As men go beyond the fourth decade of life, there is a gradual decrease in serum testosterone levels. The US Food and Drug Administration (FDA) estimates that 4-5 million men in the USA suffer from true hypogonadism, with only 5 % of these men actually being treated. Other sources estimate the range of hypogonadism in men above 40 years of age to be between 6.0 % and 43.7 %.1

Hypogonadism can be due to testicular dysfunction (primary testicular failure, primary hypogonadism, hypergonadotropic hypogonadism) or to central, hypothalamic-pituitary causes, which lead to hypogonadotropic hypogonadism (secondary hypogonadism). Primary testicular failure can be a result of the aging process but can also be caused by chemotherapy, radiation therapy, congenital defects, and genetic disorders, such as Klinefelter’s syndrome. Secondary hypogonadism is characterized by decreased luteinizing hormone (LH) production in the anterior pituitary. In addition to aging, known causes include pituitary tumors, surgery, radiation, infections, trauma, inflammation, bleeding, genetic disorders, nutritional deficiency, and hemochromatosis. Secondary hypogonadism may be associated with syndromes known as Kallmann’s, Prader-Willi, and Laurence-Moon-Biedl.

While hypogonadism is defined as a low total serum testosterone, symptomatic hypogonadism is characterized by low total serum testosterone together with clinical symptoms and signs. Symptoms include:

  • sexual dysfunction, such as reduced libido, erectile dysfunction (ED), diminished penile sensation, and difficulty attaining orgasm, as well as diminished ejaculate with orgasm;
  • reduced energy, vitality, or stamina;
  • depressed mood or diminished sense of well-being;
  • increased irritability;
  • difficulty concentrating and other cognitive problems; and
  • hot flashes in some cases of acute onset.

Many authorities have supported the position that symptomatic hypogonadism is a more realistic representation of the true hypogonadal state and thus look for a low serum testosterone level combined with one or more of the symptoms noted above to confirm the diagnosis of true hypogonadism. The prevalence of hypogonadal symptoms was demonstrated by a Swedish survey of men aged 55-75 years, in which most subjects reported some symptoms of hypogonadism, regardless of their testosterone levels. Signs of hypogonadism include anemia, muscle wasting (sarcopenia), reduced bone mass or bone mineral density, abdominal adiposity, and oligospermia or azoospermia.

Frequently, the effects of age-related hypogonadism and effective treatment modalities are not even discussed with patients, owing to a lack of comfort in discussing sexual issues by both patients and their primary care providers. Discussing the symptoms and evaluating the signs of age-related hypogonadism openly and aggressively helps to change patients ’ perspective that certain conditions are meant to be accepted as part of the aging process.

Treatment of Hypogonadism

Testosterone supplementation in hypogonadal men restores testosterone levels and improves secondary sexual characteristics, sexual function, sense of well-being, muscle mass and strength, and bone mineral density. Currently, there are many formulations of testosterone with varying advantages and disadvantages (Table Advantages and disadvantages of various testosterone formulations).

Table Advantages and disadvantages of various testosterone formulations
Formulation Route of administration Advantages Disadvantages
Buccal adhesive

17-methyl testosterone

Testosterone pellets

Testosterone undecanoate in oil

Non-genital testosterone patch

Scrotal testosterone patch

Testosterone gel

Twice-daily dosing via controlled-release patch

Oral

Placed under the skin for 4–6 months

Intramuscular injection every 6–12 weeks

Applied to non-pressure-bearing sites

Applied to the scrotum

Daily skin application

Maintains a steady state of testosterone

Infrequent physician visits

Fewer physician visits required for therapy

Ease of application

Non-invasive, painless

Less skin irritation compared with patches

Irritation at the gum line

Damages the liver; not recommended for this use

Requires a procedure; pellets may extrude from skin

Injections may be painful

Irritation at the patch site

Scrotum must be shaved for application

Potential transfer of testosterone via skin contact with partner or children

Suggested regimens of replacement therapy

Suggested regimens of testosterone replacement therapy include:

  • testosterone enanthate or cypionate, 75-100 mg by intramuscular injection weekly or 150-200 mg administered every 2 weeks;
  • testosterone patch, non-genital, one or two 5 mg patches applied nightly over non-pressure-bearing sites such as the back, chest, or upper arm;
  • testosterone gel, 5-10 mg applied daily to dry intact skin of the upper arm, back or chest; and
  • buccal testosterone, 30 mg patch applied twice daily to buccal mucosa.

Intramuscular preparations

Intramuscular injections such as testosterone cypionate and enanthate are esterified compounds that are dissolved in oil-based solutions. They can be given in varying doses ranging from 75 mg to 400 mg depending on the frequency of injections (75-100 mg weekly, 150-200 mg every 2 weeks, 300-400 mg every 3 weeks). Doses higher than 400 mg have not been demonstrated to lengthen the eugonadal period. One drawback is the frequency of injections, which may be unappealing to both physicians and patients.

For patients who prefer longer intervals between injections, testosterone undecanoate in oil is being used in Europe (1000 mg every 6-12 weeks). However, patients must be willing to tolerate a slightly more painful, larger volume injection. A preparation currently undergoing trials in the USA is testosterone undecanoate in castor oil, which may last as long as 14 weeks after an initial 6-week loading dose.

Oral preparations

Though still prescribed by some clinicians, most authorities do not recommend 17-methyl testosterone in tablet form, owing to known changes in liver function tests and the need for relatively large doses. However, capsules that contain testosterone undecanoate in oil are available in Europe and Canada and are given in a twice- or three-times-daily dosing regimen.

