-infected men.
A number of commonly prescribed drugs have been shown to interfere with normal testosterone production and bioavailability. These include GnRH agonists/antagonists, psychotropic drugs, estrogens, aldactone, progestins, thiazide diuretics, glucocorticoids, opiates (pain medications), ketoconazole, and anabolic steroids. The predominant mechanisms by which these drugs can lead to hypogonadism: by blocking testosterone production, reducing gonadotropin-releasing hormone secretions, and blocking androgen receptors. Fortunately, discontinuation of the offending drug and allowing for an adequate recuperation period is generally all that is required for effective treatment.
Since hypogonadism is the most common secondary cause of osteoporosis, TRT may improve bone density to help prevent this disease and its related complications. Studies have shown a correlation between BMD and hypogonadism through an increased risk of hip fracture in hypogonadism, with BMD being directly related to bioavailable testosterone rather than total testosterone. Additionally, long-term prospective and retrospective studies have shown that TRT therapy improves BMD in the lumbar spine and femoral neck.
The development of a validated questionnaire assessing symptoms has facilitated the diagnosis of hypogonadism. A complete physical examination focusing on virilizing characteristics, the genitalia, and a digital rectal examination should be completed.
Identifying patients who have signs and symptoms suggestive of hypogonadism should be followed by confirmatory blood tests demonstrating a low total or free testosterone level.
Serological tests are necessary to confirm the diagnosis of hypogonadism.
The goal of testosterone replacement therapy (TRT) is to provide and maintain normal levels of testosterone as well as its metabolites DHT and E2, thus providing positive effects on sexual, physical, and psychological functions.
There are several forms of TRT available for the treatment of hypogonadism including intramuscular (IM), oral, transdermal, buccal, and subcutaneous pellets.
There are 2 available injectable forms of long-acting IM testosterone, testosterone enanthate and cypionate. Serum levels are not maintained beyond 2 to 3 weeks even with higher than normal injection doses (>100-200mg per week), necessitating repeat injection every 2 to 3 weeks. DHT levels are usually normal; estradiol levels can be high, causing gynecomastia. A significant advantage to this form of therapy is the relatively low cost of treatment. Pain and anxiety about injections, lack of a circadian rhythm, and large serum variations between doses are some of the disadvantages. A longer-acting IM injection of testosterone undecanoate exists, and this is administered every 10 weeks. More info can be found at aveedusa.com.
Oral administration provides an easier route of administration in contrast to IM testosterone, but the tablet must be taken 3 to 4 times daily. Moreover, erratic absorption and no circadian variation occur during oral therapy. Preparations for oral administration include methyltestosterone, oxymetholone, and fluoxymesterone. These derivatives minimize first-pass hepatic metabolism. It is difficult to achieve therapeutic levels of testosterone after oral administration due to the extensive metabolism of testosterone in the gastrointestinal tract and liver, and its short terminal half-life (~100 minutes).
Transdermal patches are able to restore testosterone to normal levels, and peak testosterone levels can be achieved in the morning, simulating the normal diurnal variation. The greatest disadvantage of patch therapy is the high rate of skin reactions (67%) reported at the patch application site. Pretreatment with a mild topical steroid cream or a diphenhydramine spray as well as varying the application site has been shown to minimize this problem. More information can be found at androderm.com.
Testosterone therapy in a gel formulation has been introduced and has been shown to cause minimal side effects. Studies looking at the percentage of hypogonadal patients with testosterone levels in the eugonadal range following gel application is very favorable (89% to 94%) and is sustained during chronic administration (6 months). The disadvantages of transdermal gels are the need for daily application and the risk of transference to other individuals if precautions are not taken. Minimal site reactions are reported.
There are 2 topical gels that are currently approved by the FDA for use on the shoulders and upper arms. More information about these medications may be found at testim.com and androgel.com.
There is an FDA-approved topical solution that is applied under the armpit, and information about this medication may be found on at axiron.com.
There is an FDA-approved gel for use on the inner thighs, and information about this medication may be found on fortesta.com.
Lastly, there is an FDA-approved intranasal gel that reduces the concern about transference of testosterone from one person to another. More information about this medication may be found on natesto.com.
The testosterone buccal delivery system, is designed to adhere to the gum surface above the incisor tooth on either side of the mouth. This system provides controlled and sustained release of testosterone, which is delivered through the buccal tissue and not through the saliva or orally. Delivery of testosterone through the buccal mucosa avoids firstpass hepatic metabolism, minimizing hepatic toxicity. The disadvantages include minimal local irritation, a bad taste in the mouth, and poor patient compliance with twice daily dosing. More information about this delivery system may be found at striant.com.
