Male gonadal dysfunction

4 Male Gonadal Dysfunction H. W. G. BAKER BRYAN HUDSON

Normal testicular function confers upon the adult male two important attributes, virility and fertility, representing the separate functions of the Leydig or interstitial cells and of the germinal epithelium respectively. The purpose of this chapter is to provide an outline and some details of the clinical and laboratory investigations commonly used in the diagnosis of male gonadal dysfunction. We have approached this in a problem-oriented fashion, and described the investigation of certain clinical problems as they present to the physician. Although emphasis is placed on how best to use modern laboratory procedures for diagnosis, mention is also made of particular clinical points of paramount importance in diagnosis. Males with overt or suspected gonadal dysfunction may present with one or more of the following problems: androgen deficiency, infertility, impotence, gynaecomastia, and precocious puberty. Although some of these problems overlap one another, they are sufficiently distinct to be treated separately. Before considering the investigation of each of these conditions individually, a general outline is given of the clinical and laboratory procedures used in the management of male gonadal disorders.

CLINICAL ASPECTS Because the clinical features usually indicate the diagnosis and because a presumptive diagnosis is essential for the rational application of laboratory tests, the important points in the history and physical examination are shown in Table 1. Most of these are self-evident. Objective assessment of testicular size should be made by use of a Prader (1966) orchidometer constructed from plastic ellipsoids ranging in volume from I to 30 ml (Figure 1). The testis, held longitudinally between the thumb and forefinger. is compared with the appropriate ellipsoid. Healthy men (in Australia) have testicular volumes of 15 ml or greater. Calipers may be used but are less accurate because of variability in the consistency of different testes. Clinically testicular consistency is difficult to assess but small hard testes (less than 5 ml volume) associated Clinics in Endocrinology and Mnobolism-Vol. 3. No.3, November 1974.

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H. W. G. BAKER AND BRYAN HUDSON

with relatively normal sized epididymides are seen in adults with Klinefelter's syndrome. In pubertal subjects the stages of pubic hair and genital development are best assessed according to the criteria of Tanner (1962). The sense of smell should be tested in patients with features of hypogonadism because hyposmia or anosmia suggest Kallman's syndrome.

Table I. Clinical assessment of patients with gonadal dysfunction Historical

Physical examination

Pubertal development time of commencement and completion of puberty; growth pattern Secondary sex hair development and extent; change in frequency of shaving Sexual functions erections (spontaneous and during sexual arousal); seminal emissions (nocturnal and during intercourse or masturbation); sexual performance (penetration, time of ejaculation, frequency and technique); previous potency and fertility Family history age of pubertal development of siblings and parents, hypogonadism, infertility Previous illnesses testicular involvement and surgery General health alcohol consumption, drug and hormone treatment

Appearance prepubertal or hypopituitary facial appearance; stature; proportions (span, pubis to floor measurements); skeletal malformations; body fat distribution and muscular development Hair distribution beard and body hair; pubic hair staging (Tanner) Genital development penile size; scrotal development; gemtal development staging (Tanner) Scrotal contents varicocoele; testicular or epididymal abnormalities Testicular size Gynaecomastia Others anosmia; autonomic neuritis; tumours; chronic liver disease; intelligence where applicable

HORMONE MEASUREMENTS Androgens Measurement of plasma testosterone, now generally available, should replace urinary androgen determinations. Sensitive and precise radioimmunoor competitive protein-binding assays using human sex-steroid binding globulin have largely replaced the more tedious double isotope and gasliquid chromatographic methods. Many assays are not completely specific for testosterone because, for example, cross-reactivity with dihydrotestosterone is common, but this lack of specificity does not reduce the clinical value of the measurement. Most reported normal ranges faIl within the limits 3.5 to 12.0 ng/rn! 'in men between the ages of 18 and 50 years. Low levels are seen in hypogonadism. It should be noted that there is a progressive fall in the levels after the age of 40 years (Figure 2). As with the gonadotrophins (see below), there is considerable moment to moment fluctuation in plasma testosterone concentrations in healthy men and, although the majority of the fluctuations remain within the normal range, in the clinical situation

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marginally low va lues may indicate the necessity for repeated measurements for a precise assessment of androgen status (Alford et al, 1973). Measurement s of urinary 17-oxosteroids are of no value in the assessment of testicular function .

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Gonadotrophins Radioimmunoassays for the measurement of LH, FSH and HCG in serum and urine have largely replaced urinary gonadotrophin bioassays. The secretion of LH, FSH and testosterone is not a constant process in healthy men . There are one- to three-fold fluctuations in the blood levels of LH with a periodicity of two to four hours. The changes in FSH and testosterone levels are smaller and less regular (Alford et aI, 1973). Episodic secretion of LH appears at puberty and at first is seen only during sleep (Boyar et al, 1972). The occurrence of fluctuations in the blood levels of LH, FSH and testosterone indicate that marginally abnormal results in a single blood sample may require confirmation by repeated analysis. Different assay reagents-antisera and standards-are used by different laboratories and the reported ranges vary considerably. The levels of LH and FSH rise with age (Figure 2) and results must be compared with the values appropriate for the laboratory and the age group. In many laboratories, including our own normal values are difficult to differentiate from low ones.

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Oestrogens The measurement of plasma oestradiol concentrations either by radioimmuno- or a uterine cytosol binding assay, or of urinary oestrogens by chemical methods, may aid in the differentiation of testicular or adrenal tumours producing oestrogens from the more common causes of gynaecomastia. Plasma oestradiol levels are less than 40 pgjml in healthy men; urinary total oestrogen levels are normally less than IS Ilgfday. 14

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Prolactin Measurement of serum prolactin levels by radioimmunoassay is of value in the very rare patient with a prolactin-secreting pituitary tumour. The possible role, if any, of abnormal prolactin secretion in the genesis of male gonadal disorders such as infertility has not been evaluated.

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Dynamic Tests of Pituitary and Testicular Function As with the investigation of the integrity of other endocrine systems, and because of the variability of the hormone levels in healthy men, stimulation tests are necessary to define the secretory reserve of the pituitary gonadotrophic and testicular Leydig cells. The tests discussed below also permit an evaluation of the pituitary-testicular system at different levels.

