DIFFERENTIAL DIAGNOSIS OF LOW OR ABSENT SEMINAL FRUCTOSE IN MAN

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1 FERTILITY AND STERILITY Copyright 1974 The American Fertility Society Vol. 5, No.5, May 1974 Printed in U.S.A. DIFFERENTIAL DIAGNOSIS OF LOW OR ABSENT SEMINAL FRUCTOSE IN MAN JOACHIM MAUSS, M.D., P.D., GEREON BORSCH, M.D., AND L.\.SZIO TOROK, M.D t Department of Dermatologr, Univversitr of Essen, D-400 Essen, GFR. ( Seminal fructose is a readily gycolyzable substrate for sperm metabolism. Its concentration in human semen is agedependent; mean values are,800 t-tg/ml for those aged 0 to 0 years,,400 t-tg/ml for those 1 to 40,,00 t-tg/ml for those 41 to 50, 1,900 t-tg/ml for those 51 to 0, and 1,500 t-tg/ml for those 1 to 70.1 Furthermore, fructose concentrations decrease with sexual continence. 1, The rate of fructose metabolism (fructolysis) is positively correlated with the sperm concentration (ie, more spermatozoa will use up more fructose), and also with the initial fructose levels. Contrary to previous concepts, these initial levels do not suggest that substrate concentration is a rate-limiting factor in the carbohydrate metabolism of human semen,4 but that with increasing fructose levels there is an increasingly more effective competition by fructose for sperm hexokinase. 5 Findings concerning a correlation between fructolysis and sperm motility have been inconsistent. 1, The seminal fructose concentration is an indicator primarily of the size, storage, and secretory capacity of the seminal vesicles. Since the latter are testosterone-dependent, seminal fructose values Received November 0, 197. 'Present address: Department of Dermatology, Evangelisches Krankenhaus, P. O. Box 940, D-4000 Dusseldorf 1, GFR. tguest dermatologist from the Department of Dermatology, University of Szeged, Hungary. 411 have also been taken as being an easily assessable indicator of human androgenic activity.1,7-d However, recent studies of the relationship between plasma testosterone and human seminal fructose values indicate that there is no quantitative correlation between these two and that a low threshold of testosterone can produce normal fructose from seminal vesicles ("all or none" law).10-1 A further aspect of the testosterone-fructose interrelationship is the possibility of an effect of stimulation by large doses of exogenous testosterone, apparently causing functional exhaustion of the seminal vesicles; other investigators, however, disagree about thisy We have observed a sharp decrease in seminal fructose concentrations in a number of healthy males receivmg large doses of testosterone oenanthate for a detailed study on the long-term effects of exogenous androgens on male endocrine and reproductive function.14 The findings of the "all or none" interrelationship between testosterone and seminal fructose have cast doubt on the value of the fructose test as an indicator of androgenic activity. They also place more emphasis on other factors affecting fructose concentrations in human seminal plasma, which will be discussed in this report. MATERIALS AND METHODS Seminal fructose values were deter-

2 41 MAUSS ET AL May 1974 mined routinely in all males attending our department of andrology,'5 and clinical examination and semen analyses were also performed. In the years 1971 and 197, 97 males were seen because of fertility disorders and an additional 75 were studied because of potency disorders. In males with a low seminal fructose concentration, an androgen test was performed in order to distinguish between two types of insufficiency of the seminal vesicles: type A, which was responsive to androgens, and type B, which was unresponsive to androgens.' The androgen test consisted of treatment with 5 mg mesterolone (Proviron, Schering AG, Berlin) three times daily for 4 weeks and subsequent semen analysis and fructose estimation on the last day of the administration of the drug after 4 to days of sexual continence. Type A insufficiency of the seminal vesicles is characterized by an increase in fructose concentrations to the normal range. Considering the age of the patients investigated, the lower limit of the normal range has been defined as,000 JLg/ml for this study. RESULTS An age-related low concentration of seminal fructose «,000 JLg/ml) was found in 187 of the 97 males with fertility disturbances (ie, in 0% of these males, whose mean age was.4 years) and in 4 of the 75 patients with potency TABLE 1. Classification of Conditions Associated with Low Concentrations of or an Absence of Seminal Fructose in 11 Patients with Fertility or Potency Disorders Condition Insufficiency of seminal vesicles responding to androgen therapy (type A) Male climacteric Postpuberal Leydig cell insufficiency Pure form With low semen volume With low sperm concentration, motility, or morphology Klinefelter's syndrome Diabetes mellitus Hypogonadotropic hypogonadism Insufficiency of seminal vesicles not responding to androgen therapy (type B) Aplasia Occlusion Inflammation Cause not known (enzyme deficiency?) Unsatisfactory semen specimens Incomplete ejaculation Prolonged sexual continence Data insufficient No control semen analysis Normal fructose concentration in one of two baseline semen specimens No androgen test performed Fertility Type of Disorder No. in each subgroup Potency No. in each subgroup 1 187

