Article Title: Complexities of Hypogonadism

Author: Dr. Poochellam Muthalagu

Date of Publication: June 30, 2011

Dr. Poochellam Muthalagu looks at the primary and secondary reasons for hypogonadism and examines the different treatments available in this country.

Male hypogonadism is a clinical syndrome defined by low testosterone levels associated with sexual dysfunction, particularly diminished libido, mood disturbances, reduced lean body mass and increased adipose tissue mass.

A wide range of effective and well-tolerated treatment options exist. These include testosterone (T) gels and T patches. There is also a mucoadhesive sustained-release buccal tablet, but this is not available in Ireland. Intramuscular testosterone injections and subcutaneous depot implants (T pellets) are still the standard therapy.

Testosterone replacement therapy (TRT) can be individualised to enhance patient health and wellbeing. Screening and ongoing monitoring are necessary to ensure both the efficacy and safety of TRT, particularly prostate safety. Investigational agents, including selective androgen receptor modulators, may offer new pharmacodynamic and/or pharmacokinetic properties that enhance outcomes of TRT.

Male hypogonadism is defined as the failure of the testes to produce androgen, sperm or both. Although the disorder is exceedingly common, its exact prevalence is uncertain.

Testosterone production declines with advancing age; some 20 per cent of men older than 60 years and 30-40 per cent of men older than 80 years have serum testosterone levels that would be subnormal in their younger adult male counterparts.

This apparent physiologic decline in circulating androgen levels is compounded in frequency by permanent disorders of the hypothalamic-pituitary-gonadal axis. These include the transient deficiency states associated with acute stressful illnesses, such as surgery and myocardial infarction, and the more chronic deficiency states associated with wasting illnesses, such as cancer and acquired immunodeficiency syndrome (AIDS).

Circulating testosterone is largely protein-bound — the major protein is sex hormone-binding globulin (SHBG) — with only 2 per cent present as the biologically active or free fraction. Hepatic SHBG production rises with ageing and thyroid hormone excess and declines in hyperinsulinemic states (obesity and type II diabetes), so that free testosterone values may not always be concordant with total testosterone values.

The biologic effects of testosterone may be mediated directly by testosterone or by its metabolites 5a-dihydrotestosterone or estradiol. The single decapeptide gonadotropin-releasing hormone (GnRH) stimulates the release of follicle-stimulating hormone (FSH) and luteinising hormone (LH).

Pulsatile GnRH is required. Chronic exposure down regulates the GnRH receptor and causes impaired FSH and LH release, the mechanism whereby pharmacologic GnRH agonists result in chemical castration. Prolactin excess also results in impaired GnRH pulse generator function and hypo-gonadotropic hypogonadism.

Feedback inhibition of LH secretion is a sex steroid–mediated event, whereas FSH secretion has dual feedback regulation involving inhibition by sex steroids and the Sertoli cell product inhibin. Accordingly, a monotropic elevation of the FSH level (normal LH and testosterone levels) may result from deficient Sertoli cell–spermatogenic function.

Major causes of primary (hypergonadotropic) hypo-gonadism include: genetic (Klinefelter’s syndrome, XX males, XYY syndrome); congenital (anorchia, Noonan syndrome, cryptorchidism, myotonic dystrophy); toxins (alcohol, heavy metals, antineoplastics, radion); orchitis; trauma; infarction; and ageing.

Major causes of secondary (hypogonadotropic) hypogonadism include: pubertal delay; hypogonadotropism (Kallman’s syndrome); congenital or acquired; isolated or combined pituitary disease; space-occupying lesions of pituitary, hypothalamus; hyperprolactinaemia per se; infiltrative, infectious; suppression; sex steroids; gonadotropin-releasing hormone analogues; and (possibly) ageing.

Clinical features
Manifestations in adults are generally more subtle. Perhaps the minor contribution of adrenal androgens (or androgenic precursors) may substitute for testicular deficiency once the target tissues have been fully developed. Moreover, ingrained behaviour patterns may be resistant to androgenic hormone deficiency.

Certainly, prolactin excess, testosterone deficiency, or both in men may result in impaired libido and erectile dysfunction. The yield of finding hyperprolactinaemia or testosterone deficiency, or both, in patients presenting with these symptoms is generally considered to be low, usually less than 5 per cent.

A. More specific symptoms and signs
•  Incomplete or delayed sexual development, eunuchoidism;
•  Reduced sexual desire (libido) and activity;
•  Decreased spontaneous erections;
•  Breast discomfort, gynaecomastia;
•  Loss of body (axillary and pubic) hair, reduced shaving;
•  Very small (especially <5 ml) or shrinking testes;
•  Inability to father children, low or zero sperm count;
•  Height loss, low trauma fracture, low bone-mineral density;
•  Hot flushes, sweats.

B. Other less specific symptoms and signs
•  Decreased energy, motivation, initiative, self-confidence;
•  Feeling sad or blue, depressed mood, dysthymia;
•  Poor concentration and memory;
•  Sleep disturbance, increased sleepiness;
•  Mild anaemia (normochromic, normocytic, in the female range);
•  Reduced muscle bulk and strength;
•  Increased body fat, body mass index;
•  Diminished physical or work performance.

The first manifestation of hypogonadism may be a consequence of a large space-occupying intrasellar or parasellar lesion manifested by headaches, bitemporal hemianopia, or extraocular muscle palsy. Galactorrhoea as a manifestation of hyperprolactinaemia is rare, but rarely sought.