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HCG stimulation test Human chorionic gonadotrophin (HCG) stimulates the Leydig cells to secrete testosterone because of its intrinsic LH-like activity. This test is particularly useful in demonstrating the presence of testicular tissue in patients with cryptorchidism or ambiguous external genitalia (Rivarola, Bergaoa and Cullen, 1970). It is less helpful in distinguishing primary testicular failure from hypogonadotrophic hypogonadism as a diminished or absent response may occur in both conditions. However, the response may be of some prognostic significance in hypogonadotrophic hypogonadism; those subjects who show no response to acute administration generally respond poorly to long-term treatment (Bardin et al, 1969; Santen and Paulsen, I973b). Many different regimes are used but an adequate method is to give 3000 iu intramuscularly daily for four days and measure plasma testosterone on

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days 0 and 4. The range of results from healthy young men is shown in Figure 3; there is a two- to three-fold rise in the plasma testosterone level on the last day. Clomiphene stimulation test Clomiphene causes release of gonadotrophins from the pituitary in both men and women, probably by reducing negative feedback through its action as an antioestrogen in the hypothalamus. Thus the administration of clomiphene gives valuable information about the integrity of the hypothalamus and pituitary (Bardin, Ross and Lipsett, 1967). In prepubertal and hypogonadotrophic subjects there is either no rise or a paradoxical suppression of plasma LH and FSH levels. This test is useful in confirming hypogonadotrophism, particularly in the common situation where partial pubertal development has occurred. Different dosage schedules have been used. It is our practice to administer clomiphene citrate 50 mg orally twice daily for seven days, collecting blood samples on days 0, 7 and 10 for the measurement of LH, FSH and testosterone. In normal men LH levels rise by at least 50 per cent on day 7; FSH responses are more variable but rise by at least 20 per cent on day 7; testosterone levels rise by at least 30 per cent on day 10. LH/FSH-RH 100 IJO IY.

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Gonadotrophin releasing hormone (LH/FSII-RH) test LH/FSH-RH is a decapeptide produced by the hypothalamus that stimulates the secretion of LH and to a lesser extent FSH by the pituitary. Synthetic preparations are available for investigational purposes. The change in the blood levels of LH and FSH following the intravenous injection of 100 ug of synthetic LH/FSH-RH in healthy young men is shown in Figure 4. There is a marked rise in LH levels with a peak at about 25 min after the injection. FSH levels exhibit smaller and more delayed rises. In normal men plasma testosterone levels increase four to eight hours after the administration of LH/FSH-RH but the responses are irregular and not of great diagnostic value. Normal prepubertal children also respond (Job et al, 1972; Roth et al, 1973). The LH response to smaller doses is less and there may be no rise in the FSH level. Patients with pituitary lesions have either a diminished or absent response; those with hypothalamic lesions have normal or reduced responses and those with primary testicular disorders and hypergonadotrophinism have exaggerated responses (Kastin, Gual and Schally, 1972).

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Variable responses have been found in patients with hypogonadotrophic hypogonadism: normal, reduced or absent rises in LH and FSH and occasionally dissociations between the LH and FSH responses; for example, no rise in LH but a normal rise in FSH (Bell et al, 1973; Isurugi et al, 1973). This variability of response may indicate some heterogeneity in the lesions causing hypogonadotrophic hypogonadism.

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At present the full range of applications of this test in male gonadal disorders has not been established. It is of obvious value in the study of patients with pituitary and hypothalamic disorders and may have a place in the management of children with delayed puberty. The levels at which the hypothalamic-pituitary-testicular system may be evaluated by these stimulation tests are shown schematically in Figure 5. Assays for LH/FSH-RH are being developed at present and may well be of value in the investigation of male gonadal disorders in the future. Although not all laboratories are able to assay LH, FSH and testosterone, facilities are available in most large centres. The hormones are stable in stored plasma or serum, and 5 to 10 ml samples may be mailed to the appropriate laboratory but should be sent frozen if the transit time is longer than 48 hours.

ANDROGEN DEFICIENCY Delayed Puberty Although the problem of the child who presents with a delay in pubertal development can usually be resolved more easily with the aid of modern investigations than in the past. there are still some patients in whom no definitive answer can be obtained.

Causes The important question to be resolved is whether the child has a simple constitutional delay in the onset of puberty, which has a good prognosis, or whether he has one of the less common but more serious disorders which, if untreated, would lead to permanent androgen deficiency or more serious sequelae. These less common causes of pubertal delay include : I. The hypogonadotrophic disorders: craniopharyngioma or pituitary tumour; hereditary or sporadic hypopituitarism with isolated gonadotrophin deficiency such as Kallman's syndrome (olfacto-genital dysplasia) or with multiple trophic hormone deficiencies. 2. Klinefelter's syndrome which is more commonly associated with imperfect rather than delayed pubertal development. 3. Rare disorders: anorchia, certain testicular enzyme defects in which testosterone secretion is deficient or absent, testicular disorders with mental deficiency (e.g. the Prader-Willi syndrome) or emotional deprivation. Patients with these disorders, however, usually do not present simply with the problem of delayed puberty. For a more detailed review the reader is referred to Root (1973a and b). The age at which children or usually their parents first seek advice for delayed puberty varies. Usually the patients are aged between 13 and 15 years, but sometimes children present for the first time when they are much older and when incomplete pubertal development has occurred. In some there may be a history of treatment with gonadotrophins or androgens, but in others pubertal development, which may have commenced spontaneously at the appropriate age, has been arrested.

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Investigations At the time of the first visit a decision should be taken as to the extent to which the child should be investigated. This decision is determined by two factors. The first depends upon assessment of how much the sexual immaturity is causing a social or psychological problem for the boy; the second is the age of the patient in relation to how delayed the onset of puberty is. Perhaps somewhat arbitrarily we regard puberty as being delayed if there are no signs of it by the age of 16 years. Thus for children who are younger than 16 and have no obvious psychological problems we tend to limit our investigations, whereas for those who are 16 or have psychological problems we normally proceed with more comprehensive investigations. In both groups of patients the following procedures are carried out at the time of the initial visit: I. History and physical examination. It is most important to evaluate the sense of smell, because this is absent or reduced in Kallman's syndrome, and to examine for signs of hypopituitarism. 2. Precise assessment of pubertal status (Tanner, 1962). 3. Position and size of the testes (Prader orchidometer). A child who is otherwise prepubertal but has testes of volume greater than 5 ml is almost certainly entering puberty. Tiny testes « I ml) in prepubertal subjects should suggest Klinefelter's syndrome (Laron and Hochman, 1971). 4. Body measurements: height and weight, span, crown to pubis and pubis to floor to determine if the skeletal proportions are eunuchoidal. 5. Lateral skull x-ray: to assess the size of the pituitary fossa and detect suprasellar calcification. 6. X-ray of the left wrist to determine bone age. A marked discrepancy between the bone and chronological ages may indicate an associated growth hormone deficiency. The bone age should be evaluated by a radiologist conversant with the tables of Greulich and Pyle (1960). 7. Buccal smear. Abnormal numbers of chromatin-positive (Barr) bodies indicate X-chromosomal disorders such as Klinefelter's syndrome. If the result is equivocal or the presence of an abnormal chromosome pattern is suggested, a karyotype should be performed. These are the minimal investigations. It is debatable in the younger child, who is completely prepubertal and in whom all these investigations are normal, whether it is worth measuring testosterone, FSH and LH. It has, however, been our practice to make these measurements so that they may be compared with values obtained at subsequent visits. A rise in the level of FSH is commonly one of the earliest hormonal events at the onset of puberty, usually preceding subsequent rises in the levels of LH and testosterone (Kulin and Reiter, 1972). If it is possible to monitor these changes they may be of value as predictors of puberty, although they are probably no better than careful and repeated measurements of testicular volume. It was anticipated that measuring gonadotrophins and testosterone might be of value in the management of patients who present with delayed puberty. Recent studies have shown that prior to puberty the levels of LH in blood are low and constant throughout the whole 24-hour period, but with the onset

