PITUITARY AND GONADAL HORMONES IN PATIENTS WITH VARICOCELE

Transcription

1 FERTILITY AND STERILITY Copyright 1975 The Amerian Fertility Soiety Vol. 26, No. 1, Otober 1975 Printed in U.s.A. PITUITARY AND GONADAL HORMONES IN PATIENTS WITH VARICOCELE RONALD S. SWERDWFF, M.D.,* AND PATRICK C. WALSH, M.D. Department of Mediine, Harbor General Hospital Campus, UCLA Shool of Mediine, Torrane, California 959, and Department of Urology, Brady Urologial Institute, The Johns Hopkins Hospital, Baltimore, Maryland 2125 In a number of studies, varioeles have been reported to our in 8 to 2% of the healthy young adult male population. I - 6 These variosities of the spermati veins are usually unilaterap and are ommonly assoiated with abnormal spermiograms.l. 7 Dereased sperm ount and motility were found to be present in 25 to 56%, respetively, of 94 volunteer subjets with varioeles seleted from a population of 1592 United States Air Fore reruits. 1 Sperm morphology is often abnormal in suh patients; immature and abnormally tapered sperm forms are the predominant findings. 7 Testis biopsies from subfertile patients with varioeles have revealed bilateral abnormalities whih have been haraterized in one study as demonstrating germinal ell hypoplasia with premature sloughing of immature forms into the lumina of the germinal tubules. 8 The finding of bilateral testiular abnormalities in patients with a unilateral varioele suggests that a unilateral anatomial abnormality may produe bilateral testiular injuries. The ausal relationship between varioeles and subfertility has been supported by the demonstration that surgial treatment of the varioele by unilateral high ligation of spermati vein often results in improvement of the patient's spermiogram 9-13 and subsequent pregnany in the spouse. 12, 13 The pathophysiologi mehanisms by Reeived November 22, *Reipient of United States Publi Health Servie Career Development Award 5 K4 HD whih varioeles ause infertility have not been eluidated. A number of pathogeni mehanisms have been proposed, inluding (1) defetive srotal temperature regulation l4 and (2) retrograde flow of adrenal steroids through the varioele and into the testis. 7 It has been suggested that ross-venous anastomosis may explain the bilateral testiular effets. 15 Both of these hypotheses have been evaluated and neither has been onfirmed.16, 17 Sine spermatogenesis is under the ontrol of pituitary gonadotropins (luteinizing hormone (LH) and follile-stimulating hormone (FSH)) and testiular androgens, hormonal alterations in the hypothalami-pituitary gonadal axis might playa role in varioele-assoiated subfertility. Alternatively, varioeles ould result in testiular abnormalities whih in turn affet the hormonal seretion of steroids by the Leydig ells. In this regard, dereased serum testosterone levels have been reported in patients with varioeles. 18 In the present study, a detailed analysis of serum LH, FSH, testosterone, and estradiol levels was made in a group of subfertile men with varioele. MATERIALS AND METHODS Thirty-one men aged 19 to 38 years were studied: thirteen patients with varioele who were hospitalized for spermati vein ligation for infertility; ten patients without varioeles who had either normal sperm ounts or had previously fathered hildren and who were hospitalized for

