1 Fertility status and testicular alterations in older men

There is growing interest in the effect of aging on the male fertility potential, since an increasing number of couples wish to have children in their late reproductive years, when the reproductive system ceases to operate optimally. Fertility in men usually persists well into old age. Contrary to rapid changes observed in menopause, a sudden fall in Leydig cell or seminiferous tubular function does not occur.

However, a continuous age-dependent decrease of daily sperm production is observed. Similarly to other organs, there is considerable interindividual variation in age-dependent changes of the testes^[5]. One third of men over 60 and 50% of those over 80 are completely infertile. In principle, however, spermatogenesis may be retained well into senescence. Children have been fathered by men over 90 years^[6].

With regard to age and its influence on fertility, several studies have shown that significant fertility decline is only observed when the female partner is over 39 years, whereas the age of the male partner does not play a significant role in couples with infertility. In a study on 200 patients aged 65 to 93 years, Holstein^[5] demonstrated intact spermatogenesis, including the development of mature spermatids, in 90% of testes. However, kinetic disorders were observed, such as impaired spermatogoniogenesis, disturbed meiosis or spermatid malformations, parallelled by a highly significant decrease in daily sperm production. This indicates a gradual decline of fertility with increasing age, although alterations in sperm quality may be minimal. Reduced motility and a lower percentage of spermatozoa with normal morphology are most frequent^[7,8].

Considering the significant decrease in daily sperm production and tendency to reduced sperm motility and altered morphology, it was interesting to evaluate the fertilizing capacity of spermatozoa from older fathers compared with younger men. For this purpose, sperm functions were studied that had shown a positive correlation with the fertilization rate: progressive motility, acrosin activity, inducible AR and chromatin condensation^[9]. Apart from lower sperm motility in the older group, there were no differences in sperm functions. This observation was supported by studies from Nieschlag et al^[7] using the HOP test, which demonstrated an equally good penetration ability of spermatozoa from older and younger fathers.

Concerning tubular changes with advancing age, the seminiferous tubules gradually become atrophic as a result of decreasing germinal epithelium. These alterations do not affect the entire testes in like manner, but may initially occur focally. Increased desquamation of partly immature germ cells into the lumen of the seminiferous tubules is a suspicious change. The basal layers of the germinal epithelium are also disorganized. Gradually increasing quantitative and qualitative disturbances of spermatogenesis can be observed by transmission electron microscopy.

Holstein et al^[10] investigated the pathology of human spermatogenesis, including the aging testis, and identified age-dependent alterations in the seminiferous tubules. Severe pathological changes included morphologically altered spermatogonia and even spermatogenic arrest, formation of megalospermatocytes, giant spermatocytic cells, acrosomal malformation as well as anomalies of spermatid nuclei and tail, without following a typical pattern. In addition, an increased number of macrophages was observed in the tubuli seminiferi or epididymis. These large cells have incorporated numerous spermatozoa and are also called spermatophages.

Another typical age-dependent defect of the tubular structures is the occurrence of diverticula with evagination of the germinal tissue into the interstitium. The structure is filled with spermatocytes I and Sertoli cells, but no lumen is present. The lamina propria shows only one layer of myofibroblasts. Diverticula are observed in up to 80% of testicular biopsies in old men^[5].

It appears that Sertoli cells are also affected, as demonstrated by the formation of large vacuoles. Their lipid content may be so elevated as to culminate in giant inclusions, because they increasingly phagocytize degenerated germ cells. Altered Sertoli cell function will lead to increased FSH secretion. The finding that serum inhibin levels in elderly men are lower than those in young people suggests a decline in Sertoli cell function with aging^[11].

Reduced synthetic activity of the Leydig cells will be compensated by GnRH and LH. These hormones are increasingly released via the negative feed-back mechanism of the pituitary-gonadal axis, which will finally result in hyperplasia of the Leydig cells. There is no doubt that the number of Leydig cells declines with advancing age. While about 700 million such cells are present in a 20-year-old man, their number decreases by 6 to 7 million per year during the further process of aging^[12]. Thus, at the age of 80 years, about 200 million Leydig cells remain to be active. This correlates well with the observation of a yearly decrease of 1.2% in free testosterone and a decrease between 0.4% and 0.8% in total testosterone.