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of puberty the pattern of secretion of this gonadotrophin becomes episodic and sleep-related (Boyar et al, 1972). While this is an interesting physiological observation it is probably not one that can be directly applied as a routine to the study of children with delayed pubertal development. Attempts have also been made to develop dynamic tests of pituitarygonadal function that would indicate which children will enter puberty normally without further treatment. Thus, Franchimont et al (1972) have investigated the gonadotrophin responses to both clomiphene and LH/FSHRH in more than 14 patients of this kind . They claim that by using these tests two groups of patients emerge, those who respond well in terms of rises in plasma gonadotrophins to both clomiphene and LH/FSH-RH and those who respond only poorly to LH/FSH-RH and not at all to clomiphene. Children in the first group were found to enter puberty normally, whereas those in the second group were gonadotrophin deficient and required treatment to bring about pubertal development. We have not been able to show that patients who are prepubertal respond to clomiphene and thus cannot support Franchimont's data. The use of these tests has been further complicated by reports from Bell et al (1973) and Isurugi et al (1973) that the gonadotrophin responses to LH/FSH-RH were variable in patients with h)'pogonadotrophic hypogonadism. However, as normal children have been shown to respond to LH/FSH-RH before and during puberty an absent response would indicate a pituitary lesion. Thus this test will almost certainly have in the future a significant place in the elucidation of children with delayed puberty but more substantial longitudinal studies must be undertaken in order to ascertain its true value. If, following the scheme of investigation recommended, no apparent cause is found for the delay in pubertal development, these children are reviewed at approximately six-month intervals. At each visit the child is evaluated using those physical measurements to which reference has already been made. Usually at one of these visits an HCG stimulation test is done to assess Leydig cell reserve. Failure to respond to HCG indicates impairment of Leydig cell function and that puberty will not occur spontaneously; replacement therapy with androgens will therefore be required. If by the age of 16, or earlier in those boys with social or psychological problems, puberty has not commenced, we use HCG as a therapeutic agent, administering 1500 iu three times weekly intramuscularly for six months. During this period pubertal changes will become evident and the levels of plasma testosterone will usually rise to the lower end of the adult range. At the end of six months this treatment is stopped and the patient then re-examined at approximately monthly intervals, blood being taken for gonadotrophins and testosterone at each visit. Following the investigations the status of the patient should be reviewed. Patients who complete puberty spontaneously can be regarded as healthy. In patients with presumed or proven gonadotrophin deficiency the cause must be sought. Those with hyposmia have Kallman's syndrome and require no further investigation. However, because this is an inherited condition, examination of siblings and other relatives is warranted (San ten and Paulsen, 1973a). Particular attention should be given to patients with hypogonado-

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trophism without hyposmia. Many have hereditary or sporadic idiopathic isolated gonadotrophin deficiency but others have or will develop multiple trophic hormone deficiencies and some have an undetected craniopharyngioma or pituitary tumour. Thus periodic assessments and reviews of pituitary function are important in this group. Postpubertal Hypogonadism Impairment or loss of virility may occur because of primary testicular failure or hypopituitarism. Oestrogen therapy and oestrogen-producing tumours cause hypogonadism and gynaecomastia and are discussed in the section on gynaecomastia (page 527). Causes I. Primary testicular failure-trauma, torsion, orchitis, irradiation, debilitating illness, hepatic cirrhosis, chronic renal failure, myotonic dystrophy, senescence. 2. Hypopituitarism-pituitary tumours, surgery, trauma. The patient may present with impotence or infertility, or the features of hypogonadism may be found during the examination of a patient with a severe i1Iness, such as hepatic cirrhosis. As shown in Figure 2, the levels of LH and FSH rise with age and testosterone levels fall. Reduced body hair, impotence and testicular atrophy are common in men over the age of 70 years. The cause of this senescent hypogonadism is uncertain but appears to be a testicular disorder because of the elevated gonadotrophin levels. Similar hypogonadism may also be found in middle-aged men but whether all the symptoms of the so-called male climacteric (insomnia, lethargy, poor concentration and judgement etc.) are due to hypogonadism is open to question. When hypogonadism is severe these men may have hot flushes. Patients with Klinefelter's syndrome or hypogonadotrophic hypogonadism may present in adult life with impotence or infertility. Investigations The extent of the investigation of an adult with hypogonadism depends on the clinical findings, and on the degree of suffering it causes. Most elderly men and patients with severe i1Inesses are unconcerned about impotence and infertility, and thus should not be submitted to the detailed investigations used in a younger man presenting for treatment of infertility. However, a major consideration in all patients is the exclusion of a serious underlying disorder, such as hypopituitarism. The features of cirrhosis, myotonic dystrophy or a past history of testicular damage are usually sufficient to indicate the cause for the hypogonadism. In patients without such features, the visual fields should be examined, hypothyroidism and evidence of other pituitary trophic hormone deficiencies sought, and the pituitary fossa x-rayed for evidence of enlargement. In patients in whom the cause of the hypogonadism is not evident, measurements of LH, FSH and testosterone levels are helpful. Low testosterone and elevated LH and FSH levels are seen in primary testicular disorders. Low

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testosterone and low or occasional1y normal LH and FSH levels are seen in pituitary or hypothalamic disorders . Because the LH and FSH results may be within the normal range in patients with secondary hypogonadism, stimulation tests are indicated to demonstrate inadequate pituitary gonadotrophin reserve. Following the administration of clomiphene there is a subnormal rise in LH and FSH and there may be an absent or diminished rise in LH and FSH levels in response to LH/FSH-RH. In patients with suspected hypopituitarism, dynamic function tests for the other pituitary trophic hormones should also be performed: the growth hormone and corticotrophin or cortisol response to insulin-induced hypoglycaemia, serum-free thyroxine index or other thyroid function tests and the thyrotrophin response to thyrotrophin releasing hormone . Whether al1 these tests are performed, and when , depends upon the condition of the patient. In patients with severe hypopituitarism they should be performed after adequate glucocorticoid replacement therapy has been instituted, and in those with optic chiasmaI compression, after surgery.

