andrologia 7 (1) : 31-37
Received August 25, 1974
(1975)
Abteilung fur Gynakologische Endokrinologie, Zentrum der Frauenheilkunde und Geburtshilfe, J.W. Goethe Universitat, Frankfurt am Main, F.R. Germany
Increased Serum FSH Levels Correlated with Low and High Sperm Counts in Male infertile Patients D. SINA, R. SCHUHMANN, R. ABRAHAM, H.-D. TAUBERT, and J.S.E. DERICKS-TAN
Introduction Serum FSH has been shown to be elevated in men with severe depression of spermatogenesis, e.g. in Klinefelter’s syndrome. Similarly, a feedback mechanism between testosterone produced by the interstitial cells of the testis and pituitary LH secretion is known to exist in normal men (Burger - 1969; Franchimont - 1966; Franchimont et al. - 1972; Gomes et al. - 1973; de Kretser et al. - 1972; Peterson et al. - 1968; Rosen & Weintraub - 1971; Saxena et al. - 1969; van Thiel - 1972). In consideration of this, the value of hormonal assays in the diagnosis of male infertility was studied. Serum FSH, LH, and testosterone were measured in 80 virile males with normal libido and potency, ages 24 to 43, who attended a Male Infertility Clinic. They were compared to 57 normal males of proven fertility, whose ages ranged from 18 to 45 years. Methods and Subjects The 80 presumably infertile or subfertile males were assigned to one of the following groups according to their sperm count: Group 1: 0 to 1 million/ml spermatozoa Group 2: 2 to 10 million/ml Group 3: 11 to 20 millionlml Group 4: 21 to 40 million/ml Group 5: 41 to 120 million/ml Group 6: < 121 millionfml The diagnosis of idiopathc oligozoospermia (azoospermia) was given in accordance with the criteria listed in 1971 by Rosen & Weintraub: (1) No history or physical findings of kryptorchism, orchitis, epididymitis, varicocele, prostatitis, or anomalies of the spermatic cord. (2) Normal libido and potency associated with clinical evidence of virility. (3) Absence of endocrinopathy. (4) Testes measuring at least 2.5 cm in diameter. (5) Chromatin negative smears in aspermic patients. Semenanalysis: Semen samples were collected by masturbation in dry glass vessels after 72 hours or more had elapsed since the last emission. The analysis was carried out within 2 hours after the collection. The number of sperm was counted under 400fold magnification in undiluted or 1:10 diluted specimen in a standard hematocytometer. The fructose content of the seminal plasma was measured by the method of Davis and McCune (1950). When the result of a subsequent sperm count placed the patient in a different diagnostic group, the case was excluded from the present study. Key words: Monotropic FSH increase - Oligozoospermia - Azoospermia FSH, LH, Testosterone
-
Radioimmunassay for
D. SINA,R. SCHUHMANN, R. ABRAHAM, H.-D. TAUBERT and J. S. E. DERICKS-TAN
32
Hormone assays: Blood samples were obtained by venipuncture of the day the sperm count was performed. Serum FSH and LH were determined by radioimmunoassay using a second antibody in solid phase to separate free from bound labelled hormone (Franchimont et al. - 1971). The results were expressed as ng/ml FSH and LH respectively. The antisera, the labelled hormone, and the hormone standards were obtained commercially from IDW, Sprendlingen, F.R.G. (CEA-IRE-SORIN). All determinations were carried out in triplicate. One ng of the LH standard had a biological activity of 2000 mIU IInd IRP HMG, and a radioimmunological activity of 21 50 mIU 68/40 MRC, Mill Hill. One ng of FSH standard represented a biological activity of 168 ng LER 907, or 2800 mIU 68/39 MRC, Mill Hill. There was no cross-reaction between the anti-FSH serum and pituitary LH, and between the anti-LH serum and pituitary FSH in the dose range used for the measurements. Serum testosterone was measured by a radioimmunoassay utilizing a kit provided by IDW, Sprendlingen, F.R.G. (CEA-IRE-SORIN). Dextrane-coated charcoal was used for the separation of free and bound tritiated hormone. Statistical methods: The significance of the relationship between sperm count, number of motile spermatozoa, and fructose concentration in seminal plasma, and serum FSH, LH, and testosterone respectively was tested by calculating the correlation coefficients. The normalcy of distribution within the various groups was determined graphically. The significance of differences between groups without normal distribution of values was established by means of the Wilcoxon test. Results
Serum levels of FSH, LH and testosterone in normal men The mean values +- 2 SD of immunoassayable FSH, LH, and testosterone for the group of normal men were listed in Table 1. For FSH and LH, the smallest amount of hormone measurable is given as the lower limit of the range. There were no age-dependent differences for FSH and LH (FSH: r = 0.1354, p > 0.05;LH : r = 0.0024, p > 0.05). Serum testosterone on the other hand showed a negative age-dependent correlation coefficient : r = - 0.3862, p < 0.05). Bble 1: Serum FSH,LH and testosterone in normal males. The smallest measurable amount of FSH and LH respectively is listed as lower limit of the range
FSH LH Testosterone
n
mean (Z)
57 57 42
2.5 ng/ml 2.2 n g / d 540 ng/ml
SD 1.4 ng/ml 1.7 ng/ml 175 ng/lOO mi
range (? 5 2 SD) 0.25-5.3 ng/ml 0.5 -5.6 ng/ml 190-890 ng/100 ml
Serum levels of FSH, LH, and testosterone in presumably infertile men Serum FSH: Immunoassayable serum FSH was found to be elevated in 17 out of 42 men with sperm counts below 20 million/ml (Fig. l), and also in 5 out of 12 men with sperm concentrations exceeding 121 million/ml. In men with sperm counts between 21 million/ml and 120 million/ml, no FSH values extending beyond the normal range were seen. Asthenozoospermia was observed in 7 out of 8 men with hypozoospermia, and in 12 out of 18 subjects with sperm counts ranging from 41 million/ml to 120 million/ml. andrologia 7, Heft 1 (1975)
Increased Serum FSH Levels Correlated with Low and High Sperm Counts in Male
20-
0
16-
0
$-
12-
A
2
8-
0 0
0
E
0 0
w
.---:
L-
.