2 Endocrinological alterations

Altered sex hormone concentrations in aging men result from functional disturbances and a gradual decline in the number of Leydig cells, an impaired feed-back mechanism of the pituitary-gonadal axis, and reduced bioavailability of sex hormones. Lower sex hormone concentrations become manifest as early as the fifth to sixth decade of life. However, due to great interindividual variability, testosterone levels in older men may well be within the normal range for younger men. It is only after the seventh decade of life that an age-associated decrease of testosterone becomes statistically relevant^[13]. A selected population of healthy men participating in the Baltimore Longitudinal Studies on Aging had total plasma testosterone levels remaining stable until the age of 90 years. Nonetheless, advancing age generally goes along with a progressive decline in the synthesis of testosterone by Leydig cells, accompanied by an increase of LH and FSH levels.

Several investigators have clearly demonstrated that decreased testosterone levels are of primarily testicular origin. Leydig cells seem to be less responsive to stimulation by LH, demonstrated in a group of young men and elderly patients during HCG administration^[14]. Obviously, there are significant differences in T response towards HCG stimulation.

Reduction in LH receptors on Leydig cells appears to be less important. Lower responsiveness to LH is probably caused by a diminished reserve of testosterone in the Leydig cells, which is parallel to a significant reduction in total steroid content in the testes of elderly men. Furthermore, a shift in testicular androgen biosynthesis was reported by Vermeulen^[13], which favors synthesis and secretion of  -4 steroids over -5 steroids in old age, -5 steroids being the precursors of testosterone in the biosynthetic chain.

A primarily testicular origin of decreased androgen secretion in senescence is further supported by the previously mentioned reduction of Leydig cells in elderly men. Diminished testicular perfusion in aging testes has also been reported, with a decrease in the number of capillaries, indicating reduced oxygen supply in the testicular tissue of old men^[13].

Additional alterations occur at the hypothalamo-pituitary level: despite elevated LH plasma concentrations, which partly compensate for reduced synthetic activity of the Leydig cells, high amplitude LH pulses from the pituitary gland are significantly less frequent. Although GnRH stimulation reveals a large secretory reserve capacity of the pituitary, LH levels are not high enough to normalize free testosterone levels^[15].

Bremner et al^[16] and Vermeulen^[17] observed disappearance of the circadian testosterone rhythm in elderly men, while serum androgen levels in young men demonstrated nyctohemeral variations with high testosterone concentrations in the early morning. This appears to be the consequence of a decreased LH rhythm, pointing towards an alteration at the hypothalamo-pituitary level.

Coming back to the testicular level, a decline in the intratesticular testosterone concentrations cannot be avoided despite increased serum LH levels. Reduced intratubular testosterone concentrations, however, may affect spermatogenesis, which, together with age-dependent processes in the germ cells, results in elevated serum FSH levels. There is evidence that LH and FSH molecules undergo age-related changes, resulting in reduced bioactivity. Stress may also play a role in age-associated changes of plasma testosterone levels. As far as testicular function is concerned, elderly men are less sensitive to stress than are young adults.

Because of their hydrophobic nature, steroid hormones such as testosterone are bound to plasma proteins, e.g., albumin and sex hormone binding globulin (SHBG). Only 2% of testosterone are unbound and thus biologically active. After the age of 70, serum SHBG levels are increased^[18], resulting in lower concentrations of free testosterone. Thus, apart from decreased synthesis of testosterone, higher binding capacity of the testosterone binding globulin reduces the availability of biologically active free testosterone molecules.

Elevated SHBG concentrations are caused by an increase of free estradiol. Serum estrogen levels in elderly men are higher as a result of stimulated aromatization of androgens, especially in the peripheral fatty tissue which is increased during aging. Declining free testosterone levels in plasma are accompanied by a decrease in tissue testosterone and/or its active metabolite DHT.