MALE INFERTILITY Causes The causes of male infertility are numerous, complex and , in general, poorly understood. On occasions it is difficult to know which partner of a barren marriage is the infertile one, and for this reason the husband can only be deemed to be absolutely infertile if he is persistently unable to produce seminal samples containing live spermatozoa. Although the causes of male infertility cannot be discussed in detail , the important ones are categorised below in order to make clear how the investigation of an infertile male should logically proceed. The causes of male infertil ity are divided into two groups. The first group, numerically mueh the larger, comprises those patients in whom there is a defect in spermatogenesis, while the second and smaller group comprises those patients in whom no such defect is present. Patients with defective spermatogenesis The causes may be congenital, acquired or unknown. Congenital: Hypogonadotrophic hypogonadism Klinefelter's syndrome and other chromosomal abnormalities Testicular maldescent Acquired : Drug treatment: cytotoxic agents, hormones Hypopituitarism Infection Irradiation Varicocoele Unknown causes

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Patients with no apparent defect in spermatogenesis Obstruction: congenital or acquired Infection Sperm antibodies in partner Coital dysfunction Investigations These can be divided logically and logistically into two phases. The first phase comprises: history and physical examination. seminal analyses. karyotype. plasma androgens and gonadotrophins. and radiology. Procedures used in the second phase of the investigation depend upon the information obtained in the first phase and may include some or all of the following: testicular biopsy. vaso-epididymography, sperm antibodies. special endocrine investigations. stimulation with HCG and clomiphene or LHJ FSH-RH. History and physical examination The special points requiring attention include: history of testicular descent. age at puberty. infections (mumps. orchitis. penile discharge. urinary tract infections), testicular injuries. operations in the inguina-scrotal region. irradiation. drugs, and the frequency. timing and technique of sexual intercourse. The reasons for many of these enquiries are self-evident. Special mention must be made of a history of testicular maldescent because germinal cell damage is not infrequently associated with undescended testes. particularly when surgical procedures have been necessary to correct this abnormality. The precise incidence of infertility in this group of patients is. however, unknown. Irreversible impairment of fertility has followed treatment with cytotoxic agents such as cyclophosphamide and presumably occurs with other cytotoxic agents. Treatment with androgens. sometimes prescribed for patients with infertility, may result in severe oligospermia. Patients taking antihypertensive agents may have erectile incompetence or retrograde ejaculation. An enquiry into the frequency. timing and technique of sexual intercourse is important because some patients. from ignorance. may never time intercourse to coincide with ovulation. and others. from embarrassment or ignorance. may never complain of coital difficulties; on occasions the history may reveal that the marriage has not been consummated. On physical examination it is important to seek evidence of overt endocrine disorders that may lead to hypogonadism (see page 492). The finding of gynaecomastia and small testes in an infertile man strongly suggests Klinefelter's syndrome. Examination of the scrotum and its contents is essential. The measurement of testicular size should be objective (page 507). Testicular consistency is a more subjective but necessary assessment. Care should be taken to examine the epididymides and vasa deferentia; on occasions these may be absent. while induration or irregularity suggest a previous infection. It is particularly

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H. W . G. BAKER AND BRYAN HUDSON

important to determine if a varicocoele is present. This is not always easy because many varicocoeles cannot be seen and can only be detected by careful palpation of the neck of the scrotum with the patient both lying and standing. The filling of veins after a Valsalva manoeuvre, or an impulse on coughing is helpful. Semen analysis This is an essential procedure in the investigation of the infertile male . and requires attention to several important technical points. THE LABORATORY. It must be stressed that the investigation may not be meaningful if done by a laboratory that undertakes thi s procedure only occasionally. Ideally it should have at least one staff member trained in seminology, who is responsible for performing these analyses on a frequent and regular basis . THE METHOD OF COLLECTION. The specimen is best collected by masturbation after at least three days' abstinence from sexual intercourse. Coitus interruptus is not as satisfactory because the first part of the ejaculate which may be rich in sperm is sometimes lost. The use of a condom should be avoided because it renders sperm immotile. THE CONTAINER. The patient should be provided, either by his physician or by the laboratory, with an appropriate container. Sterile, large mouthed, plastic containers (volume SO to 100 ml) are satisfactory. Although sterile containers are not essential, they ensure cleanliness and, for the sample from which culture is required, extraneous contamination is minimised. DELIVERY. The sample should be delivered to the laboratory within two hours of collection and kept at ambient temperature. INSTRUCTIONS. The patient must be given explicit printed instructions about the collection and delivery of the specimen. Because patients may not be prepared to ask the appropriate questions or they receive ambiguous answers, we have found it necessary to issue the following printed instructions. In the investigation or treatment of married couples in whom fertility is a problem. it is necessary to examine and assess the quality of the husband 's semen. The husband is therefore advised to submit a specimen of semen for examination in the following manner: J. Refrain from sexual intercourse for three days before examination. 2. As the greatest concentration of sperm is found in the first portion of the ejaculate, it is recommended that the specimen be collected by masturbation. If this is not possible, collect the specimen after having intercourse in the usual way, but withdrawing just before ejaculation. Please indicate below the method of collection . Do not use any form of contraceptive device. 3. Keep the specimen at ordinary room temperature. It should not be kept warm. 4. The specimen must be examined within two hours of collection. It is suggested that the specimen be collected between 7 a.m. and 8 a.m. and taken to the pathology department of the hospital, which is located . . . . . REPEATED ANALYSIS. It is usually not possible t9 assess seminal quality by examination of a single sample. Thus individual sperm counts may differ by as much as 200 per cent (sometimes more) in samples collected at two or three-weekly intervals. Other characteristics such as volume, motility and

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morphology may also show considerable variations. For this reason seminal analysis must be repeated. and three samples should be examined at intervals of not less than two weeks. This practice also applies to the evaluation of any procedures used in the treatment of male infertility. THE REPORT. This should contain information about the volume . sperm concentration. motility. morphology and chemistry. VOLUME . This is normally between 2 and 5 ml with a mean of about 3.5 ml, Smaller and particularly larger vo lumes tend to be associated with oligospermia. SPERM CONCENTRATION. This is usually expressed as millions/ml and is measured either with a haernocytometer or an automated counting device (Coulter counter). Although the sperm concentration is normally in excess of 50 million/rnl, the debate on what constitutes an infertile semen (in terms of sperm concentration) is not resolved. In his analysis of samples from 1000 men of proven fertility, MacLeod (1964) found that 23 per cent had counts of less than 50 million/rnl . By contrast. in his analysis of 1000 men who were infertile. MacLeod found that approximately 44 per cent had a count of less than 50 million/rnl. We regard men whose sperm counts are persistently below 40 million/rnl as being oligospermic, and those with counts of less than 20 million /ml as being severely oligospermic. SPERM MOTILITY. At best this is a subjective evaluation, but many experienced seminologists regard 'aggressive' sperm motility as one of the most important aspects of semen quality. A normal sample should have at least 70 per cent of sperm that are actively motile two hours after collection. Macleod, on the basis of his studies of large populations of normal and infertile men, believes there is a significant difference between the fertile and the infertile seminal fluid once the percentage of actively motile sperm falls below 40 per cent. Another procedure commonly used in the assessment of motility is reexamination of the sample six to eight hours after collection. Good motility at this time is a further index of the quality of the motility. Apart from MacLeod's detailed studies there have been very few adequate reports as to what constitutes normal sperm morphology, although there is no doubt that the presence of increased numbers of abnormal forms can be correlated with infertil ity (MacLeod, 1970). Thus in a large population of infertile men there is a high incidence of seminal fluids which contain more than 40 per cent of abnormal forms. For an excellent and more detailed account of sperm morphology as an indicator of germinal epithelial function the reader, and indeed all laboratories involved in seminal analysis, are referred to MacLeod (1970).

SPERM MORPHOLOGY .