0 0
-
'O
a,%
0, >
e, a
&
J--0
0 Id
'0"
0
h
ct.
21 8
Mill./ml spemtozoa
10-20
0-1
Fig. 1:
2040
Lo-120
>1;
1-10 10-20 2040 Lo-120 >120 M ill./ml spermatozoa
Serum FSH, LH, and testosterone in 80 infertility patients. Closed circles denote idiopathic, open circles organiG fertility disturbance. Open triangles stand for Sertoli-cellonly-syndrome. The solid vertical line indicates the mean value in normal men, the broken lines 2 SD.
*
andrologia 7, Heft 1 (1975)
33
34
D. SINA,R. SCHUHMANN, R. ABRAHAM, H.-D. TAUBERT and J. S. E. DERICKS-TAN
In 20 out of 42 patients with less than 20 million/ml spermatozoa, the diagnosis of idiopathic oligozoospermia (azoospermia) was given. A variety of organic causes was observed in the remaining 22 cases. In 3 men with agenesis or occlusion of the spermatic cord, FSH was found to be normal, but values ranging from 6.4 ng/ml FSH to 19.0 ng/ml were observed in 3 cases of Sertoli-cell-only-syndrome.Similarly, elevated FSH levels were found in 5 cases of testicular atrophy, 1 case of kryptorchism, and in 2 out of 6 men with varicoceles. Contrary to this, normal FSH values were obtained in a case of unilateral testicular atrophy, of orchitis and dysgerminoma, and in 2 cases of hydrocele. As normalcy of distribution could not be demonstrated for the group of patients having sperm counts below 20 million/ml, the Wilcoxon test had to be employed to determine whether or not the elevation of serum FSH in these groups (columns 1 to 3, Fig. 1) was statistically significant. It could be shown that the increased FSH values found in this group were of statistical significance at the 5% level. There was no correlation between the number of motile spermatozoa and serum FSH (r = - 0.1833, p 3 0.05). Serum LH: Serum LH was found to be within the normal range in 55 out of 57 infertile patients. Only in 1 case of azoospermia due to testicular atrophy, an elevated LH level (10.0 ng/ml) corresponded well with high FSH (15 nglml) and depressed serum testosterone (105 ng/100 ml). In another oligozoospermic with testicular atrophy, both LH (5.8 ng/ml) and FSH (13.0 ng/ml) were high while testosterone was found to be normal (480 ng/100 mlj. Serum testosterone: In 8 of 42 men studied, testosterone values above the upper limit of the range were found, but no correlation could be established between sperm count and serum testosterone. Moreover, no evidence for a direct relationship between serum testosterone and the fructose content of the seminal plasma (r = 0.0482, p > 0.05), and between the latter and the percentage of motile spermatozoa could be obtained. Discussion Serum FSH was found to be increased in comparison to normal males in approximately 40% of men with a sperm count below 20 million/ml, and also in 5 out of 12 men whose sperm count exceeded 121 million/ml. Contrary to this, normal FSH values were found in men with the number of spermatozoa ranging from 21 million/ml to 120 million/ml. There was no concomitant increase of LH, and no relationship could be shown to exist between serum testosterone levels and the number of spermatozoa, their degree of motility, and seminal plasma fructose concentration. A high value of LH was found to concur with a depressed testosterone level in only 1 case. The monotropic increase of serum FSH in oligozbospermic men (Rosen and Weintraub - 1971) is possibly due to a decreased production of a hypothetical factor in the seminiferous tubules, inhibin, which influences FSH secretion. As the enhancement of serum FSH did, however, never reach the levels attained after castration in the male, or in the postmenopausal female (> 50 ng/ml), it may be assumed that there is a second level of control over FSH in the testis (Altwein et al., 1972; Swerdloff et al. 1972). An inverse relationshp between the number of spermatozoa and FSH secretion which has been described by a number of workers but has been denied by others (Franchimont et al - 1972; de Kretser et al. - 1972; Johnsen 1972; Paulsen et al. - 1972) could not be shown. Markedly elevated FSH values were, however, seen in all patients
-
andrologia 7,Heft 1 (1975)
Increased Serum FSH Levels Correlated with Low and High Sperm Counts in Male
35