To discover and monitor a relative androgen deficiency in aging men, it is discussed that determination of free and nonspecifically bound testosterone, which is associated to albumin, reflects the clinical situation more accurately than determination of total plasma testosterone (T) levels or testosterone specifically bound to SHBG. Therefore, calculated free testosterone (FT) has been suggested as an indirect parameter of bioavailable testosterone, which is the result of a seconddegree equation: T=(T-NFT)/(K_tSHBG-T+NFT)
K_t=association constant of SHBG for T(=1 L/nmol for SHBG at 37). N=Ka Ca+1(=23 for normal albumin).

This quotient is easy to calculate by determination of total testosterone and SHBG and is more reliable than direct measurement of free testosterone by analog ligand radioimmunoassay^[19].

The most exact method to determine the apparent free testosterone concentration (AFTC) is equilibrium dialysis. Undoubtedly, this procedure gives values that are physiologically most representative, but it is laborious and time-consuming. Therefore, calculation of free testosterone from total testosterone and immunoassayable SHBG represents a simple, reliable and rapid method, yielding values that are comparable to those obtained by equilibrium dialysis^[19]. Nevertheless, large-scale clinical studies to document free or non-SHBG bound bioavailable testosterone levels remain to be performed. It is the aim of future studies to confirm this hypothesis.

3 Is there a male climacteric?

The term climacterium virile was created by Wermer^[20] who described men at or beyond the fifth decade of life who suffered from vegetative complaints and a number of symptoms such as impaired memory, lack of concentration, tiredness, nervousness, and lowered resistance to stress. In analogy to the female climacteric, a sudden reduction in plasma testosterone levels and rapid senile involution of the testes were initially thought to be responsible. Later studies, however, showed that hormonal changes and morphological processes of aging in the male gonads were significantly different from those in aging women. A gradual decline in testosterone levels is observed only in old age.

As previously mentioned, the germinal epithelium is subject to age-related changes, but there is great interindividual variability. Functioning germ cells have been found even in men over 80 years. Any relation between climacterium virile and changes in the plasma testosterone levels remains doubtful. Therefore, a male climacteric does not exist! Improvement of subjective symptoms by administration of androgen derivatives is not contradictory to this, but may reflect psychotropic effects of androgens^[21]. None of the symptoms attributed to the so-called male climacteric has been demonstrated to be of statistically significant prevalence in men at the fifth or sixth decade of life.

In summary, while there is evidence of climacteric complaints in the male, these do not occur as frequently and inevitably as in women and are rather of psychosociological origin^[22,23]. Therefore, the frequently used synonym midlife crisis appears to be more appropriate than male climacteric. In recent years, the term partial androgen deficiency of aging men (PADAM)  has been established and is often used to characterize the problem of aging men.

4 Sexuality, libido and potentia coeundi in aging men

Decreased sexual activity and diminished frequency of intercourse are observed after the age of 40, but become more significant between the fifties and seventies. However, it must be considered that sexual activity in a relationship depends on the wants and needs of two individuals. Sexual desire of aging men is different from that of aging women. While 15% of men over 60 years deny to have sexual interest, the corresponding rate in women is much higher. Apart from sex, other sociologic and medical factors are responsible for these behavioral differences. Intercourse is performed more frequently by married people and least frequently by single persons. Sexuality is also influenced by the general state of health and hormonal factors.

According to the Massachusetts Male Aging Study, 10% of men between 40 and 70 years suffer from complete loss of erection, and 25% have rare erections. Erectile dysfunction is increasingly observed with advancing age. Complete erectile impotency is reported by 5% of men at the age of 40 and 15% of those aged 70 years, while moderate erectile dysfunction occurs in 17 and 34%, respectively^[24].

Results of studies on the correlation between serum testosterone levels and sexual activity in elderly men have been controversial. Endocrine insufficiency, including hyperprolactinemia, has been found in no more than 3% of men with erectile dysfunction. This indicates that the hormonal factor as a cause of impotence is of minor significance! In fact, erectile dysfunction in older men is multifactorial in origin. Chronic diseases, such as diabetes mellitus, often combined with arteriosclerosis and hypertension, cardiovascular diseases, impaired fat metabolism and renal insufficiency are major causes of impotentia coeundi. Drugs for treatment of such diseases can additionally impair sexual function. These include antihypertensive agents, e.g. beta blockers and angiotensin-converting enzyme inhibitors, psychopharmacological agents, antiandrogens, antihistamines, diuretics and cytostatics.

