DEFINITION
Andropause is defined as the collection of signs and symptoms associated with the age-related decline in gonadal function in men. In contrast to the rapid decline in ovarian function at menopause, at andropause the decline in testicular function and testosterone production is gradual.
Aging men (usually >50 year-olded) experience reductions in androgen levels, virility, and fertility, along with related metabolic changes. Nonetheless, the question of andropause remains controversial, in part because of the difficulty in discriminating the effects of age-related confounding variables, such as stress, nonendocrine illnesses, malnutrition, obesity, and drug or medication use, from aging per se, on the other hand. The reproductive changes that occur in the aging male are more subtle than the profound modifications in gonadal function that occur in women.
THE PROBLEM OF THE NAME
Andropause has also been referred to by some as “androgen deficiency in the aging male (ADAM),” “partial androgen deficiency in the aging male (PADAM),” or “aging-associated androgen deficiency (AAAD).” The term “male menopause” is inappropriate because there is no interruption or cessation of menses, and “viropause” is inaccurate because there is no loss of virilization. “Male climacteric” refers to the syndrome of endocrine, somatic, and psychic changes that occur in normal men with aging. This term emphasizes the multidimensional nature of age-related changes, including decreases in other hormones such as growth hormone (GH), insulin-like growth factor-1 (IGF-1), dehydroepiandrosterone(DHEA), and melatonin, but it does not relate aspects of the male aging syndrome specifically with androgen levels. The term “andropause” is not completely accurate because androgen secretion does not cease altogether. However, it is the only term that relates the syndrome of age-related physiological changes with the gradual and progressive decline in T levels that occurs with aging,
EPIDEMIOLOGY
It is uncertain if every man undergoes symptomatic decline in circulating androgens with aging.
It has been estimated that on the average, about 50% of healthy men above the age of 60 years old have serum bioavailable testosterone levels that are below the lower limit of normal for men aged 20-40 years.
PATHOPHYSIOLOGY
The most important male sex hormone is testosterone which is majorly produced by the testicular Leydig cells under the control of pituitary gonadotropin called luteinizing hormone (LH). Testosterone is metabolized by the enzyme 5-α reductase to dihydro-testosterone (DHT), which is the active metabolite. It is transported in the serum highly bound to sex hormone binding globulin (SHBG) and to a lesser extent (and with much less affinity) to albumin. Only about 2% exists unbound as free testosterone.
Bio-available testosterone refers to non-SHBG bound form including free testosterone and is the biologically active fraction. It acts directly at the cellular level and is responsible for development of secondary male sexual characteristics. It also contributes to hair growth, muscle mass, bone density and erythropoiesis.
Reduction in total testosterone is not usually noticed in men until the sixth decade of life; however decline in free concentration is seen earlier, at a rate of approximately 1-2% per year between the ages of 40-70 years.
The etiology of T decline is multi-factorial but testicular failure seems to be playing a major role. With advancing age, there is a gradual decline in the number as well as the secretory capacity of Leydig cells, resulting in low testosterone production. Age-related histomorphological changes in Leydig and Sertoli cells in the testis have also been observed.
Testosterone: a metabolic hormone in health and disease.
Apart from this, the hypothalamus-pituitary-gonadal axis (HPG axis) becomes less sensitive with age and elderly men seem to be unable to compensate for the reduction in circulating testosterone (while the hypothalamic centers are more sensitive to negative feedback effects).
It has also been noticed that SHBG concentration increases at the rate of about 1-2% per year (and it happens earlier than T decrease), so that many older men with low-normal total T levels have free or bioavailable T levels that are below the normal range for young men.
A plausible hypothesis is that the increase in SHBG levels is related to the age-dependent decline in circulating growth hormone or insulin-like growth factor level.
The impact of reduced T production on circulating T levels is lessened by the decrease in metabolic clearance of T that also occurs with aging.
The normal circadian variation in serum T levels, with peak concentrations in the morning and slow fall by about 35% during the day, is blunted in healthy older men compared to young men, suggesting an alteration in the hypothalamic circadian pacemaker function. Because of age-related blunting of the normal circadian variation in T levels, early morning serum T levels are lower but late afternoon values are more similar in older compared with young men.
It has moreover been proved an age-related reduction in responsivity to androgens resulting from alterations in receptor number or affinity (particularly for DHT) causing a loss of sensitivity of target tissues.
Function of the seminiferous tubule compartment of the testis also declines with aging. In older compared with young men, spermatogenesis assessed histologically is reduced, but ejaculated sperm concentration is unchanged or increased as a result of diminished ejaculatory volume and frequency. With older paternal age, the risk of inherited autosomal dominant diseases increases.
The number of Sertoli cells, seminiferous tubule cells that support spermatogenesis, and serum levels of inhibin B, a Sertoli cell peptide product responsible for feedback inhibition of follicle-stimulating hormone (FSH) secretion from the pituitary gland, decrease with aging.