2 Vol. 26, No. 1 PITUITARY AND GONADAL HORMONES IN VARICOCELE 17 hernia repair; three patients undergoing misellaneous srotal surgery for nonreprodutive problems (one with phlebolith, one with hydroele, one with hypermotile testes); and five patients about to undergo a testis biopsy for idiopathi infertility. Informed onsent was obtained from all patients, and the following tests were performed. Hormone Measurements. Peripheral and spermati vein LH, FSH, testosterone, and 17 -estradiol were measured in all subjets. Four separate peripheral vein blood samples were obtained from eah man at least lh hour apart on the day before surgery. No patient was reeiving any mediation known to alter reprodutive hormonal responses. A single spermati vein blood sample was obtained from eah patient at the time of surgery. In patients undergoing high spermati vein ligation and those undergoing herniorrhaphy, blood samples were obtained from the internal spermati vein just above or below the internal inguinal ring. Blood was sampled from the pampiniform plexus in those undergoing misellaneous srotal surgery or testis biopsy for idiopathi infertility. The blood samples were allowed to lot at room temperature for 1 hour and entrifuged in the old; the serum was separated and kept frozen at - 2 C until assayed. LH and FSH were determined by radioimmunoassay, using the methods of Odell et al Serum testosterone and estradiol levels were determined by radioimmunoassay of samples extrated with diethyl ether and separated by Celite hromatography. The speifiity of the method for testosterone 21 and for estradiol has been previously desribed. 22 The four peripheral serum samples obtained from eah patient were assayed separately. The mean onentration of the four samples in eah subjet was used in the alulation of group data. Spermati vein serum hormone onentrations were determined on a single sample from eah subjet. Testis Biopsy. Testis biopsy speimens were obtained from 17 subjets: 9 of the 13 men with varioeles, 5 of the 5 men with idiopathi infertility, and 3 of the 3 men with misellaneous srotal surgery. The speimens were fixed with Tehnion, washed in alohol, stained with hematoxylin and eosin, and examined by light mirosopy. Semen Analysis. Semen analysis was performed on two or three oasions on all patients in the varioele and idiopathi infertility groups. Neither testis biopsy nor semen analysis was performed on the hernia ontrol and the misellaneous srotal surgery patients. RESULTS Semen Analysis (Table 1) Varioele Group. Sperm ounts were greater than 4 millionlml in three patients (7, 55, and 55 millionlml); two patients ht.d sperm ounts between 2 and 4 million/ml; two patients had sperm ounts between 1 and 2 millionlml; six patients had less than 1 million sperm/ml; and no patients were azoospermi. Two patients had greater than 3% abnormal forms (immature and tapered). Ten of the thirteen patients had fewer than 6% motile sperm. One subjet had TABLE 1. Semen Analysis (18 Patients) Spenn ount Inreased abnormal Impaired Group forms motility > <1 Azoospermia (>3%) «6%) millionlml Varioele (13) Infertility (5)

3 18 SWERDLOFF AND WALSH Otober 1975 TABLE 2. Testis Biopsy (17 Patients) No. of Group Biopsy finding patients Varioele (9) Nonnal 3 Genninal hypoplasia 3 Tubular hyalinization 3 Idiopathi Nonnal 1 infertility (5) Sertoli ells only 2 Maturation arrest 1 Hypospennatogenesis 1 Srotal surgery Nonnal 3 ontrol (3) a normal spermiogram on one oasion and had had dereased sperm motility on two previous semen analyses. Idiopathi Infertility Group. Of the five idiopathi infertility patients, three were azoospermi, one had a sperm ount less than 1 million/ml, and one had a sperm ount between 1 and 2 million/ml. One of the two patients with oligospermia had assoiated abnormal sperm forms and impaired sperm motility. Testis Biopsies (Table 2) Varioele Group. Testis biopsies were performed on the side of the venous abnormality in 9 of the 13 varioele patients (1 patient had bilateral varioeles, and the left testis was biopsied). Three had normal-appearing biopsies, three had germinal hypoplasia, and three had tubular hyalinization. Idiopathi Infertility Group. One biopsy appeared normal; only Sertoli ells were present in two; one had maturation arrest; and one had hypospermatogenesis. Srotal Surgery Group. All three patients had normal testis biopsies. Hormone Measurements Peripheral vein serum LH and FSH onentrations are depited in Figure 1. In Figure 1, the ontrol group inludes the 1 patients hospitalized for hernia repair and the 3 patients undergoing srotal surgery for nontestiular disease. These two subgroups of patients were ombined, sine the peripheral serum values 2 E ::;:) E :z: 1...J :I ::;:) III 5 2 CONTROl. 13 VARICOCELE 13 INFERTIUTY 5 o,---l---l FIG 1. Serum LH and FSH onentrations in varioele and idiopathi infertility. Values were not statistially different in the three study groups. The ontrol group onsisted of 1 patients being operated on for hernia and the 3 patients operated on for nontestiular srotal disorders. E 8 g <;; 6 E....,. <>. g «... UI IIJ :I 2 ::;:) IIJ UI CONTROL VARICOCELE INFERTILITY o FIG. 2. Peripheral serum testosterone and estradiol levels were similar in the ontrol, varioele, and idiopathi infertility groups.

