Testosterone Replacement Therapy and Late-onset Hypogonadism
Testosterone Replacement Therapy and Late-onset Hypogonadism
European Endocrine Review 2006
Published: October 2008
Published: October 2008
Late-onset hypogonadism (LOH) is a clinical and biochemical syndrome associated with advancing age and characterised by typical symptoms and a deficiency in serum testosterone levels. LOH may result in significant detriment in the quality of life and adversely affect the function of multiple organ systems, particularly the musculoskeletal system.1 In a proportion of patients presenting in this way, no specific cause can be identified apart from the ageing process itself, but the case-mix will include individuals with systemic diseases and lesions of the hypothalamic–pituitary region, as well as latepresenting congenital hypogonadism.
Diagnosis
Clinical diagnosis of LOH should comprise an adequate history and physical examination, which also serve to identify any previously unsuspected systemic disease processes. The syndrome is characterised by diminished sexual desire and erectile quality and frequency, particularly nocturnal erections. Changes in mood with concomitant decreases in intellectual activity, cognitive functions, spatial orientation ability, fatigue, depressed mood and irritability may also be identified. Other characteristics include sleep disturbances, a decrease in lean body mass with an associated reduction in muscle volume and strength, increased visceral fat, reduced body hair, skin alterations and decreased bone mineral density resulting in osteopenia, osteoporosis and increased risk of bone fractures. However, signs and symptoms alone are insufficient for a conclusive diagnosis, with the specificity of screening questionnaires being notoriously low. Biochemical assessment of total testosterone level is therefore essential, preferably performed between 8am and 11am due to the circadian variation in serum levels.1 The free testosterone level can also be helpful (calculated from measured levels of testosterone and sex-hormone-binding globulin or measured through a reliable equilibrium dialysis method).
Assessment of Testosterone Levels
It is important to know the adult male range of serum testosterone, bioavailable or free testosterone of the clinical laboratory. The lower limit of normal for a healthy adult male is internationally defined by a serum total testosterone below 12nmol/litre or a free testosterone below 250pmol/litre, with total testosterone levels between 8nmol/litre and 12nmol/litre or free testosterone levels between 180pmol/litre and 250pmol/litre being regarded as borderline.
It is also important to bear in mind reference ranges from the local biochemistry laboratory. Even with apparently clear-cut biochemical hypogonadism, it is advisable to repeat the testosterone determination, with measurement of serum gonadotropins, i.e. luteinising hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH are raised in men with a primary disorder of the testis and low or ‘inappropriately’ normal in men with deficient hypothalamic–pituitary function. A diagnosis of primary hypogonadism or testicular failure is unquestionable if gonadotropin levels are chronically elevated, even if the testosterone level itself seems entirely normal.1
Hypogonadal men with low or normal gonadotropins should undergo a more detailed biochemical evaluation, particularly serum prolactin (PRL) level but also cortisol, thyroid and iron studies if more profound hypothalamic–pituitary dysfunction is at all suspected. A therapeutic trial of testosterone treatment can always be considered in men with borderline hypogonadism.1
Treatment
Commonly used testosterone formulations include injectable testosterone (testosterone cypionate, testosterone enanthate, testosterone undecanoate), oral testosterone (testosterone undecanoate), transdermal testosterone (patch or gel) and buccal testosterone.
A New, Long-acting Formulation of Testosterone Undecanoate for Intramuscular Injection
A new testosterone preparation for intramuscular (IM) injection, 1,000mg testosterone undecanoate (Nebido®), has recently been developed.2 Testosterone undecanoate is dissolved in castor oil for IM injection, and this depot formulation allows a remarkable extension of the injection interval from one to three weeks with testosterone enanthate (i.e. 17–52 injections a year) to 10–14 weeks (i.e. usually four injections a year in longterm therapy). These characteristics of testosterone undecanoate can substantially improve both the acceptability and tolerability of testosterone injection therapy, as well as contributing to far more stable serum testosterone levels within the physiological normal range.
Pharmacokinetic studies have shown IM testosterone undecanoate to have a prolonged duration of action, allowing for the gradual extension of the injection interval from six to 12 weeks.3 Subsequent clinical studies have shown that one injection of IM testosterone undecanoate 1,000mg maintained serum testosterone concentrations within the normal range for around three months, while avoiding nonphysiological peaks.4,5
References:
- Nieschlag E, Swerdloff R, Behre H M et al., “Investigation, treatment and monitoring of late-onset hypogonadism in males.ISA, ISSAM and EAU recommendations”, Eur. Urol. (2005);48: pp. 1–4.
- Schubert M, Minnemann T, Hubler D et al., “Intramuscular testosterone undecanoate: pharmacokinetic aspects of a noveltestosterone formulation during long-term treatment of men with hypogonadism”, J. Clin. Endocrinol. Metab.(2004);89(11): pp. 5,429–5,434.
- Behre H M, Abshagen K, Oettel M, Hubler D, Nieschlag E, “Intramuscular injection of testosterone undecanoate for thetreatment of male hypogonadism: phase I studies”, Eur. J. Endocrinol. (1999);140(5): pp. 414–419.
- Nieschlag E, Buchter D, Von Eckardstein S et al., “Repeated intramuscular injections of testosterone undecanoate forsubstitution therapy in hypogonadal men”, Clin. Endocrinol. (1999);51(6): pp. 757–763.
- von Eckardstein S, Nieschlag E, “Treatment of male hypogonadism with testosterone undecanoate injected at extendedintervals of 12 weeks: a phase II study”, J. Androl. (2002);23(3): pp. 419–425.
- Hubler D, Schubert M, Minnemann T et al., “Effect of longterm treatment with a new sustained-action testosteroneundecanoate (TU) formulation for intramuscular androgen replacement therapy on sexual function and mood in hypogonadalmen”, Int. J. Impot. Res. (2002);14(suppl. 4): p. S51.
- Wang C, Swerdloff R S, Iranmanesh A et al., “Transdermal Testosterone Gel Improves Sexual Function, Mood, MuscleStrength, and Body Composition Parameters in Hypogonadal Men”, J. Clin. Endocrinol. Metab. (2000);85(8):pp. 2,839–2,853.
- Wang C, Cunningham G, Dobs A et al., “Long-term testosterone gel (AndroGel) treatment maintains beneficial effects onsexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men”, J. Clin. Endocrinol.Metab. (2004);89(5): pp. 2,085–2,098.
- Morales A, “Androgen replacement therapy and prostate safety”, Eur. Urol. (2002);41(2): pp. 113–120.
- Kaufman J M, “The effect of androgen supplementation therapy on the prostate”, Aging Male (2003);6(3):pp. 166–174.
- Morales A, Buvat J, Gooren L J et al., “Endocrine aspects of sexual dysfunction in men”, J. Sex. Med. (2004);1(1):pp. 69–81.
- Slater S, Oliver R T, “Testosterone: its role in development of prostate cancer and potential risk from use as hormonereplacement therapy”, Drugs Aging (2000);17(6): pp. 431–439.
- Rhoden E L, Morgentaler A, “Risks of testosterone-replacement therapy and recommendations for monitoring”, N. Engl.J. Med. (2004);350(5): pp. 482–492.