with marked reduction of testicular size, and in cases where the histologic examination of testicular biopsies revealed the presence of Sertoli cells only. As only 6 out of 17 men with high FSH were given the diagnosis of idiopathic oligozoospermia (azoospermia), the concurrence of depressed spermatogenesis and elevated FSH levels seems to be a relatively good indicator for the presence of organic disorders of the testis. Increased FSH values have, however, to our knowledge not been reported before in association with sperm counts exceeding 121 million/ml. It had been shown by Franchimont et al. (1972) that FSH was ordinarily within the normal range when spermatids were seen in histologic sections of testicular biopsies. High FSH values were always found in cases where the spermatogenesis was arrested prior to Stage 5 (Clermont 1963). As these 5 patients did not present with any other consistent findings, it would be premature to speculate on possible mechanisms responsible for the elevation of FSH in men with high sperm counts. It may be presumed, however, that the feedback between the germinal epithelium and FSH secretion is disturbed in a subtle manner. In conclusion, the measurepent of serum FSH appears to be much more informative than the determination of LH and testosterone in the diagnostic work-up of the viril, male infertile patient. Its prognostic value as to whether or not fertility can be restored in the individual case remains, however, to be shown. Summary Serum FSH, LH and testosterone were measured in 57 (42) normal men and in 80 male infertile patients. In the former, mean (X) FSH was found to be 2.5 ng/ml with a range (X ? 2 SD) from 0.25 ng/ml to 5.3 ng/ml, mean LH was 2.2 ng/ml with a range from 0.5 ng/ml to 5.6 ng/ml, and mean testosterone was 540 ng/100 ml with a range from 190 ng/ml to 890 ng/100 ml. Immunoassayable FSH was found to be elevated in 17 out of 42 presumably infertile males with sperm counts below 20 million/ml, and in 5 out of 12 men with sperm counts above 120 million/ml. There was no correlation between testosterone and sperm number, motility, and seminal fructose content. The concurrence of depressed spermatogenesis and elevated FSH levels seems to be a relatively good indicator for the presence of organic disorders of the testis.
Erhohung des Serum-FSH bei infertilen Mannern mit Oligo- und Polyzoospermie
Zusammenfassung FSH, LH und Testosteron wurden mittels radioimmunologischer Methoden im Serum von 57 (bzw. 42) gesunden Kontrollpersonen und 80 Patienten einer Sterilitatssprechstunde fur Manner gemessen. Bei der ersteren Gruppe wurde fur FSH ein Mittelwert von 2,5 ng/ml mit einem Streubereich von 0,25-5,3 ng/ml gefunden. Der Mittelwert des LH betrug 2,2 ng/ml(O,5-5,6 nglml), der des Testosteron 540 ng/100 m l ( l 9 0 890 ng/ml). Das radioimmunoreaktive FSH war bei 17 von 42 Stenlitatspatienten, deren Ejakulate > 20 Mio./ml Spermien enthielten, und bei 5 von 12 Mannern mit Spermienzahlen von > 120 Mio./ml Ejakulat erhoht. Dagegen lie6 sich zwischen LH und Testosteron auf der einen Seite und der Spermienzahl, der Motilitat und dem Fruktosegehalt des Seminalplasmas auf der anderen keine Korrelation herstellen. Ein erhohter Serum FSH Spiegel scheint also bei Mannern mit verminderter Spermienzahl ein relativ zuverlassiger Indikator fur das Vorliegen einer organischen Hodenschadigung zu sein. andrologia 7,Heft 1 (1975)
36
D. SINA,R. SCHUHMANN, R. ABRAHAM, H.-D. TAUBERT and J. S. E. DERICKS-TAN Correlacion de niveles elevados de FSH drica, con recuentos espermaticos bajos y altos en varones infertiles
Re sumen Se midi6 la FSH, LH y testosterona plasmltica en 57 ( 4 2 ) hombres normales y en 80 pacientes infertiles. En 10s primeros, se encontr6 una media d e FSH d e 2,s ng/ml con oscilaci6n desde 0,25 n g /m l a 5,3 ng/ml, la media d e LH f u e d e 2,2 n g / m l con oscilaci6n desde 0,5 ng/lm a 5,6 n g /m l y la media d e testosterona f u e de 540 n g / 1 0 0 ml, con oscilaci6n desde 190 ng/ml a 890 ng/ 100 ml. En 17 de 10s 42 hombres presumiblemente infkrtiles, se encontr6, por inmunoensayo, la FSH elevada, con recuentos espermlticos por debajo d e 20 millones y en 5 de 10s 1 2 pacientes con recuentos superiores a 1 2 0 millones/ml. No habia correlaci6n entre la testosterona y el recuento, motilidad y c on t en i d o d e fructosa seminal.
