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Pituitary-gonadal function in the ageing male: the male climacteric LUBOMIR J VALENTA, MD, PhD and ALAN N ELLAS, MD

commonly manifested are increased irritability, nervousness, depression, lack of interest, and a loss of purpose.

Impotence was once viewed as psychological in origin in up to 95% of patients. However, organic causes are being increasingly discovered with sophisticated hormone testing and equipment to monitor penile tumescence.

Differential diagnosis of hypogonadism The ageing process in men is associated with increased frequency of impotence and infertility. The incidence of impotence in the older male population is not precisely known, but is estimated to be at least 75% in men aged 80 and older. Apart from normal ageing of reproductive physiology ('Reproductive functions in the ageing male', page 88), the male climacteric has specific clinical presentations for which there are appropriate diagnostic and, in some c a s e s , t h e r a p e u t i c methods. Clinical features Symptoms and signs of the male c l i m a c t e r i c develop gradually and are less dramatic than the symptoms of the female menopause. A decrease in potency and libido generally occurs along with some somatic and psycholog-

ical symptoms. Most of these changes can be attributed to a decrease in androgen concentrations. Ageing is accompanied by a loss of muscle mass and simultaneous increase in body fat, particularly over the abdomen, hips and breasts. Skin loses its elasticity, and wrinkles appear around the lips and eyes. Facial hair is unaffected, although body hair decreases. Penile size is unaltered/ although the testes are characteristically small and soft. A multitude of nonspecific complaints such as fatigue, weakness, insomnia, and impaired memory and attention span also develop. True psychoses are estimated to occur in 2,5% of men with climacteric symptoms. More Dr Valenta is director, Diabetes and Endocrine Clinic of North County, Oceanside, California, and DrElias is associate professor of Medicine and assistetnt chief, Endocrinology Division, University of California at Irvine, USA. They wrote this article specially for Modern Medicine.

Various systemic diseases such as diabetes mellitus, chronic alcohol abuse (with or without cirrhosis), malignancy, and accelerated atherosclerosis are associated with premature onset of impotence and infertility. A thorough search for systemic disease must be made before evaluation of the male climacteric can be attempted. In addition, such other possible causes of impotence as traumatic, neoplastic, degenerative, or infectious causes of spinal cord and peripheral nerve injury must be excluded. Physical agents such as ionising radiation and heat are sometimes responsible for hypogonadism. Varicocele may also cause hypogonadism. Effects of drugs should be considered, especially in patients taking antihypertensive, psychotropic, or chemotherapeutic agents. The most

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frequent offenders are methyldopa, reserpine, guanethidine sulphate, propranolol HC1, spironolactone, digitalis, marijuana, alkylating agents, and antimetabolities. Vasoactive drugs such as hydralazine HC1 can cause testicular damage by compromising testicular blood supply. Discontinuation or replacement of the offending drug would bring about the desirable restoration of potency. Occasionally, patients with genetic abnormalities (such as Klinefelter's syndrome) associated with hypogonadism may not come to medical attention until they are of advanced age. Patients with Klinefelter's syndrome are characteristically tall, with relatively long legs, small firm testes, gynaecomastia, and wide hips. Microscopic examination of testicular biopsy has revealed hyalinisation of the seminiferous tub u l e s with pseudohyperplasia of the Leydig's cells in these patients. In addition to diseases primarily involving the testes, destructive lesions affecting the pituitary and/or hypothalamus must also be considered in the differential diagnosis of hypogonadism. In variance with hypergonadotropic hypogonadism of primary testicular failure, these conditions MODERN MEDICNEOF SOUTH AFRICA/JUNE 1986

The incidence of impotence in the older male population is not precisely known.