Compared with young men, older men demonstrate slightly diminished gonadotropin responsiveness to acute GnRH but a normal LH response to chronic pulsatile GnRH administration, suggesting that pituitary gonadotropin secretion remains intact with aging. Together, these findings suggest that aging is associated with impairments in both testis function and hypothalamic GnRH regulation of gonadotropin secretion.
Androgen receptor gene expression in the CA1 region of the hippocampus and the number of androgen receptor binding sites in genital skin are decreased in older compared with young men, but it doesn't happen in the prostate.
The length of trinucleotide CAG repeats in the androgen receptor gene is variable and is associated with differences in transcriptional activity, with a shorter CAG repeat length associated with greater androgen receptor activity and possibly overall greater androgen action.
Older men with lower serum T levels had an androgen receptor genotype characterized by a shorter CAG repeat length, suggesting overall greater androgen activity. It is hypothesized that, in older men with shorter CAG repeat length, increased androgen action at the level of the hypothalamic-pituitary axis may result in greater feedback suppression of gonadotropin and, in turn, endogenous T secretion. This may be an intrinsic mechanism that underlies the physiological decline in serum T levels with aging. A shorter CAG repeat length in the androgen receptor gene also has been associated with an increased risk and severity of BPH and prostate cancer and an earlier age at diagnosis and aggressiveness of prostate carcinoma.
T is actively metabolized to the potent estrogen, estradiol (E2), by the enzyme aromatase, which is located primarily in adipose tissue, and to 5 alpha-dihydrotestosterone (DHT), a more potent androgen than T, by the enzymes 5 alpha-reductase type 1 and 2, which are located predominantly in skin and the prostate. Many of the actions of T are mediated, at least in part, by its active metabolites, E2 (e.g., bone, brain, and lipids) and DHT (e.g., prostate).
Despite declining T levels, serum total E2 and DHT levels do not change or decrease only slightly with aging. This suggests that, with aging, there is a relative increase in aromatization of T to E2 (perhaps due to increased adipose tissue mass) and 5 alpha-reduction of T to DHT and/or reductions in the metabolic clearance of E2 and DHT. Recent studies suggest that bioavailable E2 levels decline with aging and correlate better than T with bone mineral density in men.
Tissue concentrations of DHT decrease within the epithelial compartment and E2 increase within the stromal compartment of the normal and BPH prostate gland with aging, emphasizing the importance of active metabolism of T in androgen target organs and within specific regions of these organs.
Serum concentrations of DHEA , a weak adrenal androgen that is a precursor of T, decline more rapidly and more profoundly than those of T with aging, but this has no physiological explanation.
Modifications of testosterone levels in diseases and lifestyle
Among confounding extra-testicular factors contibuting to T decline, massive obesity in elderly men lowers serum testosterone levels of 63%. A reversable dose-dependent reduction as a result of alcohol use has been documented.
Furthermore, acute critical illness or surgical injury cause a profound, generally transient, decrease of free testosterone ([F]T) levels.
As far as chronic diseases are concerned, decreased testosterone and sex hormone-binding globulin (SHBG) levels are observed in elderly men with diabetes mellitus, with an inverse correlation between testosterone and plasma glucose.
Coronary atherosclerosis has been reported to be associated with low testosterone levels.
Chronic renal failure generally induces a hypogonadotropic hypogonadism with impaired pulsatile release of pituitary luteinizing hormone (LH).
Chronic liver disease is accompanied by decreased (F)T levels and increased SHBG.
Sleep apnea syndrome, with its hypoxia, is accompanied by lowered testosterone levels, secondary to a hypogonadotropism; these patients are often obese, which may aggravate the hypogonadism.
Among drugs that may adversely affect Leydig cell function in the elderly, the frequently used glucocorticoids, as long-term therapy, often induce a marked suppression of (F)T levels as the result of both testicular and central actions of the drug, as well as a decrease of SHBG levels.
Smokers have higher testosterone levels than nonsmokers.
The influence of diet can influence testosterone levels. Fasting may affect testosterone production through diminished gonadotropic testicular control.
CLINICAL MANIFESTATION (SYMPTOMS)
There is a great variability in terms of perception and intensity of andropausal symptoms in elderly men, the clinical manifestations are not specific and are usually multifactorial. Some men are completely asymptomatic while some experience certain symptoms that they accept as normal accompaniment of aging or what they call “mid-life crisis”.
However, aging in men is generally accompanied by a decrease in general wellbeing; changes in mood with concomitant decrease in intellectual activity; spatial orientation ability fatigue; lethargy and sleep disorders; depression and anger; decrease in virility, sexual desire and erectile quality; decrease in skin thickness; decrease in energy; decrease in muscular mass (sarcopaenia) and in strength; an increase in upper- and central-body fat; decrease in bone mineral density resulting in osteoporosis and risk of pathological fractures; decrease in body hair, hot flashes and night sweats.