References Altwein, J.E., and R. Gittes: Effect of cryptorchism and castration on FSH and LH levels in the adult rat. Invest. Urol. 10, 167-170 (1972). Burger, H.H.: In: Protein and Polypeptide Hormones. Intern. Congr. Series, No. 161. Excerpta Medica Foundation, Amsterdam (1969), p. 729-732. Margoulies, M. (Ed.). Davis, M.E., and W.W. McCune: Fructolysis of human spermatozoa. Fertil. Steril. 1, 362-372 (1950). Clermont, Y.: The cycle of the seminiferous epithelium in Man. Am. J. Anat. 112, 35-51 (1963). Franchimont, P.: Le dosage des hormones hypophysaire somatotrope et gonadotrope et son application en clinique. Arscia, Brussels (1966). Franchimont, P., J.C. Hendrick,, A. Reuter, and J.J. Legros: The Gonadotropins: Radioimmunoassay Technique and physiologic Evidence of specificity. In: Saxena, B.B. et al.(Eds.), Gonadotropins, Wiley-Interscience, New York (1971), 361-376. Franchimont, P., D. Millet, E. Vendrely, J. Letawe, J.J. Legros, and A. Netter: Relationship between spermatogenesis and serum gonadotropin levels in azoospermia and oligospermia. J. Clin. Endocr. Metab. 34, 1003-1008 (1972). Gomes, W.R., R.W. Hall, S.K. Jain, and L.R. Boots: Serum gonadotropin and testosterone levels during loss and recovery of spermatogenesis in rats. Endocrinology 93, 800-809 (1973). Johnsen, S.G.: Studies on the pituitary-testicular axis in male hypogonadism, particularly in infertile men with “Cryptogenic” hypospermatogenesis. In: Saxena, B.B. et aL (eds.), Gonadotropins, Wiley-Interscience, New York (1972), p. 593-608. de Kretser, D.M., H.G. Burger, D. Fortune, B. Hudson, A.R. Long, C.A. Paulsen, and H.P. Taft: Hormonal, histological and chromosomal studies in adult males with testicular disorders. J. Clin. Endocr. Metab. 35, 392-401 (1972). Paulsen, C.A., J.M. Leonard, D.M. de Kretser, and R.B. Leach: Interrelationship between spermatogenesis and follicle-stimulating hormone levels. In: Saxena, B.B. et al. (eds.), Gonadotropins, Wiley-lnterscience, New York (1972), p. 628-639. Peterson, N.T., A.R. Midgley Jr., and R.B. Jaffe: Regulation of human gonadotropins. 111. Luteinking Hormone and Follicle-stimulating Hormone in sera from adult males. J. Clin. Endocr. Metab. 28, 1473-1478 (1968). Rosen, S.W. and B.D. Weintraub: Monotropic increase of serum FSH correlated with low sperm count in young men with idiopathic oligospermia and aspermia. J. Clin. Endocr. Metab. 32, 410-416 (1971). Saxena, B.B., G. Leyendecker, W. Chen, H. Gandy, and R.E. Peterson: Radioimmunoassay of Follicle-stimulating hormone (FSH) and Luteinizing hormone (LH) by chromatoelectrophoresis. Acta Endocr. (Kbh.) (Suppl. 142) 63, 185-206 (1969). Swerdloff, R.S., H.S. Jacobs, and W.D. Odell: Hypothalamic-pituitary-gonadal interrelationships in the rat during sexual maturation. In: Saxena, B.B. et al. (eds.), Gonadotropins, Wiley-Interscience, New York (1972), p. 546-566.
.
.
andrologia 7,Heft 1 (1975)
Increased Serum FSH Levels Correlated with Low and High Sperm Counts in Male van Thiel, D.H., R.J. Sherins, G.H. Myers Jr., and V.T. de Vita Jr.: Evidence for a specific seminiferous tubular factor affecting follicle-stimulatinghormone secretion in man. J. C h . Invest. 51,1009-1019 (1972).
Acknowledgement: The expert technical assistance of Mrs. I. Kemmann, Miss I. Fritz, and of Mr. H. Sauer are gratefully acknowledged.
Address: (Mrs.) Dr. J.S.E. DERICKS-TAN, Abteilung fur gynakologische Endokrinologie, Zentrum der Frauenheilkunde und Geburtshilfe, J . W. Goethe Universitat, Frankfurt am Main, Theodor-Stern-Kai 7, F. R. Germany.
1 Announcement Diisseldorfj Germany : 1.-5.4.1975 70. Versammlung der Anatomischen Gesellschaft. Themen: Endokrine Organe und Systeme. Hirnrinde. Auskunft: Prof. Dr. med. W. Kiihnel, 5 1 Aachen, Melatener Str. 211 Abt. Anatomie der Med. Fakultat. Anmeldungen fur Vortrage und Demonstrationen bis 15.1.1975. DetroitjNorth America: American Society of Andrology. Initiation: Because of increasing interest in the growing and important field of Andrology, a Society of Andrologists will be formed in Detroit, 1975. This Society Initiation will occur in conjunction with the International Conference o n “The Human Semen and Fertility Regulation in the Male” t o be held at the Wayne State University School of Medicine, April 24-26, 1975. The organizational meeting, held in the afternoon of April 24, will be followed by an initiation banquet. Aims of the society: The aim of this society will be t o bring American and nonAmerican scientists, clinicians, etc. who share an interest in male reproduction, together in an annual meeting t o exchange ideas and introduce new concepts. With the growth of the society, there will be consequent symposia and international conferences, for the purpose of encouraging basic and clinical research in male reproduction. The society will be affiliated with CIDA (Cornit6 Internacional de Andrologia) and will share its publication arm, the journal ANDROLOGIA. Initiation banquet: (Thursday, April 24, 1975 6 : O O t o 9:OO p.m.). If interested, mail the attached form along with $ lO.OO.(payable “Wayne State University”) to: Mr. Stephen Fedak, C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, 275 E. Hancock, Detroit, Michigan 48201. Deadline ofreservation: January 1, 1975
andrologia 7, Heft 1 (1975)
37
Received August 25, 1974
(1975)
Abteilung fur Gynakologische Endokrinologie, Zentrum der Frauenheilkunde und Geburtshilfe, J.W. Goethe Universitat, Frankfurt am Main, F.R. Germany
Increased Serum FSH Levels Correlated with Low and High Sperm Counts in Male infertile Patients D. SINA, R. SCHUHMANN, R. ABRAHAM, H.-D. TAUBERT, and J.S.E. DERICKS-TAN