Possible risk factors for long-term vascular impairment, e.g. heavy smoking, may significantly contribute to impotence, as may neurological diseases and operations. Therefore, older men with erectile dysfunction should be carefully investigated, because in many cases erectile dysfunction as a symptom is the first clinical sign of a severe vascular situation which helps discover a hitherto unknown coronary disease. It is well known that impaired arterial circulation plays the most important role in erectile dysfunction, with a prevalence of 50% and more.

Therapeutically, apart from causal treatment of the underlying disease, administration of sildenafil (Viagra) is the method of choice today^[25]. Caution should be taken in patients receiving any kind of nitrate medication. These men may be offered vacuum pumps, penile rings, intracavernous prostaglandin injections, penile protheses, arterial operations or psychotherapy. The risk of an older patient for coronary complications during sexual activity resulting from treatment of erectile function is low. Of more than 1700 men with myocardial infarction, only 3% had had intercourse within 2 hours before the heart attack^[26].

Endocrine deficiency with gradually decreasing serum testosterone levels is not a predominant cause of erectile dysfunction in old age. Less than 10% of patients with erectile dysfunction show signs of hypogonadism. In cases of reduced serum testosterone, improved libido is achieved by administration of testosterone.

Other androgens, such as dehydroepiandrosterone (DHEA), are also effective in the therapy of old men, but controlled randomized studies in large patient groups are not available. In principle, the possibility of accelerated growth of initial or still undetected prostatic cancer should be cautiously considered during androgen substitution in old men.

5 Changes in muscles and bones

In the following, some brief remarks will be made on osteoporosis. Aging processes of muscles and bones, i.e. loss of function and substance, begin at the age of approximately 30 years. Factors contributing to these changes are genetic disposition, endocrinological factors, immobilization and nutritional changes. Thus, osteoporosis in men in most cases is due to alcohol intoxication, probably affecting the osteoblasts.

With advancing age, changes are also observed at the skeleton. Starting at the age of 30, there is a continuous reduction in the amount of bone, approximately 30% of the original bulk being lost during the following 40 years. Compared with the aging process in women, loss of bone in men is less dramatic. The occurrence of osteoporosis depends on the original bulk of bone during the third decade of life. Therefore, the risk of osteoporotic fracture is significantly lower in men than in women.

Hypogonadism is the major risk factor for osteoporosis in both women and  men. As early as 1948, Albright and Reifenstein^[27] reported that eunuchs developed osteoporosis. However, the effects of androgen on bone metabolism are still poorly understood. In adults, bone density at a given age is determined by the peak bone mass achieved at sexual maturity and the subsequent amount of bone loss. Androgens affect both of these processes and they are a major determinant of bone mass in men. Several studies have demonstrated the important effect of pubertal increase in androgens on bone mass. Pubertal rise in testosterone secretion is followed closely by an increase in alkaline phosphatase activity and subsequently of cortical bone density. Peak cortical and trabecular bone mass are reached in men during their mid-twenties. Thereafter, bone density declines linearly as men age.

Diminishing gonadal function in the aging male has been suggested as being responsible for bone loss; however, further prospective studies are needed to determine whether the modest testosterone decrease that occurs during aging is a significant factor in age-associated bone loss.

In young men after castration, progressive bone loss has been observed with increasing years after orchidectomy. It is possible that gonadal steroids directly act on osteoblasts to stimulate bone formation, as androgen and estrogen receptors have been demonstrated in osteoblasts. Androgens may also affect bone metabolism by interaction with calcium regulatory hormones such as calcitonin. In addition, testosterone can be converted to dihydrotestosterone in human bone cultures, indicating that DHT is the active androgen in bone. However, it cannot be excluded that the effect of androgens on osteoblasts may require their aromatization into estrogens.