‘Associated conditions include diabetes, AIDS, chronic renal failure, RA, ageing and cancer cachexia’

Unexplained osteoporosis or mild anaemia sometimes is the clue to an underlying hypogonadal state.

Some common clinical conditions associated with male hypogonadism are: chronic illness; diabetes; AIDS; chronic renal failure; rheumatoid arthritis; ageing; and cancer cachexia.

Because of the well-known diurnal rhythm of serum testosterone, which appears to be lost with age (older than 60 years), with values 30 per cent or so higher near 8am versus the later-day trough, a testosterone value should be determined first thing in the morning. Normal ranges vary among laboratories. Although the usually quoted range for young men is 300-100 ng/dL, the lower limit is 220ng/dL. In general, values below 220-250ng/dL are clearly low in most laboratories; values between 250ng/dL and 350ng/dL should be considered borderline low.

Similarly, in some reference laboratories, the lower limit of the normal range for serum free testosterone level, measured by the equilibrium dialysis method, is 5–9pg/ml (0.17-0.31nmol/l). The clinicians should use the lower limit of normal range for healthy young men established in their laboratory.

Because the acute effect of stressful illness may result in a transient lowering of testosterone levels, a confirmatory early-morning specimen should be obtained. Measurement of free testosterone levels or bioavailable testosterone levels, determined adequately in select commercial laboratories, may provide additional information.

For example, free testosterone levels may be lower than expected from the total testosterone level as a result of ageing and higher than expected in insulin-resistant individuals, such as in obesity. In addition, serum FSH, LH and prolactin levels should be determined to help delineate the cause of the testosterone-deficient state.

If gonadotropin levels are not elevated, despite clearly subnormal testosterone values, anterior pituitary (thyroid-adrenal) function should be determined by measuring free thyroxine and thyroid-stimulating hormone levels, as well as an early-morning cortisol level. A magnetic resonance imaging (MRI) scan of the brain and sella should be considered.

An exception to this recommendation is the condition of morbid obesity, in which both total and free testosterone levels are typically low and gonadotropin values not elevated. Hyperprolactinaemia, even of a small degree, may also warrant ordering MRI, because interference of hypothalamic-pituitary vascular flow by space-occupying, stalk-compressing lesions will lead to disruption of the tonic inhibitory influence of hypothalamic dopamine, and result in modest hyperprolactinaemia (20- to 50ng/mL range).

The ideal TRT should replace testosterone to physiologic levels using natural (unmodified) testosterone. The TRT should offer: safety, efficacy, value for money, convenience, a good release profile, dosing flexibility, and effective normalisation of testosterone levels.

TRT is relatively straightforward. Typically, the depot esters are administered by the deep intramuscular route once every two weeks at a dose of 200mg in adults. A usual dosage for the transdermal or the buccal preparations results in the systemic absorption of 2.5-10mg daily. If the parenteral route is chosen, patients should and can be taught to self inject.

The major disadvantage with the parenteral route is that testosterone levels exhibit a saw-toothed pattern, with high-normal or supranormal levels on days two to four and low-normal or borderline low trough values before the next injection. Mood, sense of wellbeing and libido may vary accordingly in some individuals.

Dosages may be adjusted by aiming for mid-normal (400-600ng/dL) testosterone levels after one week or at the low end (250-350ng/dL) just before the next injection is due at two weeks. Values are stable within a few days or weeks of the skin patch, gel, or newer buccal preparation.

It must be ascertained that the preparation was actually used on the day the sample was drawn; again, a value in the midnormal range (400-600ng/dL) is the goal. Although comparable testosterone levels are reached by the patch and the gels, skin reactions at the application site are much more common with the patch. Also, the buccal preparation is difficult for patients to get used to. Alkylated oral androgens should be viewed as potentially hepatotoxic and should not be used.

Testosterone preparations available in Ireland

  • Oral – Restandol (testosterone undecanoate)
  • Intramuscular – Undecanoate, Nebido
  • Gel – Testogel, Tostran, Testim

Contraindications for testosterone replacement include: breast carcinoma (history or presence); prostate carcinoma (history or presence); severe benign prostatic hyperplasia; abnormal digital rectal examinations; elevated levels of prostate-specific antigen; age (no limit established, possibly older than 80 years); psychopathology; sleep apnoea (potential for worsening); hypercoagulable states; and polycythaemia (haematocrit >51 per cent).

In genuinely hypogonadal men, testosterone administration can be expected to result in improvements in a variety of clinical areas. These include: increase in lean body mass; decreased fat mass; increased bone density (no fracture data available); improved mood and wellbeing; improved sexual function; better cognitive function; better muscle strength, physical function. Least predictable of these are the effects on sexual function, cognitive function and muscle strength.

Male hypogonadism is defined as the failure of the testes to produce androgen, sperm, or both. Although the disorder is exceedingly common, its exact prevalence is uncertain.

Signs and symptoms vary, according to age.

Diagnosis requires the determination of low testosterone levels. Normal ranges vary among laboratories. Measurement of free testosterone levels or bioavailable testosterone levels (performed adequately in select commercial laboratories) may provide additional information, in addition to serum follicle-stimulating hormone, luteinising hormone and prolactin levels. MRI scans of the brain and sella should be considered.

Androgen replacement therapy is used for the treatment of male hypogonadism. In addition to monitoring testosterone levels periodically, prostate screening by digital rectal examination and prostate-specific antigen determinations at periodic intervals when the patient is on therapy should be carried out.

Haemoglobin and haematocrit levels should also be checked periodically.

References on request.

  • Dr Poochellam Muthalagu, Consultant Physician/Endocrinologist, Cavan/Monaghan Hospital Group