test most commonly employed to differentiate psyc h o l o g i c a l from o r g a n i c causes of impotence is measurement of nocturnal penile tumescence. During sleep, enhanced autonomic activity occurs every 90 to 110 minutes. These episodes are associated with an increase in penile tumescence that can be measured by strain gauges and recorded. Erection can be documented in patients in whom the impotency has a psychological basis. Patients with organic causes for impotence obviously do not exhibit any nocturnal erection. IncreasLaboratory tests A combination of these find- ing diagnostic precision, inings suggests the diagnosis of cluding the measurement of nocturnal penile tumescence, the male climacteric: • low or low normal serum suggests that the true incidence of organic impotence is testosterone concentration; 40 to 60%. • low free testosterone; •high normal or elevated serum oestradiol; and Therapy •high normal or elevated To understand fully the prinLH; and/or •occasionally, high normal ciples on which therapy of or elevated FSH serum con- erectile impotence is based, it might be helpful to review centration. A recently developed test normal male reproductive has dispelled some of the my- physiology ('Male reproducthology concerning erectile tive functions', page 5 3 ) . impotence. This was formerly Treatment of the male climacbelieved to be due to psycho- teric consists especially of: logical factors in as much as •restoration of androgen ef95% of patients. An organic fects by hormonal treatment, cause for impotence is being and increasingly discovered. The •restoration of erections by characteristically present as hypogonadotropic hypogonadism; ie, serum luteinising hormone (LH) and folliclestimulating hormone (FSH) are low or inappropriately low for the serum testosterone concentration. Hypothalamic and pituitary causes consist of vascular, infiltrative, and neoplastic lesions or are a result of the empty-sella syndrome. There are currently no data on incidence. In such cases, serum gonadotropin concentrations are characteristically low.

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The male climacteric does exist and has multiple causation and symptomatology.

Reproductive functions in the ageing male The incidence of impotence and Infertility increases dramatically in men after the age of 40. This decrease in sexual activity may be due either to primary gonadal senescence or to disturbance of the central control mechanisms, so that gonadal function is secondarily impaired. The testes in elderly men are smaller and softer than those in younger men. Histologically, there is thickening and hyaline degeneration of the basement membrane, with areas of germ cell arrest and aplasia, together with interstitial fibrosis. Some, but not all, investigators have found the Leydig's cells structurally altered and decreased in number. Although fertility may be preserved In the elderly, it generally declines sharply with advancing years. Sperm density is similar to that in younger men, although the proportions of abnormal and nonmotile sperm increase with age. Serum testosterone concentration in aged men tends to remain wtthin the normal range. This may be because there is a parallel decrease in both the testosterone production rate and its metabolic clearance. The decrease in testosterone production rate affects other androgen precursors as well, and spermatic vein cannulation studies show a shift in androgen synthesis with a relatively larger testicular secretion of progesterone and 17-hydroxyproteslerone occurring in older men. In contrast to the relative uniformity of reports on the serum concentrations of total testosterone, there are some reports that demonstrate a decrease in serum free testosterone alone with ageing. This decline in free testosterone has been linked to a parallel increase in the sex hormone binding globulin (SHBG). It has been proposed that

artificial prosthesis. Before using surgical means to correct erectile impotence, a thorough diagnostic work-up should be done to characterise the type of hypogonadism present, to exclude reversible MODERN MEDICINE OF SOUTH AFRCA/UNE 1986

the fall in free testosterone as a result of testicular degeneration with age results in an increase of LH and FSH from the pituitary (Fig 1). The increase in FSH induces aromatase enzyme activity that leads to an increase in the conversion of testosterone to oestradiol. The oestradiol promotes the elaboration of SHBG, which results in a decrease in free testosterone. In contrast to reported changes in serum testosterone with age, the findings with regard to dlhydrotestosterone (DHT) are less well documented. However, SHBG has even higher affinity for DHT than for testosterone. Therefore, higher proportions of DHT would be neutralised' by increasing SHBG concentration. It appears that primary gonadal failure is the initial event in male reproductive senescence. In support of this concept is the observation that human chorionic gonadotropin (HCG) stimulation results In an inadequate testosterone response. Furthermore, an increase of FSH and LH concentrations with age is consistent with the decrease of the negative feedback effect of testosterone, which is secreted in inadequate quantities by the ageing testes. In addition to the gonadal failure described above, there appears to be. in some but not all elderly men. a diminished gonadotropin response to hypothalamic gonadotropin-releasing hormone (GnRH). in rats, this has been linked to a decrease in brain GnHH, as well as in brain neurotransmitters known to regulate GnRH synthesis and release. Serum prolactin also increases with age. This may contribute to Ihe relative hypogonadal state, because prolactin blunts the gonadotropin response to GnRH.

causes of impotence, and to exclude psychogenic impotence. Patients with suggestion of a hormonal problem, even of a questionable nature, should be subjected to more detailed laboratory testing, including the

gonadotropin releasing hormone test. When the results suggest hypogonadism, the patient should be offered testosterone therapy for at least six months before surgical treatment is reconsidered.