Finally, there seems to be evidence that locally active cytokines play an important role in bone metabolism, which comprise different prostaglandins, TGF and the local production of insulinlike growth factor 1, which stimulates collagen production by osteoblasts.

6 Possible hormonal supplementation in old age

As discussed before, lower total testosterone concentrations in men over 60 years are accompanied by clinical signs of reduced virility. Therefore, testosterone supplementation with different preparations is discussed as a useful therapy for aging men^[28]. However, there is scanty information about whether androgen supplementation in older man might be beneficial in terms of improving bone density or muscle mass and strength, or whether potential benefits might be outweighed by negative effects on lipid profiles, hematological parameters, or the prostate.

In a double-blind, placebo-controlled crossover study, Tenover et al^[11] investigated the effect of testosterone enanthate (100 mg/week) in a small group of healthy men aged 57 to 76 years for a short treatment period of 3 months. Injections of testosterone enanthate resulted in elevated concentrations of both total and free testosterone in all men, and increased libido or aggressiveness in business transactions in some men. In others, a general improvement in sense of well-being was reported. All men showed an increase in weight, but not in body fat. Urinary excretion of hydroxyproline decreased, indicating delayed bone absorption. Positive effects of testosterone enanthate on hematological parameters and lipid metabolism were observed.

As far as the prostate is concerned, testosterone injections did not lead to significant changes in prostate size and residual urine; however, a significant increase in prostate-specific antigen (PSA) was observed. 30% of the men showed elevated levels of PSA even 3 months after cessation of therapy.

In principle, testosterone supplementation in old patients may produce the following side-effects:
(1)  changes in fat metabolism (possible changes of LDL/HDL ratio) = cardiovascular risk?
(2)  stimulating effect on erythropoiesis with a risk of polycythemia;
(3)  more rapid development of benign prostatic hyperplasia;
(4)  stimulation of subclinical prostatic carcinoma.

Hajjar et al^[29] published a retrospective analysis of long-term testosterone replacement in 45 older hypogonadal men who received 200 mg testosterone enanthate or cypionate i.m. every 2 weeks for at least 2 years. The control group consisted of 27 hypogonadal men taking no testosterone. After 2 years, only the hematocrit showed a statistically significant increase in the testosterone-treated group. In particular, contrary to the study by Tenover et al^[11], there were no significant changes in the prostate-specific antigen concentration. Twenty-four percent of the testosterone-treated subjects developed polycythemia sufficient to require phlebotomy or temporary withholding of testosterone. Dramatically improved libido was reported by the testosterone-treated group. There was no increase of angina, myocardial infarction or strokes in patients receiving testosterone for up to 3 years. Furthermore, total cholesterol in the testosterone-treated group and the control group did not significantly differ in this study. The authors concluded that testosterone replacement therapy was well tolerated by over 84% of the subjects.Thus, long-term testosterone supplementation appears to be a safe and effective means of treating hypogonadal elderly men, provided that frequent follow-up blood tests and urological examination are performed.

Despite these positive experiences with long-term testosterone replacement, androgen therapy in the aging male is still controversial. Prospective studies on beneficial and undesired effects of testosterone administration aimed at life quality are urgently needed.To date, androgen therapy in aging men can only be recommended for substitution of manifest testosterone deficiency. This is in agreement with recommendations published by the Canadian Andropause Society^[30].

The different choices of testosterone supplementation include intramuscular injection of testosterone esters as T-enathate or T-buciclate, testosterone pellets and oral administration of T-undecanoate. Apart from these, transscrotal and transdermal testosterone patches with a daily early morning application are currently preferred, which provide testosterone levels in the low normal to medium range and thus imitate the physiological day rhythm^[31]. However, compliance depends on good patient care. Through the use of transdermal enhancers, skin irritation is a possible side-effect. Less irritation is observed after transscrotal application, but patients must be carefully counselled.

If long-term use of androgens is considered, it should be emphasized that to date there have been no signs of cardiovascular risk^[32,33]. On the other hand, low testosterone levels and an increased E2/T ratio in older men seem to increase the cardiovascular risk! In addition, maintenance of physiological levels of testosterone does not induce an atherogenic profile in aged men.

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