Chemical analysis of the semen permits an assessment of the function of various male accessory sex structures. Thus, quantitative determination of fructose and acid phosphatase or citric acid gives some indication as to the secretory function of the seminal vesicles and prostate respectively. Many laboratories do not routinely make these chemical estimations, but they should be done, because a combined citric acid-fructose estimation can be a diagnostic aid for the detection of such defects as bilateral

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aplasia of the seminal ducts and vesicles or occlusion of the ejaculatory ducts. In patients with these abnormalities azoospermia is found in association with no fructose and abnormally elevated citric acid levels. Although there are many other compounds which are peculiar to seminal plasma, e.g. glycerophosphoryl choline and prostaglandins, the usefulness of measuring these compounds has yet to be determined. OTHER ABNORMALITIES. To be complete the seminal analysis report should contain a comment on the presence or absence of pus cells. Normal semen contains no leucocytes and if they are present in large numbers suggests quite strongly that infection may be the basis of the infertility. In these circumstances culture of the seminal fluid is needed. SEMINAL FLUID CULTURE. Although bacteriological culture is not undertaken routinely, T-mycoplasma has recently been implica ted as a cause of infertility (Gnarpe and Friberg, 1973). Patients with mycoplasma infection usually have normal sperm counts, normal morphology and normal motility. Although we have had little personal experience with this investigation , it should be undertaken in patients with apparently normal seminal analyses and a normal partner.

The karyotype Approximately 0.5 per cent of all live-born males have an abnormal chromosome composition, the most common being 47,XXY, 47,XYY, 47,XY +21 and balanced translocations. Kjessler (1973) has shown that an abnormal karyotype is found in about 20 per cent of azoospermic males. Because chromosome abnormalities contribute significantly to the aetiology of male infertility, a karyotype should be routinely requested in all males with azoosperm ia. The finding of one or more additional X chromosomes confirms the diagnosis of Klinefelter's syndrome or one of its variants. For practical purposes all such patients are infertile. The finding of an additional Y chromosome in an azoospermic male would suggest that an irreversible disorder of spermatogenesis is present (Shakkebaek et al, 1973).

Hormonal measurements At the time of the first consultation 10 to 20 ml of blood is taken for measurement of gonadotrophins and testosterone. Although many infertile men have normal levels, their estimation is of value because it enables two groups of patients to be distinguished. The first are those with raised gonadotroph in levels . High levels of both FSH and LH strongly suggest severe testicular damage, as for instance in Klinefelter's syndrome or one of its variants. High levels of FSH and normal levels of LH in association with oligospermia or azoospermia is presumptive evidence of severe germinal cell damage. The second group are those with low values for both the gonadotrophins and testosterone. Hypopituitarism is likely in these patients. Although it is unusual for men with d iminished pituitary function to present with infertility rather than other features of androgen deficiency, such patients may be encountered if they have had prior therapy with androgens.

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Radiology Radiological investigations are not commonly required in the diagnosis of infertility. Skull and wrist x-rays may be indicated in patients suspected of having hypopituitarism to evaluate the size of the pituitary fossa and the bone age. A decision to proceed to investigations in the second phase, particularly testicular biopsy, will depend largely on the results of the first phase procedures. The following groups of patients require no further investigation: I. Patients with Klinefelter's syndrome or one of its variants characterised by small firm testes, azoospermia, chromatin-positive (Barr) bodies, high FSH and LH and low testosterone levels. 2. Patients with severe germinal cell damage causing testes smaller than normal, azoo- or severe oligospermia, high FSH, but usually normal LH and testosterone levels. 3. Patients with a varicocoele having oligo- or sometimes azoospermia, low motility and abnormal morphology (classically tapering forms), but with normal FSH, LH and testosterone levels. The varicocoele should be ligated and the result assessed by repeated seminal analyses commencing four to six months postoperatively and at one to two-monthly intervals for a year thereafter.

Testicular biopsy Over the past 25 years testicular biopsy has been of value as a research procedure in that it has enabled correlations to be made between the results of seminal analysis, hormonal levels and the treatment of identifiable disorders of spermatogenesis or Leydig cell structure. The knowledge derived from these studies now makes it possible to be more selective in deciding for which patients this procedure is not indicated and those for which it is. In patients with chromosomal abnormalities, those with severe oligo- or azoospermia, usually having some degree of testicular atrophy and high serum levels of FSH (sometimes LH), and in patients with a varicocoele little or nothing is gained by doing a testicular biopsy. Experience with the first two groups clearly indicates that at present no treatment can be given to restore fertility. In patients with a varicocoele, biopsy adds little information and, if performed at the same time as the varicocoele ligation, may lead to complications. e.g. hydrocoele. On the other hand, testicular biopsy is indicated in patients suspected of primary hypogonadotrophic hypogonadism with androgen deficiency. small testes (usually less than 5 ml) and low levels of gonadotrophins and testosterone. It is also indicated in patients suspected of having obstructive azoospermia and who show a normal androgen status, normal sized testes, normal hormonal levels and azoospermia. At present testicular biopsy is probably indicated in those patients with a normal androgen status, normal hormonal levels and severe or moderate oligospermia. Even in this group of patients the benefit in terms of ultimate therapeutic success is probably only marginal, but the biopsy findings may be

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of prognostic value in terms of advising infertile couples as to how they might proceed with regard to adoption or artificial insemination with donor semen . Although the technical details of the biopsy procedure will not be described, the following practical points are made . The biopsy should be bilateral; it can be undertaken as an outpatient procedure under local anaesthesia; the patient should be given a scrotal support postoperatively to minimize discomfort; and the tissue must be fixed in Cleland's or Bouin's solution for proper interpretation. Fixation in formaldehyde results in artefactual shrinking of the tubules and renders interpretation difficult or impossible. Examination of testicular tissue obtained by biopsy may show a number of different histological pictures. NORMAL SPERM ATOGENESIS. If associated with azoospermia, this is strong presumptive evidence of obstruction. HYPOSPERMATQGENESIS. This is not uncommon in men with mild to moderate oligospermia. Although the tubules are usually normal in size there may be areas in the biopsy where they are smaller than normal and show some peritubular fibrosis. A common defect is sloughing of immature cells into the lumen; there may be atypical mitosis and abnormal nuclei with mature and immature sperm in the lumen rather than attached to the Sertoli cells. There are often some tubules in which spermatogenesis appears to be proceeding normally. TUBULAR HYALINISATION. The tubules show varying degrees of shrinkage and fibrosis, and contain either no cells or a few abnormal Sertoli cells. If there is much tubular shrinkage the interstitial cells may appear to be more numerous and arranged in clumps or sheets, probably because of the overall decrease in testicular volume. This is the classical appearance in Klinefelter's syndrome or its variants. It is also the end-stage appearance of severe testicular damage from other causes. Patchy or generalised peritubular fibrosis and hyalinisation of variable degree are commonly associated with other germinal epithelial abnormalities. GERMINAL CELL ARREST . This is characterised by failure of spermatogenesis at a particular stage, commonly primary spermatocytes or spermatids. Few, if any, mature sperm are produced. There may be some peritubular fibrosis . GERMINAL CELL APLASIA (Sertoli cell only syndrome). The tubules are usually smaller than normal and populated entirely by Sertoli cells. Commonly this process affects all tubules. This appearance may be seen in patients treated with cytotoxic drugs ; it may follow irradiation or may be seen in patients with a history of testicular maldescent. Usually there is no ob vious causal association. IMMATURE, PREPUBERTAL TESTIS. The tubules are small and contain only immature germinal cells (gonocytes) and Sertoli cells, the nuclei of which contain no nucleoli. The interstitial cells are not developed and are represented by fibroblast-like cells between the tubules. Th is appearance indicates deficient gonadotrophic stimulation. Some degree of maturation may be seen in those patients in whom the deficiency is partial or who have received treatment with gonadotrophins.