For men who have benifitted from testosterone replacement but who desire a long-acting form of therapy, subcutaneous pellets may be a worthwhile treatment option. These pellets are about the size of grain of rice and provide steady testosterone levels for 3-6 months. Side effects are uncommon, however if they occur, the pellets can not be removed. More information is available at testopel.com.
The theoretical risks of testosterone replacement therapy include:
These theoretical risks still concern many healthcare providers and prevent their use of TRT in hypogonadal patients.
Although information is available demonstrating an acceptable safety profile for TRT, unequivocal data are still lacking regarding the risks of therapy.
The erythropoietic-stimulating effect of TRT has been well known for many years. Polycythemia is associated with the type of TRT used and has been reported to be as high as 40% in patients using IM injections but rarely (<5%) with transdermal applications. Predisposed individuals usually manifest polycythemia within 6 months of initiating therapy. TRT requires annual monitoring of patients and discontinuation of therapy when the hematocrit is above 52%.
All forms of testosterone supplementation have a similar effect by lowering the amount of hormones produced from the pituitary and hypothalamus. This, in turn, causes decreased secretion of FSH/LH leading to diminished endogenous testicular function. Testicular atrophy is commonly seen in patients on TRT. All exogenously administered testosterone acts, likewise, as a male contraceptive by lowering sperm densities to zero. This effect is evident even at minimal doses administered.
Endogenous testosterone is essential for sperm production, epididymal maturation, and production of seminal plasma. A common misconception by practitioners is that in hypogonadal patients, placing them on TRT will improve all of these parameters. Despite improvements in serum testosterone levels, TRT has the secondary effect of eliminating FSH stimulation of Sertoli cells necessary to produce sperm. Fortunately, most, but not all, of these patients with impaired sperm production following TRT will recuperate their testicular size and sperm production within 6 months of discontinuation of therapy.
Painful gynecomastia is a reported side effect of therapy in some patients. This is related to increased estrogen levels due to aromatization of testosterone. Gynecomastia is more commonly encountered in patients using IM therapy because their testosterone levels tend to be higher and, hence, they have higher estradiol levels. Dose titration or treatment with aromatase inhibitors (anastrozole, letrozole) or selective estrogen receptor modulators (tamoxifen) are effective options for reducing this side effect.
Studies evaluating TRT have shown only minimal changes in prostate volume or prostate-specific antigen (PSA) in younger men and only a modest increase (15%) in older men. Clinical trials evaluating TRT have shown no change in objective voiding parameters, such as post-void residual and uroflowmetry, or even in subjective clinical symptoms.
The concern over development of de novo prostate cancer exists because of the established androgen dependence of this disease demonstrated by Huggins and Hodges in 1941. However, concern that giving TRT to hypogonadal men will increase the risk of developing prostate cancer has not been proven true. Longitudinal studies using frozen sera from men who went on to develop prostate cancer have provided good evidence showing that men with elevated testosterone levels do not have any higher incidence of developing prostate cancer. Rhoden and Morgentaler compared 20 hypogonadal men with prostate intraepithelial neoplasia (PIN) to 55 hypogonadal men without it. Both groups were treated with TRT showing a similar rise in PSA (0.3 ng/mL) and only 1 case of prostate cancer (5%) was detected in the PIN positive group and none in the PIN negative group. This incidence of cancer still represents a much lower incidence of prostate cancer than the expected rate of 25% at 3 years seen in previous evaluations in this high-risk population.
The evidence that men have a greater incidence of coronary artery disease (CAD) than women has suggested that high testosterone levels are associated with an increased risk of CAD. The possible causal role of testosterone in the development of CAD has not been proven, and there are no epidemiologic data, to date, implicating TRT. Studies investigating men with and without CAD have shown that total and free testosterone levels are similar. In a 2001 study, testosterone improved symptoms of angina and delayed time to ischemic threshold in hypogonadal men with coronary disease. In a recent meta-analysis reviewing 19 studies, the authors found that TRT reduced total cholesterol (-14 mg/dL), low-density lipoprotein (-5 mg/dL), high-density lipoprotein (-4 mg/dL), and triglycerides (-1mg/dL). Collectively, these data would suggest even a protective role of testosterone in men.
FDA notice about risks associated with abuse and dependence
A better understanding of the significant role hypogonadism plays in ageing males as well as in a variety of other medical conditions is growing. Hypogonadism is associated with a wide range of symptoms and comorbidities that are exacerbated by the typical age of hypogonadism patients. Without awareness or appropriate diagnostic testing, hypogonadism—and the comorbidities associated with the disorder—will remain underdiagnosed and undertreated in our male population.
The Endocrine Society Guidelines
Dr. Williams' article about low testosterone
Women's International Pharmacy
Information about Compounding Pharmacies from Urology Times
Data fail to support concerns over testosterone therapy and cardiovascular risk
Alternatives to testosterone therapy
Update for Men on Testosterone Replacement Therapy
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