Gels

Testosterone gels are applied to the skin in varying doses ranging from 5 mg to 10 mg daily. These preparations allow for steady states of testosterone and cause fewer adverse reactions at application sites. A drawback is the potential risk of testosterone transfer via skin contact to the partner or children.

Buccal patches

Buccal testosterone comes as a tablet-shaped patch, which is applied to the upper gum. It is a 30 mg controlled-release tablet, which is applied every 12 hours. It has been shown to have good results in attaining eugonadal serum levels. However, drawbacks include irritation at the gum line and a twice-daily dosing schedule.

Transdermal patches

Current transdermal routes include daily patches that can be placed on the appendages or torso as well as scrotal patches. They have been shown to provide an adequate clinical response and appropriately increase serum testosterone levels. The most common complaint is irritation at the site of patch placement. The scrotal patch also increases levels of dihydrotestosterone secondary to high 5-alpha-reductase activity in scrotal skin. Another issue for some patients is the need for constant shaving of the scrotal skin for better adherence.

Monitoring of men receiving testosterone therapy

The patient should be initially evaluated 3 months after treatment starts and then annually to assess whether symptoms have responded to treatment and whether the patient is suffering any adverse effects.

  1. Obtain testosterone levels 2–3 months after initiation of testosterone therapy. Therapy should aim to raise serum testosterone to within the normal range.
  2. Check hematocrit at baseline, at 3 months, and then annually. If hematocrit is 54 % or greater, stop therapy until hematocrit decreases to a safe level. The clinician must evaluate the patient for hypoxia and sleep apnea, and then may reinitiate therapy at a reduced dose.
  3. Measure bone mineral density of lumbar spine or femoral neck after 1–2 years of testosterone therapy in hypo-gonadal men with osteoporosis or a history of traumatic fracture, consistent with the regional standard of care.
  4. Perform a digital rectal examination and check the prostate-specific antigen (PSA) level before treatment (at baseline), at 3 months, and then in accordance with guidelines for prostate cancer screening depending on the age and race of the patient. One study showed that parenteral testosterone replacement therapy in older hypogonadal men increased the serum PSA level by a mean of 0.96ng/ml over a mean treatment duration of 30.2 months.
  5. Obtain urological consultation if there is:
  • an increase in serum PSA concentration of 1.4ng/ml or greater within any 12-month period of treatment;
  • PSA velocity of > 0.4ng/ml/year using the PSA levels after 6 months of testosterone administration as the reference (only applicable if PSA data are available for a period exceeding 2 years);
  • any prostatic anomaly on digital rectal examination;
  • AUA or American Urological Association prostate symptom score or International Prostate Symptom Score of 19 or more.
  1. Evaluate formulation-specific adverse effects at each visit:
  • buccal testosterone tablets – enquire about alterations in taste and examine the gums and oral mucosa for irritation;
  • injectable testosterone – ask about fluctuations in mood or libido and pain at the injection site;
  • testosterone patches – examine for skin reaction at the injection site;
  • testosterone gels – advise patients to cover the application sites with a shirt and wash the skin with soap and water before having skin-to-skin contact, because testosterone gels leave a testosterone residue on the skin that can be transferred to a woman or child who might come in close contact; serum testosterone levels are maintained when the application site is washed 4-6 hours after application of the testosterone gel.

Contraindications to testosterone therapy

Treatment with testosterone is effective for the aging hypo-gonadal male. However, care must be taken during the initial screening and subsequent treatment regimen to assure that the patient does not have or develop conditions that would contraindicate initiating or continuing therapy. Conditions in which testosterone should not be administered include prostate cancer, breast cancer, prostate nodule without biopsy-confirmed histology, elevated PSA without work-up, erythrocytosis (hematocrit >50%), severe lower urinary tract symptoms associated with benign prostatic hypertrophy, and unstable severe congestive heart failure (New York Heart Association class III or IV). Prostate and breast cancers are usually hormone-dependent initially and may be stimulated with any form of testosterone therapy. In a similar fashion, benign prostatic tissue also responds to testosterone therapy. A thorough prostate evaluation needs to be performed prior to initiation of replacement therapy.

Adverse effects of testosterone therapy

The adverse effects of testosterone administration must be discussed with any patient contemplating replacement therapy.

Adverse events for which there is evidence of association with testosterone administration

Patients should be notified that conditions such as increased acne, decrease in sperm production, possible decreased fertility rates, and elevations in the red blood cell count are possible. There should also be a discussion about the increased likelihood of detecting subclinical prostate cancer and the growth of hormone-sensitive metastatic prostate cancer.

Less common adverse events

Patients should be notified of the remote possibility of side-effects such as gynecomastia, initiation of male pattern baldness, and worsening of obstructive sleep apnea.

Medication-specific adverse effects

When the physician and patient are deciding on a form of testosterone therapy, formulation-specific effects should be discussed. For instance, oral methyltestosterone, if used, can damage the liver. Subcutaneous pellets can be extruded from the skin. Intramuscular injections of testosterone can cause problems such as fluctuations in mood, pain at the injection site, and excessive erythrocytosis. Transdermal testosterone patches can cause localized skin reactions. Transdermal testosterone gels and creams can potentially be absorbed by others via skin contact. Buccal testosterone patches can interfere with taste sensations and cause gum irritation.

 

Selections from the book: “Textbook of Erectile Dysfunction”, 2009

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