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This brief and somewhat oversimplified account of the abnormalities observed on testicular biopsy can be amplified by reference to the detailed reviews of Nelson (1953) or Albert et al (1953). Vaso-epididymography In this procedure a small amount (about I ml) of a radio-opaque solution is introduced into the vas in the direction of the epididymis in order to demonstrate obstruction in the region of the epididymis. It has been used. in those patients with obstructive azoospermia on whom an anastomotic operation is contemplated to overcome the obstruction . The literature on this technique is neither abundant nor recent (Abeshouse, Heller and Salik, 1954) and our experience with it is small. We are not completely convinced that this is a helpful procedure, and believe that a better approach to the problem of obstructive azoospermia is first to demonstrate the patency of the proximal (ampullary) vas by the injection of a dye into the lower inguinal portion of the vas that can be visualised cystoscopically. If the vas is patent, the next step is to open the head of the epididymis, remove a small amount of fluid and examine this for the presence of spermatozoa. If none are seen, the obstruction is probably in the region of the rete testis. If spermatozoa are seen, an anastomotic procedure between the vas and epididymis may reasonably be attempted, bearing in mind that the success of such procedures, in terms of ultimate fertility, is very low, probably of the order of five per cent. Sperm antibodies Sperm and other constituents of semen are antigenic and in female animals infertility can be produced by immunisation with semen. Franklin and Dukes (1964) found a high incidence (80 per cent) of sperm agglutinins in the sera of female partners of infertile marriages in which there was no other obvious disorder. They reported that the titres fell with the use of condoms during intercourse to avoid exposure to semen , and that pregnancies occurred after the agglutinins disappeared. Subsequent workers have found sperm agglutinins in 10 to 40 per cent of women with unexplained infertility but also in the same or a greater proportion of women during pregnancy, in women with infertility due to tubal obstruction, and in prostitutes. No relationship between the presence or absence of agglutinins in the serum and the occurrence of pregnancy has been demonstrated. Only one in ten women with serum agglutinins had agglutinins in the genital tract secretions (Pacheco-Romero et al, 1973). Thus the presence of sperm agglutinins probably only indicates exposure to semen and has no significant influence on fertility . Sperm immobilising antibodies may be more important. There appears to be a better correlation between the presence of these antibodies and unexplained infertility (lsojima et al, 1972). Further work is necessary before the significance and importance of treatment of sperm antibodies can be decided. In the meantime sperm immobilisation rather than sperm agglutination tests should be performed when other investigations ha ve excluded the known causes of infertil ity. If antisperm act ivity is detected. a three to six-month period of condom usage should be tried.

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Special endocrine investigations Occasionally patients with hypogonad otrophism present with infertility. In these patients tests of pituitary and Leydig cell reserve including HCG. clomiphene and LH /FSH-RH stimulation tests should be performed to determine the site of the lesion and to obtain prognostic information on the outcome of treatment. These tests may also disclose minor abnormalities of gonadotrophin secretion and Leydig cell function in patients with idiopathic oligosperm ia. However. the significance of these abnormalities is unclear at present. IMPOTENCE Types Impotence is commonly divided into erectile or ejaculatory incompetence of primary or secondary types . Primary impotence. sign ifying life-long ab sence of erections and ejaculations. is seen in hypogonadism occurring before puberty. It is exceptionally rare in otherwise healthy men (Kinsey. Pomeroy and Martin. 1948). Ejaculatory failure with adequate erections occurs specifically as a complication of certain antihypertensive drugs such as guanethidine, during acute intoxica tio n with alcohol a nd rarely as a psychiatric disorder. Some authors include premature ejaculation in the profile of impotence but. as Kinsey. Pomeroy and Martin have stated: "It would be difficult to find another situation in which an individual who was quick and intense in his responses was labelled anything but superior". It is certainly not a feature of degenerating copulative function . Patients presenting for treatment of impotence usually have secondary erectile incompetence and complain of decreased sexual performance because of inadequate or absent erections. There mayor may not be a decrease in ejaculations and sexual urge. While impotence can be the presenting complaint of a patient suffering from hypogonadism associated with a chronic illness such as hepatic cirrhosis. peripheral neuritis or diabetes mellitus, this is uncommon and the underlying disorder is usually easily discovered by clinical examination. In the majority of patients who complain of impotence no clear-cut evidence of hormonal deficiency or neurological abnormality can be found. A number of authorities would consider all such patients to have psychogenic impotence. However, because these patients as a group have significantly lower plasma testosterone levels than do sexually active men. we would prefer to avoid this diagnosis unless there is unequivocal evidence of psychiatric disorder. as, for example, in selective impotence. This does not deny the importance of psychic influences, particularly the fear of inadequate performance, in aggravating and perpetuating the condition. Causes A clinically orientated classification of the causes of impotence is as follows : Functional (idiopathic) Psychogenic

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Hypogonadism (including hypogonadism associated with senescence and chronic illness such as hepatic cirrhosis or chronic renal failure) Drugs-antihypertensives, tranquillisers, oestrogens and spironolactone Alcoholism Neural disorders-autonomic and peripheral neuropathies, temporal lobe tumours Oestrogen-producing tumours The history and physical examination will usually disclose drugs, androgen deficiency and neurological disorders when these are the causes of impotence. The detailed investigation of patients with hypogonadism has been discussed on page 517. In the majority of patients, who do not have such disorders, particular attention should be paid to the history. Psychic factors are obviously important in a man who has satisfactory sexual intercourse with other women but is impotent with his wife (selective impotence) and in those who have spontaneous erections and masturbate successfully but cannot get erections in the presence of a woman. TJ1e drinking habits of the patient should be noted because alcoholism may produce prolonged although transient erectile impotence. A relatively sudden onset of impotence may suggest an oestrogen-producing tumour particularly if there is an associated loss of sexual urge and the development of gynaecomastia. Investigations Measurement of the blood levels of testosterone, LH and FSH may disclose some patients with subclinical hypogonadism particularly in those over the age of 50 years. Men with psychogenic and functional impotence may have marginally low plasma testosterone levels, and elevated levels of oestradiol may be found in patients with alcoholism, cirrhosis and oestrogen-producing tumours. However these tests generally add little to the management of most impotent patients. The extent of investigation of these patients depends on the attitude of the physician and on the facilities available for treatment. We refer patients with psychogenic impotence for behaviour therapy and treat men with functional impotence, particularly those with low plasma testosterone levels, with androgens in high dosage initially (for example, testosterone oenanthate 250 mg fortnightly by intramuscular injection for three months), and refer them for behaviour therapy if the response is inadequate. The administration of one injection of testosterone and two weeks later of a placebo injection of oil may help distinguish patients who will benefit from androgen therapy. It should be remembered that androgen therapy is inappropriate for those seeking fertility because spermatogenesis is depressed by the feedback suppression of pituitary gonadotrophin secretion. GYNAECOMASTIA Causes The management of a patient presenting with gynaecomastia may be difficult. Minor degrees of gynaecomastia are common in apparently healthy males, particularly during puberty and in old age. The subject has been discussed