Introduction Serum FSH has been shown to be elevated in men with severe depression of spermatogenesis, e.g. in Klinefelter’s syndrome. Similarly, a feedback mechanism between testosterone produced by the interstitial cells of the testis and pituitary LH secretion is known to exist in normal men (Burger - 1969; Franchimont - 1966; Franchimont et al. - 1972; Gomes et al. - 1973; de Kretser et al. - 1972; Peterson et al. - 1968; Rosen & Weintraub - 1971; Saxena et al. - 1969; van Thiel - 1972). In consideration of this, the value of hormonal assays in the diagnosis of male infertility was studied. Serum FSH, LH, and testosterone were measured in 80 virile males with normal libido and potency, ages 24 to 43, who attended a Male Infertility Clinic. They were compared to 57 normal males of proven fertility, whose ages ranged from 18 to 45 years. Methods and Subjects The 80 presumably infertile or subfertile males were assigned to one of the following groups according to their sperm count: Group 1: 0 to 1 million/ml spermatozoa Group 2: 2 to 10 million/ml Group 3: 11 to 20 millionlml Group 4: 21 to 40 million/ml Group 5: 41 to 120 million/ml Group 6: < 121 millionfml The diagnosis of idiopathc oligozoospermia (azoospermia) was given in accordance with the criteria listed in 1971 by Rosen & Weintraub: (1) No history or physical findings of kryptorchism, orchitis, epididymitis, varicocele, prostatitis, or anomalies of the spermatic cord. (2) Normal libido and potency associated with clinical evidence of virility. (3) Absence of endocrinopathy. (4) Testes measuring at least 2.5 cm in diameter. (5) Chromatin negative smears in aspermic patients. Semenanalysis: Semen samples were collected by masturbation in dry glass vessels after 72 hours or more had elapsed since the last emission. The analysis was carried out within 2 hours after the collection. The number of sperm was counted under 400fold magnification in undiluted or 1:10 diluted specimen in a standard hematocytometer. The fructose content of the seminal plasma was measured by the method of Davis and McCune (1950). When the result of a subsequent sperm count placed the patient in a different diagnostic group, the case was excluded from the present study. Key words: Monotropic FSH increase - Oligozoospermia - Azoospermia FSH, LH, Testosterone
-
Radioimmunassay for
D. SINA,R. SCHUHMANN, R. ABRAHAM, H.-D. TAUBERT and J. S. E. DERICKS-TAN
32
Hormone assays: Blood samples were obtained by venipuncture of the day the sperm count was performed. Serum FSH and LH were determined by radioimmunoassay using a second antibody in solid phase to separate free from bound labelled hormone (Franchimont et al. - 1971). The results were expressed as ng/ml FSH and LH respectively. The antisera, the labelled hormone, and the hormone standards were obtained commercially from IDW, Sprendlingen, F.R.G. (CEA-IRE-SORIN). All determinations were carried out in triplicate. One ng of the LH standard had a biological activity of 2000 mIU IInd IRP HMG, and a radioimmunological activity of 21 50 mIU 68/40 MRC, Mill Hill. One ng of FSH standard represented a biological activity of 168 ng LER 907, or 2800 mIU 68/39 MRC, Mill Hill. There was no cross-reaction between the anti-FSH serum and pituitary LH, and between the anti-LH serum and pituitary FSH in the dose range used for the measurements. Serum testosterone was measured by a radioimmunoassay utilizing a kit provided by IDW, Sprendlingen, F.R.G. (CEA-IRE-SORIN). Dextrane-coated charcoal was used for the separation of free and bound tritiated hormone. Statistical methods: The significance of the relationship between sperm count, number of motile spermatozoa, and fructose concentration in seminal plasma, and serum FSH, LH, and testosterone respectively was tested by calculating the correlation coefficients. The normalcy of distribution within the various groups was determined graphically. The significance of differences between groups without normal distribution of values was established by means of the Wilcoxon test. Results
Serum levels of FSH, LH and testosterone in normal men The mean values +- 2 SD of immunoassayable FSH, LH, and testosterone for the group of normal men were listed in Table 1. For FSH and LH, the smallest amount of hormone measurable is given as the lower limit of the range. There were no age-dependent differences for FSH and LH (FSH: r = 0.1354, p > 0.05;LH : r = 0.0024, p > 0.05). Serum testosterone on the other hand showed a negative age-dependent correlation coefficient : r = - 0.3862, p < 0.05). Bble 1: Serum FSH,LH and testosterone in normal males. The smallest measurable amount of FSH and LH respectively is listed as lower limit of the range
FSH LH Testosterone
n
mean (Z)
57 57 42
2.5 ng/ml 2.2 n g / d 540 ng/ml
SD 1.4 ng/ml 1.7 ng/ml 175 ng/lOO mi
range (? 5 2 SD) 0.25-5.3 ng/ml 0.5 -5.6 ng/ml 190-890 ng/100 ml
Serum levels of FSH, LH, and testosterone in presumably infertile men Serum FSH: Immunoassayable serum FSH was found to be elevated in 17 out of 42 men with sperm counts below 20 million/ml (Fig. l), and also in 5 out of 12 men with sperm concentrations exceeding 121 million/ml. In men with sperm counts between 21 million/ml and 120 million/ml, no FSH values extending beyond the normal range were seen. Asthenozoospermia was observed in 7 out of 8 men with hypozoospermia, and in 12 out of 18 subjects with sperm counts ranging from 41 million/ml to 120 million/ml. andrologia 7, Heft 1 (1975)
Increased Serum FSH Levels Correlated with Low and High Sperm Counts in Male
20-
0
16-
0
$-
12-
A
2
8-
0 0
0
E
0 0
w
.---:
L-
.
