Risks and benefits of late onset hypogonadism treatment: an expert opinion

Abstract

Late-onset hypogonadism (LOH) is a syndromic condition that has a well-recognized association with sexual and reproductive failure. LOH is frequently associated with chronic conditions including cardiovascular diseases (CVD), obesity, osteoporosis, HIV infection, renal failure, and obstructive pulmonary diseases. Despite this evidence, in patients with these conditions, LOH is still only rarely investigated and testosterone replacement therapy (TRT) rarely considered. In this paper, we critically reviewed the available evidence on LOH treatment focusing on possible risks and benefits. Medical therapy of LOH should be individualized depending on the etiology of the disease and the patient's expectations. The fear of prostate cancer and the risk of erythrocytosis probably represent the main limitations of TRT in aging men. However, TRT in healthy older men in near physiological doses does not appear to incur serious adverse events, although regular monitoring of prostate-specific antigen and hematocrit levels is required. Available evidence also suggests that TRT might ameliorate central obesity and glycometabolic control in patients with metabolic syndrome and type 2 diabetes. In addition, TRT has been associated with an increase in bone mineral density in men with osteoporosis, with an improvement in lean body mass in subjects with human immunodeficiency virus infection or chronic obstructive pulmonary disease, as well as with peripheral oxygenation in patients with chronic kidney diseases. Despite this evidence, however, it should be recognized that the results of these trials were heterogeneous and limited by small sample sizes. Hence, further research is required regarding the long-term benefits and adverse effects of TRT in LOH.

Keywords: Diabetes mellitus; Erectile dysfunction; Hypogonadism; Prostate; Testosterone.

Fig. 1

Classification of male hypogonadism as a function of age onset and patient's phenotype. Schematic prevalence in male population is also shown. Size of ellipsis reflects on abscissa (log scale): age of onset and on ordinates (log scale): incidence (right axis) or female to male phenotype (left axis, arbitrary unit). Adapted from ref. # 7. HCG: human chorionic gonadotropin, VEOH: very early onset hypogonadism, i.e. starting during foetal life for absence of testosterone formation or activity (e.g complete androgen insensitivity or Morris' syndrome, blue ellipsis) or impaired secretion or activity of GnRH (e.g., Kallmann's syndrome or mutation in GPR54 and GnRH receptor, red ellipsis), EOH: early onset hypogonadism (i.e peri-pubertal onset, such as in Klinefelter's syndrome, green ellipsis), LOH: late onset hypogonadism, i.e. in adulthood or aging (brown ellipsis).

Fig. 2

Prevalence of hypogonadism according to the European Male Aging Study (EMAS) criteria (13) in Florentine subjects of the EMAS study (n=433) and in a consecutive series of (n=3,293) output-patients attending medical care for sexual dysfunction between 2000~2011 at our center (UNIFI study).

Fig. 3

PSA levels as a function of total testosterone deciles in a consecutive series of 1,715 patients attending our Unit seeking medical care for sexual dysfunction and apparently free from prostate diseases: history of prostatitis, BPH, or suspected prostate cancer as assessed by urological examination and/or an abnormal (tender, enlarged, or with suspect nodules) digital rectal examination of the prostate, and/or total PSA above 4 ng/ml, and/or previous prostatic surgery or radiotherapy, and/or using drugs altering prostate growth (testosterone, alpha-blockers, vitamin D, and antiandrogen drugs including GnRH analogues, bicalutamide, 5-alpha-reductase inhibitors, serenoa repens and mepartricin). ANOVA Tukey post hoc was p<0.005 for 1st decile vs. 2nd or higher. PSA: prostate-specific antigen, BPH: benign prostatic hyperplasia.

Fig. 4

Age adjusted (adj) relationship between testosterone levels and hematocrit (A), hemoglobin (B), predicated cardiovascular (CV) risk as detected by Progetto Cuore risk engine (C) and homeostatic model assessment (HOMA) index (D). Data were obtained from a consecutive series of patients attending our unit seeking medical care for sexual dysfunction.

Fig. 5

Age adjusted (adj) relationship between testosterone levels and penile doppler ultrasound parameters performed before (flaccid) and after (dynamic) prostaglandin-1 stimulation. Data were obtained from a consecutive series of 2,345 patients attending our unit seeking medical care for sexual dysfunction. PSV: peak systolic velocity.

Fig. 6

Odds ratio (OR) for overall mortality in patients treated vs. not treated with testosterone replacement therapy (TRT). CI: confidence interval, LL; lower limit, UL: upper limit.

Fig. 7

Weighted differences (with 95% confidence interval [CI]) of waist circumference (A), homeostatic model assessment (HOMA) index (B), triglycerides (C) and high density lipoprotein (HDL) cholesterol (D) at endpoint across randomized controlled trials evaluating the combination of testosterone replacement therapy (TRT) and lifestyle modifications vs. lifestyle alone. The size of the circles reflects the sample dimension. LL: lower limit, UL: upper limit, Diff: difference.