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in detail by Hall (1959). A clin ical classification of the causes of gynaecomastia is as follows: Pubertal gynaecomastia Gynaecomastia associated with hypogonadism as occurs in Klinefelter's syndrome or hypogonadotrophic hypogonadism Drug-induced gynaecomastia-oestrogens, testosterone, chorionic gonadotrophin (HCG), spironolactone, digoxin, tranquillisers, amphetamines, reserpine, chlorpromazine and methyl dopa Non-endocrine tumours, particularly bronchial carcinoma Oestrogen-producing tumours of the testes or adrenals Teratomas producing HCG-like material Pituitary prolactin-producing tumours Miscellaneous associations of uncertain pathogenesis-chronic liver disease, chronic renal failure, recovery from severe illness including malnutrition, chronic lung disease, chest trauma , immobilisation, paraplegia and thyrotoxicosis Such causes or associations of gynaecomastia, as drugs, hepatic cirrhosis, paraplegia etc., are obvious in a number of patients. The main problem is the detection of an underlying neoplasm or, particularly in young men, the differentiation of pubertal gynaecomastia from hypogonadism with associated gynaecomastia. The investigation of hypogonadism has been described on page 517. Investigations Endocrine studies aid in the diagnosis of hormone-producing tumours which are, however, rare. At present the measurement of blood levels of sex steroids and gonadotrophins is of little help in the diagnosis or elucidation of pathogenetic mechanisms of gynaecomastia occurring in chronic hepatic, renal and pulmonary diseases. Plasma levels of oestradiol may be mildly to moderately elevated and plasma testosterone levels low. But these changes are not seen in all patients, and the LH and FSH levels may be low, normal or high. Fortunately the diagnosis of these conditions is seldom a problem and in clinical practice the gynaecomastia is usually incidental to the symptoms of the underlying condition. Very high levels of oestradiol and suppressed LH and FSH levels may be found in patients with oestrogen-producing adrenal or testicular tumours. Teratomas producing chorionic gonadotrophin-like material may cause elevated oestradiol levels, variable testosterone levels and suppressed FSH levels. 'LH' levels may be high or low depending on the cross-reactivity of the HCG-like material in the assay system used. The HCG levels may be measured by specific radioimmunoassays or estimated by the use of pregnancy test kits. The presence of a prolactin-secreting tumour may be confirmed by measuring serum prolactin and by x-rays of the pituitary fossa. These tumours are very rare. The symptom of galactorrhoea is highly suggestive of prolactin over -production. Prolactin levels are, however , not elevated in the majority of patients with gynaecomastia (Turkington, 1972). When in middle-aged and elderly men the cause of the gynaecomastia is

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not obvious, the chest x-ray and sputum should be examined at intervals for evidence of a bronchial carcinoma. In all age groups thyrotoxicosis should be considered as a possible cause of gynaecomastia.

PRECOCIOUS PUBERTY Causes Sexual precocity is the development of secondary sexual characteristics before the normal age . A boy may be considered to be sexually precocious if these characteristics appear before the age of nine and one-half to ten years (Marshall and Tanner, 1970). This is an unusual disorder which in boys has an unknown aetiology in about two-thirds of the patients encountered. The important causes can be listed: Idiopathic (occasionally familial) Central nervous defects such as cysts, tumours or inflammato ry lesions that interfere with hypothalamic function Gonadotrophin-secreting tumours of the testis or liver Testicular interstitial cell tumours Adrenal disorders such as congenital hyperplasia or tumours Clinical examination Clinical examination may lead to a presumptive diagnosis. Patients with central nervous lesions may show other abnormalities that indicate the true nature of the lesion. If clinical examination shows bilateral testicular enlargement commensurate with the degree of pubertal development, this suggests that the testicular growth is the result of gonadotrophin stimulation; asymmetrical or irregular testicular enlargement is strongly suggestive of a testicular lesion, either one that is producing gonadotrophins (chorionepithelioma) or an interstitial (Leydig) cell tumour. Small testes indicate that the androgen excess is adrenal in origin and are found in patients with congenital adrenal hyperplasia or tumours. A hepatoblastoma with hepatic enlargement is an extremely rare cause of sexual precocity. Investigations The most discriminating endocrine investigation is the measurement of the levels of circulating gonadotrophins. If these are low or undetectable, the cause is likely to be excess androgen production from the adrenals or from a testicular tumour. If the levels of LH and FSH are in the normal adult range, the condition is likely to be idiopathic or the result of a lesion in the central nervous system. Extremely high levels of an 'LH-Iike' gonadotrophin are usually found in patients with gonadotrophin-producing tumours . The measurement of plasma testosterone is not a particularly discriminating investigation, because it is commonly ra ised in all conditions which cause sexual precocity in boys, the possible exception being adrenal tumours. Patients with congenital adrenal hyperplasia, if untreated, commonly have elevated levels of plasma testosterone which can be suppressed with cortico-

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steroids (cortisone acetate, 25 mg twice daily for five to seven day s). Such patients also have inappropriately elevated levels (for their age) of urinary 17-oxosteroids and pregnanetriol, the excretion of which is also suppressed with exogenous corticosteroids. This is probably one of the few indications in the male for which urinary oxosteroid determinations are requi red. If the cause of the sexual precocity is thought to be idiopathic, studies to determine if a central nervous lesion is present are often initiated. In patients without obvious central nervous system defects, however, these are usually unrewarding. Furthermore many bo ys with idiopathic precocious puberty have minor EEG changes that should not be interpreted as indicating a major lesion of the central nervous system.

