Q. A 52-year-old man is referred by his GP complaining of increasing fatigue, mood changes and decreased libido. How would you assess him?
A. I would take a full medical history and perform a full physical examination including height, weight and waist circumference. I would then ask for baseline blood tests including a fasting glucose, lipids and early morning hormone profile.
Q. You find that he has no previous medical problems and takes no medication currently.
He stopped smoking 10 years ago. There is a family history of hypertension and a father who died of a myocardial infarction at age 62. His body mass index is 30.8 kg/m2; waist circumference is 41 inches; blood pressure is 143/87 mm, cardio-respiratory examination is unremarkable. Which hormone tests would you request and when?
A. Hypogonadism can be confirmed by checking a testosterone level; morning values (between 8 a.m. and 11 a.m.) are preferred to afternoon blood samples because testosterone levels peak in the morning. This should include total testosterone, SHBG, LH, and FSH.
Q. Would you request an oestradiol level?
A. Not routinely. Oestradiol is useful when the patient has a higher body mass index as in this case. Prolactin and a thyroid profile can also be useful in diagnosing secondary causes in selected cases.
Q. His laboratory test results are fasting plasma glucose 6.2; HbAlc 6.2%; total cholesterol 6.7 nmol/L; triglycerides 3.1 nmol/L; creatinine 78 umol/L. His total testosterone level in an early morning sample is 7.2 nmol/L. How would you manage this patient?
A. The European Atherosclerosis Society suggests levels of total cholesterol between 5.2 and 6.5 require dietary advice and correction of other risk factors. As his level is greater than 6.5, I would counsel the patient on starting regular exercise and would consider initiation of therapy with a statin by notifying his GP. As his morning testosterone level is below 8 nmol/L I would also consider starting testosterone replacement therapy.
Q. What is your diagnosis?
A. This man is suffering from late-onset male hypogonadism. This is defined as a symptom complex resulting from the age-related decline in testosterone levels in men.
Q. What are the common causes of this condition?
A. Hypogonadism is a failure of the testes to produce normal levels of testosterone and/or sperm. Primary causes of hypogonadism are commonly due to testicular failure, while secondary causes are due to pituitary or hypothalamic causes (Kallman’s syndrome), and combined hypogonadism is due to the combinations of the decreased pulsatile release of the pituitary gonadotropins coupled with the decreased response of the testicular Leydig cells. Hypogonadism is more common in aging males who have passed through their reproductive stage.
Q. What are the common signs and symptoms of this condition?
A. Hypogonadism in the adult commonly results in changes in sexual function, behaviour, muscle mass and loss of secondary sexual characteristics. The patient may also report changes in mood and behavioural symptoms (depression, irritability, loss of motivation) in addition to complaints of lethargy or loss of energy. Physical examination may demonstrate some regression of secondary sexual characteristics such as hair loss and possible loss of muscle bulk in addition to the findings of softer small volume testes.
Q. On examination you find he has bilateral gynaecomastia. How do you explain this?
A. Obesity can lead to the peripheral aromatization of testosterone in adipose tissue to oestradiol, leaving less bioavailable testosterone for maintenance and virilization functions. As a result of lowered free testosterone, a clinically obese male may demonstrate evidence of feminization such as gynecomastia.
Q. How would you treat this?
A. The most definitive treatment is weight loss, but some patients may also respond well to treatment with clomiphene citrate, a synthetic non-steroidal anti-oestrogen or tamoxifen.
Q. How common is late-onset hypogonadism?
A. It may occur in up to 18.4% of men older than 70 years of age regardless of ethnic background.
Q. Why is a DEXA (dual energy x-ray absorptiometry) scan relevant in patients with hypogonadism?
A. Height loss, low-trauma fractures and lowered bone-mineral density are more common in the aging male. Testosterone deficiency is more common in men who have experienced a hip fracture. There fore it is important to check the bone mineral density in men who are recognized to be hypogonadal with a DEXA scan.
Q. On further questioning he also admits to suffering from ED for 2 years. What percentage of patients with ED also have hypogonadism?
A. Overall, fewer than 10% of men who present with ED are found to have testosterone deficiency.
Q. What is the relationship between ageing and testosterone levels?
A. Several population-based studies have demonstrated that serum testosterone levels fall with advancing age.
Q. What is the relationship between testosterone levels and sex hormone binding globulin?
A. Free and albumin-bound testosterone make up the circulating bioavailable testosterone. Testosterone that is bound to sex hormone binding globulin (SHBG) is tightly bound and not available to tissues; this portion constitutes approximately 45% of the total circulating testosterone in healthy young men. Numerous factors can alter SHBG and thus total testosterone without affecting the bioavailable testosterone.
Q. What factors may increase the level of the SHBG?
A. SHBG levels are increased by ageing, hepatic cirrhosis, hyperthyroidism, use of anticonvulsants, use of oestrogens and HIV infection.