0 0
-
'O
a,%
0, >
e, a
&
J--0
0 Id
'0"
0
h
ct.
21 8
Mill./ml spemtozoa
10-20
0-1
Fig. 1:
2040
Lo-120
>1;
1-10 10-20 2040 Lo-120 >120 M ill./ml spermatozoa
Serum FSH, LH, and testosterone in 80 infertility patients. Closed circles denote idiopathic, open circles organiG fertility disturbance. Open triangles stand for Sertoli-cellonly-syndrome. The solid vertical line indicates the mean value in normal men, the broken lines 2 SD.
*
andrologia 7, Heft 1 (1975)
33
34
D. SINA,R. SCHUHMANN, R. ABRAHAM, H.-D. TAUBERT and J. S. E. DERICKS-TAN
In 20 out of 42 patients with less than 20 million/ml spermatozoa, the diagnosis of idiopathic oligozoospermia (azoospermia) was given. A variety of organic causes was observed in the remaining 22 cases. In 3 men with agenesis or occlusion of the spermatic cord, FSH was found to be normal, but values ranging from 6.4 ng/ml FSH to 19.0 ng/ml were observed in 3 cases of Sertoli-cell-only-syndrome.Similarly, elevated FSH levels were found in 5 cases of testicular atrophy, 1 case of kryptorchism, and in 2 out of 6 men with varicoceles. Contrary to this, normal FSH values were obtained in a case of unilateral testicular atrophy, of orchitis and dysgerminoma, and in 2 cases of hydrocele. As normalcy of distribution could not be demonstrated for the group of patients having sperm counts below 20 million/ml, the Wilcoxon test had to be employed to determine whether or not the elevation of serum FSH in these groups (columns 1 to 3, Fig. 1) was statistically significant. It could be shown that the increased FSH values found in this group were of statistical significance at the 5% level. There was no correlation between the number of motile spermatozoa and serum FSH (r = - 0.1833, p 3 0.05). Serum LH: Serum LH was found to be within the normal range in 55 out of 57 infertile patients. Only in 1 case of azoospermia due to testicular atrophy, an elevated LH level (10.0 ng/ml) corresponded well with high FSH (15 nglml) and depressed serum testosterone (105 ng/100 ml). In another oligozoospermic with testicular atrophy, both LH (5.8 ng/ml) and FSH (13.0 ng/ml) were high while testosterone was found to be normal (480 ng/100 mlj. Serum testosterone: In 8 of 42 men studied, testosterone values above the upper limit of the range were found, but no correlation could be established between sperm count and serum testosterone. Moreover, no evidence for a direct relationship between serum testosterone and the fructose content of the seminal plasma (r = 0.0482, p > 0.05), and between the latter and the percentage of motile spermatozoa could be obtained. Discussion Serum FSH was found to be increased in comparison to normal males in approximately 40% of men with a sperm count below 20 million/ml, and also in 5 out of 12 men whose sperm count exceeded 121 million/ml. Contrary to this, normal FSH values were found in men with the number of spermatozoa ranging from 21 million/ml to 120 million/ml. There was no concomitant increase of LH, and no relationship could be shown to exist between serum testosterone levels and the number of spermatozoa, their degree of motility, and seminal plasma fructose concentration. A high value of LH was found to concur with a depressed testosterone level in only 1 case. The monotropic increase of serum FSH in oligozbospermic men (Rosen and Weintraub - 1971) is possibly due to a decreased production of a hypothetical factor in the seminiferous tubules, inhibin, which influences FSH secretion. As the enhancement of serum FSH did, however, never reach the levels attained after castration in the male, or in the postmenopausal female (> 50 ng/ml), it may be assumed that there is a second level of control over FSH in the testis (Altwein et al., 1972; Swerdloff et al. 1972). An inverse relationshp between the number of spermatozoa and FSH secretion which has been described by a number of workers but has been denied by others (Franchimont et al - 1972; de Kretser et al. - 1972; Johnsen 1972; Paulsen et al. - 1972) could not be shown. Markedly elevated FSH values were, however, seen in all patients
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andrologia 7,Heft 1 (1975)
Increased Serum FSH Levels Correlated with Low and High Sperm Counts in Male