Most epidemiological studies find a positive correlation between free T levels within the physiological range and high-density lipoprotein (HDL) cholesterol levels, and an inverse correlation between T concentrations and hypertension, insulin and glucose levels, prothrombotic factors, atherosclerotic vascular disease, and the presence or severity of coronary artery disease (CAD).
DIAGNOSIS
Andropause is essentially a diagnosis of exclusion. Chromosomal disorders like delayed diagnosis of Klinefelter's syndrome can simulate fetures of andropause and should be ruled out by karyotyping. Other causes of hypotestosteronaemia include traumatic, infectious or neoplatic diseases of the testes.
Post-puberal mumps, torsion of the testes as well as certain drugs (like ketoconazole, cimetidine and cytotoxic agents) have been associated with gonadal dysfunctions.
The best parameter to determine hypogonadism is measurement of bioavailable testosterone, which includes free and albumin-bound fractions. In the aging male, total testosterone may be misleading due to alterations in SHBG and flattening of the circadian rhythm. Serum testosterone non-fasting assessment should be done twice between 8 and 11 am. If the testosterone level is below or at the lower limit, it is prudent to confirm the results with a second determination with assessment of LH and folliclestimulating hormone (FSH).
In addition, the diagnosis of andropause requires the presence of some or all the extra-gonadic symptoms.
Andropause (androgen deficiency of the aging male): diagnosis and management
TREATMENT
The tratment of choice for symptomatic men with documented diagnosis is Testosterone Replacement Therapy (TRT).
The goals of the therapy are to relieve symptoms caused by androgen deficiency, restore libido and sexual functions, and improve the overall quality of life.
Use of T in elderly men is however controversial and risks and benefits should always be considered.
T treatment should be instituted in these men if both the clinician and the patient feel that the potential benefits of treatment outweigh the potential risks and if no contraindications exist. Absolute contraindications to T therapy are prostate and breast cancer, and relative contraindications are untreated BPH (Benign Prostatic Hyperplasia) with severe bladder outlet obstruction.
BENEFICAL EFFECTS OF TRT
The anabolic effect of T is well replaced by TRT as it increases bone mass density in all elderly hypogonadal osteopenic men, plus a noticed increase in the lean body mass, leg muscle strength and upper body strength.
Total body fat mass as well as visceral fat declines.
Several studies have shown improvement in spatial cognition with androgen therapy. Others have reported improvement in sense of wellbeing and/or an increase in libido with testosterone.
Sexual function and attitude are improved, with the significant increase of erectile events per day, mean duration of events and mean penile rigidity, at the same time as improvement of sexual desire, arousal, orgasmand satisfaction.
The therapy also increases haematocrit level and corrects anemia, while its effects on mood and cognitive functions are not significant.
Androgens have also a profound effect on the skin: they regulate, by means of receptors, the sebaceous glands and hair growth function.
ADVERSE EFFECTS OF ANDROGEN SUBSTITUTION (TRT)
The long-term effect on prostatic health is a major problem, because testosterone (and particularly its derivate DHT) is a key regulator of prostatic growth.
There are reports of the elevations of prostate specific antigene ( PSA ) level during treatment, as well as the notice of progression of benign prostatic hyperplasia (BPH), but not the initiation of it.
Testosterone Replacement Therapy in Patients with Prostate Cancer After Radical Prostatectomy
The stimulatory effects of androgen on erythropoiesis are well known. Both testosterone and DHT stimulate renal production of erythropoietin. There is evidence for a direct effect of androgens on erythropoietic stem cells. Androgen receptors have been found in cultured erythroblasts.
Because healthy older men tend to have slightly lower hematocrit values and hemoglobin levels than do young adult men, the erythropoietic effects of testosterone in the older age group may not uniformly lead to problems with polycythemia.
Testosterone administration has been reported to exacerbate pre-existing sleep apnea, but none of the reports of testosterone therapy in older men have noted the development of sleep apnea. The ensuing oxygen desaturation may lead to cardiovascular complications. Care must be exercised in men who are overweight, heavy smokers or who have chronic obstructive airway disease.
Administration of aromatizable androgens may lead to gynecomastia in the aging male, in all likelihood when the subsequent increases of estrogens and androgens tip the balance in favor of a higher estrogen/androgen ratio.Patients with liver or renal disease (which means a slower catabolism of hormones) may be particularly predisposed to the development of gynecomastia.
Testosterone therapy inhibits triglyceride uptake and lipoprotein lipase activity and causes a more rapid turnover of triglycerides only in the abdominal adipose tissue region.