3 Vol. 5, No.5 LOW OR ABSENT SEMINAL FRUCTOSE 41 > disorders (in % of this group, the mean age was 8.1 years 1. Among 75 patients with fertility disorders who underwent the androgen test, type A insufficiency of the seminal vesicles was found in (1 %) and type Blow seminal fructose was present in 5 (9 % ). In the group with potency disorders, type A low seminal fructose was observed in 4 out of 10 patients. The complete results and the classification of the patients are summarized in Table 1. DISCUSSION An increase in the fructose concentrationsafter administration of exogenous androgen may reflect a severe depression of endogenous androgen to levels below the necessary threshold for seminal vesicle stimulation; this may occur during the male climacteric, in Klinefelter's syndrome, and in diabetes mellitus, and it invariably occurs in the syndrome of hypogonadotropic hypogonadism. On the other hand, the seminal vesicles in some persons may respond to normal androgen levels with a subnormal fructose production, which increases to normal after additional, exogenous stimulation? 7,18 Both possibilities -low endogenous androgen levels'l,8,9,19 and a subnormal response of seminal vesicles to normal testosterone levelsare of interest in the interpretation of the postpuberal Leydig cell insufficiency. This syndrome is characterized by normal findings on clinical examination and normal analytical values on semen analysis except for an androgen responding low seminal fructose.'l,8,9,19 Among the patients with fertility disorders, we observed 11 males~ with the pure form of the syndrome, whereas eight other patients showed additional pathologic features in semen volume, sperm concentration, sperm motility, or morphology. A postpuberal failure of luteinizing hormone (LH) secretion has been assumed since the original description of this syndrome.1,,8,9,19 However, estimations of urinary LH excretion in seven males with postpuberal Leydig cell insufficiency revealed significantly elevated mean LH values in comparison with mean values of normal males. This suggests that certainly not the pituitary, but possibly the Leydig cells, may be affected in this condition. 0 More research is needed to corroborate the latter possibility and to elucidate the possibility of a subnormal response of human seminal vesicles to normal endogenous androgen levels. A type B low seminal fructose was found in 5 (9%) of the patients with fertility disorders who underwent the androgen test. Rare causes of such an insufficiency of the seminal vesicles are aplasia or occlusion of the male accessory glands. 1, (Only one patient with either of these conditions was observed.) Other causes include various diseases of the male genital tract (eg, prostatovesiculitis), which are almost regularly associated with disorders of the secretory function of the prostate and the seminal vesicles; low fructose values may persist long after patients appear to be clinically healed.,4 There was a significant number of patients in whom the exact nature of the type B low seminal fructose could not be elucidated. A deficiency of certain enzymes involved in fructose metabolism has been suggested as an important etiologic factor in instances of low seminal fructose levels. 5 More probably, a considerable number of the low fructose values may not be pathologic in origin; these values may merely reflect the exceptionally large individual variation in size and storage capacity of the seminal vesicles in man., Further factors affecting seminal fructose concentrations are incomplete ejacu-

4 414 MAUSS ET AL May 1974 lations and prolonged sexual continence;1, 1 patients were in this category. In a last group of patients, the data remained incomplete because 5 patients did not attend for control semen analyses, 9 had no androgen test, and patients had a low fructose concentration in the first semen specimen but had normal values in the control sample, or vice versa. The latter is further evidence for variations in fructose concentrations in one individual; such variations have already been reported by other investigators.1o,,z7 In an appreciably greater number of patients with potency disorders there were low seminal fructose values, as compared with patients with fertility disorders. This may be explained in part by the higher mean age of patients with potency disorders, and it stresses the need for morphologic and biochemical semen analyses in these patients. H Although some investigators have considered seminal fructose estimations to be of major importance in the evaluation of male infertility,1,8,9 the value of such estimations as an indicator of androgenic activity in the human has become doubtful in view of the lack of any quantitative relationship between plasma testosterone and seminal fructose values. Furthermore, there is preferential utilization of glucose over fructose in human semen. 4 Despite the low concentration of seminal glucose, more than half of the sugar consumed by sperm in semen should be glucose and not fructose, when affinity constants of sperm hexokinase for fructose and glucose are taken into consideration. 5 These findings clearly indicate that an adequate biochemical assessment of human semen in the evaluation of male subfertility and infertility must not be confined to seminal fructose, but should also involve additional estimations of initial seminal glucose. However, this diagnostic schedule may likewise be of limited value, for the continuous formation of glucose from seminal plasma constituents provides a ready reserve for this sugar, in addition to the amount of glucose present in the uterine environment 5 -and both factors are unasssessable by estimations of initial glucose levels. SUMMARY Seminal fructose concentrations have been estimated in 97 males with fertility disorders and in 75 males with potency disorders. An age-related low seminal fructose was found in 187 (0%) of the fertility patients and in 4 (%) of the patients with potency disorders. Androgen tests were performed to distinguish between two types of insufficiency of the seminal vesicles: that responding to an androgen and that not responding to an androgen. Low seminal fructose values increased in the course of androgen stimulation in : of 75 fertility patients and in 4 of 10 patients with potency disorders. The differential diagnosis of conditions with a low or zero concentration of seminal fructose is presented. Its significance and the value of fructose estimations in the assessment of male subfertility and infertility are discussed. Acknowledgment. The authors gratefully acknowledge the technical assistance of Ingrid Atteln. REFERENCES 1. Schirren C: Praktische Andrologie. First edition. Berlin, Bruder Hartmann, 1971, p 8. Niermann H: Ejackulat und sexuelle Karenz. Z Haut Geschlechtskr :44, 194. MacLeod SJ, Freund M: Influence of Spermatozoal concentration and initial fructose level on fructolysis in human semen. J Appl Physiol 1:501, 1958 <