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with marked reduction of testicular size, and in cases where the histologic examination of testicular biopsies revealed the presence of Sertoli cells only. As only 6 out of 17 men with high FSH were given the diagnosis of idiopathic oligozoospermia (azoospermia), the concurrence of depressed spermatogenesis and elevated FSH levels seems to be a relatively good indicator for the presence of organic disorders of the testis. Increased FSH values have, however, to our knowledge not been reported before in association with sperm counts exceeding 121 million/ml. It had been shown by Franchimont et al. (1972) that FSH was ordinarily within the normal range when spermatids were seen in histologic sections of testicular biopsies. High FSH values were always found in cases where the spermatogenesis was arrested prior to Stage 5 (Clermont 1963). As these 5 patients did not present with any other consistent findings, it would be premature to speculate on possible mechanisms responsible for the elevation of FSH in men with high sperm counts. It may be presumed, however, that the feedback between the germinal epithelium and FSH secretion is disturbed in a subtle manner. In conclusion, the measurepent of serum FSH appears to be much more informative than the determination of LH and testosterone in the diagnostic work-up of the viril, male infertile patient. Its prognostic value as to whether or not fertility can be restored in the individual case remains, however, to be shown. Summary Serum FSH, LH and testosterone were measured in 57 (42) normal men and in 80 male infertile patients. In the former, mean (X) FSH was found to be 2.5 ng/ml with a range (X ? 2 SD) from 0.25 ng/ml to 5.3 ng/ml, mean LH was 2.2 ng/ml with a range from 0.5 ng/ml to 5.6 ng/ml, and mean testosterone was 540 ng/100 ml with a range from 190 ng/ml to 890 ng/100 ml. Immunoassayable FSH was found to be elevated in 17 out of 42 presumably infertile males with sperm counts below 20 million/ml, and in 5 out of 12 men with sperm counts above 120 million/ml. There was no correlation between testosterone and sperm number, motility, and seminal fructose content. The concurrence of depressed spermatogenesis and elevated FSH levels seems to be a relatively good indicator for the presence of organic disorders of the testis.
Erhohung des Serum-FSH bei infertilen Mannern mit Oligo- und Polyzoospermie
Zusammenfassung FSH, LH und Testosteron wurden mittels radioimmunologischer Methoden im Serum von 57 (bzw. 42) gesunden Kontrollpersonen und 80 Patienten einer Sterilitatssprechstunde fur Manner gemessen. Bei der ersteren Gruppe wurde fur FSH ein Mittelwert von 2,5 ng/ml mit einem Streubereich von 0,25-5,3 ng/ml gefunden. Der Mittelwert des LH betrug 2,2 ng/ml(O,5-5,6 nglml), der des Testosteron 540 ng/100 m l ( l 9 0 890 ng/ml). Das radioimmunoreaktive FSH war bei 17 von 42 Stenlitatspatienten, deren Ejakulate > 20 Mio./ml Spermien enthielten, und bei 5 von 12 Mannern mit Spermienzahlen von > 120 Mio./ml Ejakulat erhoht. Dagegen lie6 sich zwischen LH und Testosteron auf der einen Seite und der Spermienzahl, der Motilitat und dem Fruktosegehalt des Seminalplasmas auf der anderen keine Korrelation herstellen. Ein erhohter Serum FSH Spiegel scheint also bei Mannern mit verminderter Spermienzahl ein relativ zuverlassiger Indikator fur das Vorliegen einer organischen Hodenschadigung zu sein. andrologia 7,Heft 1 (1975)
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D. SINA,R. SCHUHMANN, R. ABRAHAM, H.-D. TAUBERT and J. S. E. DERICKS-TAN Correlacion de niveles elevados de FSH drica, con recuentos espermaticos bajos y altos en varones infertiles
Re sumen Se midi6 la FSH, LH y testosterona plasmltica en 57 ( 4 2 ) hombres normales y en 80 pacientes infertiles. En 10s primeros, se encontr6 una media d e FSH d e 2,s ng/ml con oscilaci6n desde 0,25 n g /m l a 5,3 ng/ml, la media d e LH f u e d e 2,2 n g / m l con oscilaci6n desde 0,5 ng/lm a 5,6 n g /m l y la media d e testosterona f u e de 540 n g / 1 0 0 ml, con oscilaci6n desde 190 ng/ml a 890 ng/ 100 ml. En 17 de 10s 42 hombres presumiblemente infkrtiles, se encontr6, por inmunoensayo, la FSH elevada, con recuentos espermlticos por debajo d e 20 millones y en 5 de 10s 1 2 pacientes con recuentos superiores a 1 2 0 millones/ml. No habia correlaci6n entre la testosterona y el recuento, motilidad y c on t en i d o d e fructosa seminal.