A significant decline in urinary excretion of hydroxyproline, or an increase in serum osteocalcin, was reported in men after 3 months of testosterone therapy. Bone density is increased and bone turnover slows in elderly men undergoing testosterone therapy.
The administration of testosterone can produce fluid retention, aggravating hypertension, peripheral edema, and compulsive heart failure. Men treated with testosterone produce a decrease in fasting glucose in blood and a decrease in insulin resistance.
In conclusion TRT could carry some potential risks, especially in the older man who may have certain coexistent medical problems. Water retention, development of polycythemia, hepatotoxicity, exacerbation of sleep apnea, development of detrimental effects on the cardiovascular system, and exacerbation of pre-existent benign or malignant prostate disease can be observed. Water retention could lead to hypertension, peripheral edema, or exacerbation of congestive heart failure.
Modalities of testosterone replacement
Testosterone comes in different formulations including oral, buccal, transdermal (patches or gel), intramuscular and subdermal implants.
The intramuscular (T esters at a dosage of 150-200 mg every two weeks) is the most cost effective as esters are effective, safe and the least expensive formulation available. Although it's not the most convenient, because of the transient supraphysiological levels during the first few days following injection and its side effects (like erythrocitosis), followed by fluctuations in the serum level and eventually decline to subphysiological T levels during the days preceding the next injection.
Oral preparations like 17-methyl testosterone are associated with hepatotoxicity and greater suppression of HDL cholesterol levels hence the natural T is preferred.
Daily application of transdermal delivery system is emerging as the therapy of choice because of its convenience (and rapid possibility of discontinuity in case of side effects) but it causes skin irritation in some users. Testosterone gel causes much less skin reaction.
Where TRT is considered inappropriate because of side effects, men with clinical andropause should be treated symptomatically (e.g. Phosphodiesterase-inhibitors like sildenafil for erectil dysfunction).
Andropause and testosterone deficiency: how to treat in 2012
Selective androgen receptor modulators (SARMs) or “designer” androgens are being developed for T replacement therapy. An ideal SARM would be an agent that had all the beneficial effects of T on muscle, bone, sexual function, mood, cognition, and the cardiovascular system without any of the adverse effects on the prostate and cardiovascular system. 7 α-methyl-19-nortestosterone (MENT) is synthetic androgen that does not undergo 5 α-reduction but is aromatizable to an estrogen.
In animal studies, it is approximately 10 times more potent than T in suppressing gonadotropin levels and increasing muscle size, but only two-times more active than T in stimulating prostate growth. Therefore, it is possible that a low dose of MENT given to hypogonadal men may be able to maintain muscle strength and brain function without stimulating the prostate gland. Preliminary studies suggest that it is able to maintain libido and sexual function in hypogonadal men.
MONITORING
In older men, clinical examination including a digital rectal examination, hematocrit, and PSA should be repeated 3 and/or 6 months after institution of T treatment then monitored every 12 months or possibly more frequently thereafter, depending on the clinical status of the patient. Efficacy is determined primarily by subjective and objective clinical responses to T therapy.
During T treatment, the following clinical situations require further urological evaluation: development of findings suspicious for prostate cancer on digital rectal examination (e.g., a nodule or induration), a confirmed increase in PSA (prostatic specific antigene)of 1.5 ng/ml between two consecutive values over 3–6 months, a rate of rise in PSA levels of 0.75 ng/ml/y on sequential values performed over at least 2 years, or severe symptoms of Benign Prostatic Hyperplasia (BPH) not complicated by medications or a urinary tract infection.
Development of an increase in hematocrit at 52% requires reduction in T dosage or discontinuation of therapy. For severe erythrocytosis (e.g., hematocrit 55%), T therapy should be discontinued.
After the hematocrit is normalized, T treatment may be reinstituted using a lower dosage or a transdermal formulation.
CONCLUSIONS
Age-related alterations in body composition, sexual function, mood, cognitive function, sleep, and erythropoiesis occur in conjunction with the declining serum T levels.
Several studies suggest that aging men with low serum testosterone levels could benefit from testosterone replacement therapy for bone, muscle, and psychosexual functions. However, in short-term follow-up, significant adverse effects can be observed,and for long-term follow-up, larger clinicalstudies are needed before a risk-benefit profile for testosterone therapy in hypogonadal aging men can be assessed.
At present, the most prudent course of action is to treat only older men with repeatedly low serum T levels and symptoms and signs consistent with androgen deficiency in whom the potential benefits of therapy clearly outweigh the potential risks, and to carefully monitor treated men for adverse effects. Attention to appropriate exercise and nutrition, and evaluation and treatment of other etiological factors that may contribute to clinical manifestations are essential for optimal management of age-related functional decline in older men.
PRIMARY SOURCES
Male andropause: myth, reality, and treatment
Andropause: an emerging world health problem
Testosterone Replacement in Men with Andropause: An Overview