REFERENCES Abeshouse, B. S., Heller, E. & Salik, J. O. (1954) Vasoepididymography and vasoseminalvesiculography. Journal of Urology, 72. 983-981. Albert, A.. Underdahl, L. 0., Greene, L. F. & Lorenz, N. (1953) Male hypogonadism: normal testes . Proceedings of Staff Meeungs of the Mayo Clinic. 28, 409-422. Alford, F. P., Baker, H. W. G., Burger. H. G., de Kretser, D. M., Hudson, B., Johns, M. W., Masterton, J. P., Patel, Y. C. & Rennie, G. C. (1973) Temporal patterns of integrated hormone levels during sleep and wakefulness. II. Follicle stimulating hormone, luteinizing hormone, testosterone and estradiol. Journal of Clinical Endocrinology and Metabolism, 37, 848-854. Bardin, C. W., Ross, G. T. & Lipsett, M. B. (1967) Site of action of clomiphene citrate in men : a study of the pituitary-Leydig cell axis. Journal of Clinical Endocrinology and Metabolism , 27, 1558-1564. Bardin, C. W., Ross, G . T .• Rifkind, A. B., Cargille, C. M. & Lipsett, M. B. (1969) Studies on the pituitary-Leydig cell axis in young men with hypogonadotroph ic hypogonad ism and hyposmia: comparison with normal men, prepubertal boys and hypopituitary patients. Journal of Clinical Investigation, 48, 2046--2056. Bell, J., Spitz, I., Sionim, A., Perlman, A., Segal, A., Palti, Z. & Rabinowitz, D. (\973) Heterogeneity of gonadotropin response to LH-RH in hypogonadotrophic hypogonad ism. Journal of Clinical Endocrinology and Metabolism, 36, 791-794. Boyar, R., Finkelstein, J., Roffwarg , H., Kappen, S., Weitzman, E. & Hellman, L. (1972) Synchronization of augmented luteinizing hormone secret ion with sleep du ring puberty. New England Journal of Medicine, 287, 582-5R6. Franchimont, P., Legros, J. J., Ernould, C ., Valcke, J. C. & Deconinck, B. (1972) In Problemes Actuels d'Endocrinologie et de Nutrit ion (Ed.) Klotz. H. P. p. 129. Paris: Expansion. Franklin, R. R. & Dukes, C. D. (1964) Antispermatozoal ant ibody and unexplained infertility . American Journal of Obstetrics and Gynecology, 89, 6-9 . Gnarpe, H. & Friberg, J. (1973) T-mycoplasmas as a possible cause of reproductive failure. Nature, London, 242, 120-121. Greulich, W. W. & Pyle, S. I. (1960) Radiographic Atlas of Skeletal Development of the Hand and Wrist. 2nd edition. Stanford : Stanford University Press. Hall. P. F . (1959) Gynaecomastia, Sydney : Australasian Medical Publishing Co. lsojima, S., Tuchiya, K., Koyama, K., Tanaka, C., Naka, O. & Adachi, H. (1972) Further studies on sperm-immobilizing antibody found in sera of unexplained cases of sterility in women . American Journal of Obstetr ics and Gynecology, 112, 199-207. lsurugi, K., Wakabayashi, K., Fukatani, K., Jakayasu, H ., Tarnaoki, B. & Okada. M. (1973) Responses of serum luteinizing and follicle stimulating hormone levels to synthetic luteinizing hormone-releasing hormone (LH-RH) in various forms of testicular disorders. Journal of Clinical Endocrinology and Metabolism, 37, 533-539.

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Job, J. c., Garnier, P. E., Chaussain, J. L. & Milhaud, G. (1972) Serum gonadotropins (lH & FSH) after releasing hormone (lH-RH) injection in normal children and in patients with disorders of puberty. Journal of Clinical Endocrinology and Metabolism, 35,473-476. Kastin, A. J., Gaul, C. & Schally, A. V. (1972) Experience with hypothalamic releasing hormones. Part 2. luteinizing hormone-releasing hormone and hypophysiotropic releasing hormones. Recent Progress in Hormone Research, 28, 201-227. Kinsey, A. c., Pomeroy, W. B. & Martin, W. B. (1948) Sexual Behaviour in the Human Male. Philadelphia: W. B. Saunders. Knessler, B. (1973) Genic and chromosomal factors in male infertility. In Endocrinology (Ed.) Scow, R. O. p. 956. Excerpta Medical International Congress Series, No. 273. Amsterdam: Excerpta Medica. Kulin, H. E. & Reiter, E. D. (1972) Gonadotropins during childhood and adolescence: a review. Pediatrics, 51, 260-271. Laron, Z. & Hochman, I. H. (1971) Small testes in prepubertal boys with Klinefelter's syndrome. Journal of Clinical Endocrinology and Metabolism, 32, 671-671. Macleod, J. (1964) Human seminal cytology as a sensitive indicator of the germinal epithelium. International Journal of Fertility, 9, 281-295. Macleod, J. (1970) The significance of deviations in human sperm morphology. In The Human Testis (Ed.) Rosemberg, E. B. & Paulsen, C. A. pp. 481-492. New York, london: Plenum Press. Marshall, W. A. & Tanner, J. M. (1970) Variations in the pattern of pubertal changes in boys. Archives of Diseases in Childhood, 45, 13-23. Nelson, W. O. (1953) Interpretation of testicular biopsy. Journal of the American Medical Association, 151, 449-454. Pacheco-Romero, J. c., Gleich, G. J., Loegering, D. A. & Johnson, C. E. (1973) Sperm agglutinating activity and female infertility. A study of semen and genital tract secretions. Journal of the American Medical Association, 224, 849-852. Paulsen, C. A., Gordon, D. L., Carpenter, R. W., Gandy, H. M. & Drucker, W. D. (1968) Klinefelter's syndrome and its variants: a hormonal and chromosomal study. Recent Progress in Hormone Research, 24, 321-363. Prader, A. (1966) Testicular size: assessment and clinical importance. Triangle, 7,240-243. Rivarola, M. A., Bergaoa, C. & Cullen, M. (1970) HCG stimulation test in prepubertal boys with cryptorchidism, bilateral anorchia and in pseudohermaphroditism. Journal of Clinical Endocrinology and Metabolism, 31, 526-530. Root, A. W. (l973a) Endocrinology of puberty. I. Normal sexual maturation. Journal of Pediatrics, 83, 1-19. Root, A. W. (l973b) Endocrinology of puberty. II. Aberrations of sexual maturation. Journal of Pediatrics, 83, 187-200. Roth, J. C., Kelch, R. P., Kaplan, S. L. & Grumbach, M. M. (1972) FSH and lH response to luteinizing hormone-releasing factor in prepubertal and pubertal children, adult males and hypergonadotropic hypogonadism. Journal of Clinical Endocrinology and Metabolism, 35, 926-930. Santen, R. J. & Paulsen, C. A. (l973a) Hypogonadotropic hypogonadism. I. Clinical study of the mode of inheritance. Journal ofClinical Endocrinology and Metabolism, 36,47-54. Santen, R. J. & Paulsen, C. A. (l973b) Hypogonadotropic eunuchoidism. II. Gonadal responsiveness to exogenous gonadotropins. Journal of Clinical Endocrinology and Metabolism, 36, 55-63. Skakkebaek, N. E., Zeuthen, E., Nielsen, J. & Yde, H. (1973) Abnormal spermatogenesis in XYY males: a report of 4 cases ascertained through a population study. Fertility and Sterility, 24, 390-395. Tanner, J. M. (1962) Growth at Adolescence. 2nd edition. Oxford: Blackwell Scientific PUblications. Turkington, R. W. (1972) Serum prolactin levels in patients with gynecomastia. Journal of Clinical Endocrinology and Metabolism, 34, 62-66.