References Altwein, J.E., and R. Gittes: Effect of cryptorchism and castration on FSH and LH levels in the adult rat. Invest. Urol. 10, 167-170 (1972). Burger, H.H.: In: Protein and Polypeptide Hormones. Intern. Congr. Series, No. 161. Excerpta Medica Foundation, Amsterdam (1969), p. 729-732. Margoulies, M. (Ed.). Davis, M.E., and W.W. McCune: Fructolysis of human spermatozoa. Fertil. Steril. 1, 362-372 (1950). Clermont, Y.: The cycle of the seminiferous epithelium in Man. Am. J. Anat. 112, 35-51 (1963). Franchimont, P.: Le dosage des hormones hypophysaire somatotrope et gonadotrope et son application en clinique. Arscia, Brussels (1966). Franchimont, P., J.C. Hendrick,, A. Reuter, and J.J. Legros: The Gonadotropins: Radioimmunoassay Technique and physiologic Evidence of specificity. In: Saxena, B.B. et al.(Eds.), Gonadotropins, Wiley-Interscience, New York (1971), 361-376. Franchimont, P., D. Millet, E. Vendrely, J. Letawe, J.J. Legros, and A. Netter: Relationship between spermatogenesis and serum gonadotropin levels in azoospermia and oligospermia. J. Clin. Endocr. Metab. 34, 1003-1008 (1972). Gomes, W.R., R.W. Hall, S.K. Jain, and L.R. Boots: Serum gonadotropin and testosterone levels during loss and recovery of spermatogenesis in rats. Endocrinology 93, 800-809 (1973). Johnsen, S.G.: Studies on the pituitary-testicular axis in male hypogonadism, particularly in infertile men with “Cryptogenic” hypospermatogenesis. In: Saxena, B.B. et aL (eds.), Gonadotropins, Wiley-Interscience, New York (1972), p. 593-608. de Kretser, D.M., H.G. Burger, D. Fortune, B. Hudson, A.R. Long, C.A. Paulsen, and H.P. Taft: Hormonal, histological and chromosomal studies in adult males with testicular disorders. J. Clin. Endocr. Metab. 35, 392-401 (1972). Paulsen, C.A., J.M. Leonard, D.M. de Kretser, and R.B. Leach: Interrelationship between spermatogenesis and follicle-stimulating hormone levels. In: Saxena, B.B. et al. (eds.), Gonadotropins, Wiley-lnterscience, New York (1972), p. 628-639. Peterson, N.T., A.R. Midgley Jr., and R.B. Jaffe: Regulation of human gonadotropins. 111. Luteinking Hormone and Follicle-stimulating Hormone in sera from adult males. J. Clin. Endocr. Metab. 28, 1473-1478 (1968). Rosen, S.W. and B.D. Weintraub: Monotropic increase of serum FSH correlated with low sperm count in young men with idiopathic oligospermia and aspermia. J. Clin. Endocr. Metab. 32, 410-416 (1971). Saxena, B.B., G. Leyendecker, W. Chen, H. Gandy, and R.E. Peterson: Radioimmunoassay of Follicle-stimulating hormone (FSH) and Luteinizing hormone (LH) by chromatoelectrophoresis. Acta Endocr. (Kbh.) (Suppl. 142) 63, 185-206 (1969). Swerdloff, R.S., H.S. Jacobs, and W.D. Odell: Hypothalamic-pituitary-gonadal interrelationships in the rat during sexual maturation. In: Saxena, B.B. et al. (eds.), Gonadotropins, Wiley-Interscience, New York (1972), p. 546-566.
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Increased Serum FSH Levels Correlated with Low and High Sperm Counts in Male van Thiel, D.H., R.J. Sherins, G.H. Myers Jr., and V.T. de Vita Jr.: Evidence for a specific seminiferous tubular factor affecting follicle-stimulatinghormone secretion in man. J. C h . Invest. 51,1009-1019 (1972).
Acknowledgement: The expert technical assistance of Mrs. I. Kemmann, Miss I. Fritz, and of Mr. H. Sauer are gratefully acknowledged.
Address: (Mrs.) Dr. J.S.E. DERICKS-TAN, Abteilung fur gynakologische Endokrinologie, Zentrum der Frauenheilkunde und Geburtshilfe, J . W. Goethe Universitat, Frankfurt am Main, Theodor-Stern-Kai 7, F. R. Germany.
1 Announcement Diisseldorfj Germany : 1.-5.4.1975 70. Versammlung der Anatomischen Gesellschaft. Themen: Endokrine Organe und Systeme. Hirnrinde. Auskunft: Prof. Dr. med. W. Kiihnel, 5 1 Aachen, Melatener Str. 211 Abt. Anatomie der Med. Fakultat. Anmeldungen fur Vortrage und Demonstrationen bis 15.1.1975. DetroitjNorth America: American Society of Andrology. Initiation: Because of increasing interest in the growing and important field of Andrology, a Society of Andrologists will be formed in Detroit, 1975. This Society Initiation will occur in conjunction with the International Conference o n “The Human Semen and Fertility Regulation in the Male” t o be held at the Wayne State University School of Medicine, April 24-26, 1975. The organizational meeting, held in the afternoon of April 24, will be followed by an initiation banquet. Aims of the society: The aim of this society will be t o bring American and nonAmerican scientists, clinicians, etc. who share an interest in male reproduction, together in an annual meeting t o exchange ideas and introduce new concepts. With the growth of the society, there will be consequent symposia and international conferences, for the purpose of encouraging basic and clinical research in male reproduction. The society will be affiliated with CIDA (Cornit6 Internacional de Andrologia) and will share its publication arm, the journal ANDROLOGIA. Initiation banquet: (Thursday, April 24, 1975 6 : O O t o 9:OO p.m.). If interested, mail the attached form along with $ lO.OO.(payable “Wayne State University”) to: Mr. Stephen Fedak, C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, 275 E. Hancock, Detroit, Michigan 48201. Deadline ofreservation: January 1, 1975
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