Q. Should the SHBG be measured in all patients?
A. No - it should only be measured in cases where there is a low total testosterone level or conditions known to affect the SHBG concentration such as ageing. The age-related fall in serum testosterone levels may underestimate the fall in free and bioavailable testosterone levels because SHBG increases with age.
Q. How would you manage the patient?
A. After I have fully evaluated the patient and ensured there are no contraindications and the patient is aware of the side effects of testosterone replacement therapy, I would commence testosterone replacement initially using a short-acting agent.
Q. Are there any contraindications to testosterone treatment?
A. The presence of active prostate or breast cancer is an absolute contraindication to treatment.
Polycythaemia, or an excessive increase in the number of red blood cells, may be seen in some men over age 50 years who have been treated with testosterone replacement. tterefore pre-existing polycythaemia is a contraindication as an increase in the haematocrit above 54% or 55% is associated with increased blood viscosity and decreased blood flow.
Hypogonadal men who are treated with testosterone may develop or may have an exacerbation of sleep apnoea. Sleep apnoea should be treated and testosterone levels evaluated again before considering testosterone replacement.
Testosterone is an anabolic agent that increases retention of nitrogen, sodium, potassium and water. Men who have diseases such as congestive heart failure, liver failure or renal failure, which cause fluid retention, may experience a worsening of these conditions when treated with testosterone. thus, testosterone replacement therapy is to be avoided in men with stage III or IV heart failure or severe renal or liver failure.
Patients with significant lower urinary tract symptoms may find that these may get worse. Men who are still wishing to remain fertile should not be started on testosterone as it will render a large proportion of them azoospermic.
Q. What delivery methods for testosterone are you aware of?
A. When testosterone is administered orally, it is metabolized by the liver on the first pass, too rapidly for it to have an effect. In order to render it clinically useful, the chemical structure of testosterone has been modified or reformulated for alternate routes of administration (Table 13.5).
Formulations of testosterone are now available for oral administration, intramuscular injection and transdermal administration by gel or patch, subcutaneous implantation of testosterone pellets or intramuscular injections.
Table 13.5 Formulations available for testosterone therapy
|
Route |
Dose |
|
Oral |
|
|
Testosterone undecanoate |
120-160 mg once daily during first 2-3 weeks, then 40-120 mg daily |
|
Buccal T system |
30 mg every 12 hours |
|
Intramuscular injections |
|
|
Testosterone cypionate/enanthate |
100-200 mg every 2 weeks |
|
Testosterone undecanoate |
1000 mg every 6 weeks during first 12 weeks, then 1000 mg every 3 months |
|
Transdermal |
|
|
T gel |
5-10 g daily (5-10 mg testosterone) |
|
T patch |
5-10 mg daily |
|
Subdermal |
|
|
T pellets |
4 (200 mg) pellets every 5-7 months |
Q. How would you monitor the testosterone replacement therapy?
A. It is important to measure serum testosterone in patients receiving replacement therapy to determine whether the treatment is raising the level to the desired range. Furthermore, the clinical signs and symptoms that initially caused the patient to be diagnosed and treated for testosterone deficiency should be monitored. Additionally, it is useful to assess bone mineral density prior to treatment and this may require re-evaluation at regular intervals.
In the older man it is very important to monitor for potential adverse effects of testosterone treatment and for delivery system-specific adverse effects. The most common adverse effect is an excessive rise in the hematocrit (>54%). When this occurs, treatment should be stopped to allow the hematocrit to normalize, after which treatment should be resumed at a lower dose.
The most serious safety concern is the potential for stimulating an occult prostate cancer to become a clinically significant prostate cancer. One should also consider using shorter- acting delivery systems when initiating testosterone treatment in older men. Should a patient develop a significant rise in hematocrit or PSA, or an abnormal DRE, it would be easier to stop this treatment while further evaluation is being conducted. This usually is of less concern after a patient has been on testosterone replacement therapy for at least 3 months whereupon a longer-acting depot form can be used.
Q. What is the relationship between testosterone levels, testosterone replacement and prostate cancer?
A. Prospective epidemiological studies have found no positive correlation with both total or bioavailable testosterone levels and prostate cancer. However, there are reports that men with low testosterone levels are more likely to have prostate cancer and perhaps a higher grade of prostate cancer than men who are eugonadal. These findings have not been duplicated in population-based studies. ttere is also some evidence that low testosterone levels may cause some reduction in PSA levels and that replacement therapy will consequently be associated with some increase in PSA levels. The relatively small clinical trials that have been conducted have not shown an increase in clinical prostate cancer in the testosterone groups compared with the placebo groups, but the small size of these trials and the short follow-up do not provide enough data for definitive conclusions concerning the safety of testosterone replacement therapy in regard to prostate cancer.
Q. What are the common side effects of testosterone treatment?
A. Younger men receiving testosterone replacement therapy may experience acne, increased oiliness of the skin, gynaecomastia, suppression of fertility, and some testicular atrophy. These changes may also be seen in the older male, but they rarely limit therapy.