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An organic cause for impotence can frequently be discovered, especially by measurement of nocturnal penile tumescence.

Male reproductive functions Critical factors of male reproductive function are: • production of male hormones, • spermatogenesis, and • penile erection and ejaculation, dependent on vascular mechanisms and regulation by the autonomic nerve system.

concentration of testosterone in the vicinity of the germinal cells. They also secrete an inhibiting peptide - inhibin - that exerts negative feedback effects on FSH. The cells are also capable of converting androgens to oestrogens.

Production of male hormones

Ejaculation and penile erection depend on the integrity of the autonomic nervous system. Erection is mainly a parasympathetic event, whereas ejaculation is determined by sympathetic nerves. The normal ejaculate, which consists of sperm, seminiferous tubular secretion, and secretion from the seminal vesicles and prostate, has a volume of 2,5 to 6ml. The sperm in a normal ejaculate number at least 40 million per m€, with 60% motile.

Testosterone is the principal androgen secreted by the interstitial cells or Leydig's cells of the testes. Most of the circulating testosterone comes from this source. A small amount is produced by the adrenal glands. The testes also secrete small quantities of oestrogen. Between 30 and 95% of circulating oestrogen is derived from peripheral conversion (aromatisation) of androstenedione and testosterone. The sex steroids are carried to target tissues bound to SHBG. Since biologically active hormone is free or unbound, alterations in the concentration of SHBG will be reflected in the amount of free hormone available to the tissues.

Autonomic nerve function

Physiology of the hypothalamic-pituitarygonadal axis

The initiation of spermatogenesis is dependent on adequate stimulation by FSH. Once spermatogenesis is initiated, it can be maintained by high local Circulating testosterone is either peripherally conconcentrations of testosterone. This high local converted to oestradiol or reduced under the influence of centration is achieved by the proximity of the testos5-alpha reductase to dihydrotestosterone. The major terone-producing Leydig's cells to the germinal epiportion of testosterone is catabolised in the liver to thelium, as well as by the production of ABP by the 17-ketosteroids, such as androsterone and etiochoSertoli's cells. Testosterone produced by the Leylanolone, which are excreted in the urine as the dig's cells is dependent on stimulation by LH. In the corresponding glucuronides or sulphate conjugates. absence of endogenous gonadotropin secretion, Serum testosterone concentration in the normal spermatogenesis cannot occur. It can be induced in adult male is 350 to 1 000 ng/100m€ with 1,5 to 3,2% some men by testosterone, but some require stimufree and biologically active. lation with HCG. Spermatogenesis Testosterone exerts a negative feedback effect on Spermatogenesis occurs in the seminiferous tubules gonadotropin secretion, so that a fall in testosterone of the testes. These structures are responsible for the concentration leads to an increase in both FSH and bulk of the testicular mass. Sperm production is initi- LH. Inhibin, a peptide secreted by the Sertoli's cells, ated by proliferation and differentiation of germ cells, similarly exerts negative feedback effects on FSH whose maturation is dependent on the secretion of secretion. Gonadotropin secretion is further regulatgonadotropic hormones by the pituitary. In addition to ed by GnRH, a tetradecapeptide whose secretion is the germinal cells, the seminiferous tubules contain influenced by the hypothalamic concentrations of the Sertoli's cells, which appear to perform at least two sex steroids, which exert both positive and negative functions. Sertoli's cells elaborate an androgen bind- feedback effects. Normal FSH and LH values in the ing protein (ABP), which sequesters and raises the adult male range from 5 to 20 mll)/m€.

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Artificial prostheses are worth considering.

bladder

vas deferens

seminal vesicle

epididymis

testis

Fig 1 feedback decreased tosterone.

Proposed loop