5 Vol. 5, No.5 LOW OR ABSENT SEMINAL FRUCTOSE Freund M, MacLeod I: Effect of addition of fructose and of glucose on the fructolysis and motility of human semen. I Appl Physiol 1:50, Peterson RN, Freund M: Factors affecting fructose utilization and lactic acid formation by human semen. The role of glucose and pyruvic acid. Fertil Steril :9, Mann T, Lutwak-Mann C: Secretory function of male accessory organs of reproduction in mammals. Physiol Rev 1:7, Landau RL, Loughead R: Seminal fructose concentration as an index of androgenic activity in man. I Clin Endocrinol Metab 11:1411, Nowakowski H, Schirren C: Spermaplasmafructose und Leydigzellenfunktion beim Manne. Klin Wochenschr 4:19, Kimmig I, Steeno 0, Schirren C: Ergebnisse der modernen biochemischen Forschungen auf dem Gebiete der Andrologie. Internist (Berlin) 8:5, Moon KH, Osborn RH, Yannone ME, et al: Relationship of testosterone to human seminal fructose. Invest Urol 7:478, Moon KH, Bunge RG: Seminal fructose as an indicator of androgenic activity: critical analysis. Invest Urol 8:7, Dondero F, Sciarra F, Isidori A: Evaluation of relationships between plasma testosterone and human seminal citric acid. Fertil Steril : 18, Lavieri IC, Calamera IC: Effect of gonadotropins and androgens on fructose and citric acid of seminal fluid. In The Human Testis. Edited by E Rosemberg, CA Paulsen. New York - London, Plenum Press, 1970, p Mauss I, Borsch G, Richter E, et al. (Submitted for publication) 15. Roe IH: A colorimetric method for the determination of fructose in blood and urine. I BioI Chem 107:15, Mauss I: Zur Differentialdiagnose und Therapie der erniedrigten Spermaplasmafructose. Verh Dtsch Ges Urol :74, Mauss I: Andrologische Untersuchungen bei Jungeren Miinnern mit Impotentia coeundi. Hautarzt :5, Lischka G: Normozoospermie mit erniedrigter Fructosekonzentration, ein polylltiologisches Syndrom. Dtsch Med Wochenschr 9:19~, Schirren C: The treatment of the postpuberal Leydig cell insufficiency. Excerpta Medica Int Congr Series 1:808, Mauss I: Immunochemical estimation of urinary LH in males with low seminal fructose. Horm Metab Res 4: 18, Amelar RD, Hotchkiss RS: Congenital aplasia of the epididymides and vasa deferentia: effects on semen. Fertil Steril 14:44, 19. Moon KH, Bunge RG: Observations on the biochemistry of human semen., I. Fructose. Fertil Steril 19: 18, 198. Eliasson R, Fredricsson B, Iohannison E, et al: Biochemical and morphological changes in semen from men with diseases in the accessory genital glands. Excerpta Medica Int Congr Series 1:5, Eliasson R: Biochemical analyses of human semen in the study of the physiology and pathophysiology of the male accessory genital glands. Fertil Steril 19:44, Bygdeman M, Eliasson R: Distribution of prostaglandins, fructose and acid phosphatase in human seminal plasma. Andrologie 1:5, 199. Harvey C: Relations between the volume and fructose content of human semen. Nature (Lond) 1:81, Tyler ET: Seminal fructose studies in infertility. Fertil Steril :47, 1955