4 Vol. 26, No. 1 PITUITARY AND GONADAL HORMONES IN VARICOCELE SPERMATIC VEIN AT INGUINAL CANAL SPERMATIC VEIN AT PAMPINIFORM PLEXUS CONTROL VARICOCELE CONTROL INFERTILITY SCROTAL SUM. 3 II Z Iii Iii CONTROL VARICOCELE CONTROL INFERTILITY 12 8 J. 4 U)... E 2 15!::: I en 5 o... ::.: FIG. 3. Spermati vein testosterone and estradiol onentrations were not abnormal in varioele patients, ompared with those of ontrol subjets in whom blood was sampled at Ii similar loation (internal spermati vein at the inguinal ligament level). Likewise, those patients with idiopathi infertility had spermati vein testosterohe and estradiol onentrations similar to those of ontrol subjets in whom the blood was sampled from the pampiniform plexus. The shaded area above the ontrol bar represents spermati vein serum testosterone data obtained from the literature. The peripheral vein testosterone and estradiol levels are plotted (dotted line) aross the bottom of eah bar. for LH, FSH, testosterone, and estradiol were the same in both subgroups of patients. These data do not indiate any signifiant differenes in serum LH and FSH onentrations in any of the groups (ontrol, varioele, and idiopathi infertility). The large standard error for the FSH values in the idiopathi infertility group is due to elevated FSH levels in the two subjets with Sertoli ell only syndrome. Serum testosterone and estradiol onentrations for eah study group are shown in Figure 2. There were no signifiant differenes in peripheral serum testosterone and estradiol levels in the three groups. Spermati vein testosterone and estradiol onentrations are plotted in Figure on FIG. 4. The ratio of spermati vein to peripheral vein (J3CIPV) testosterone and estradiol for the four groups desribed in Figure 3. Neither the varioele nor the idiopathi infertility groups differed from their appropriate ontrol group. 3. There were no signifiant differenes in spermati vein testosterone levels in the varioele group when ompared with the hernia ontrol subjets. (Samples from these two groups were olleted from the spermati vein, just above or below the internal inguinal ring.) Spermati vein blood samples from the srotal surgery group and the idiopathi infertility group were olleted from the pampiniform plexus. The latter two groups had spermati vein serum testosterone levels lower than the two previous groups but not different from eah other. Spermati vein estradiol levels had a similar but less striking relationship in the four groups; the onentration of spermati vein estradiol in varioele patients was not different from that of the ontrol group. In all ases, spermati vein testosterone and estradiol onentrations were onsiderably higher than peripheral vein steroid onentrations. The spermati vein to peripheral vein ratios were the same in the varioele and hernia ontrol groups, and the same in the idiopathi infertility and the srotal surgery groups (Fig. 4).

5 11 SWERDLOFF AND WALSH Otober 1975 E... g...j Q I- m z iii > u 2 f=.. ::I! a: 55 1 D VARICOCELE o JDtOPATHIC.6. CONTROL HERNIA 6,5' C.. C C 6 L./ SOO SPERMATIC VEIN TESTOSTERONE "g/ml FIG. 5. The relationship between spennati vein testosterone and estradiol onentrations in all subjets is plotted. There was a strong orrelation between the onentrations of the two honnones. Figure 5 desribes the relationship between spermati vein estradiol and testosterone levels in the individual subjets. The strong orrelation is obvious (r =.782), indiating a fairly onstant relationship in the seretion of the two hormones from the testes. DISCUSSION Varioeles are one of the most ommonly identifiable linial situations assoiated with infertility. Dubin and Amelarl3 found varioeles in 39% of their series of 1294 onseutive ases of male infertility. This figure would appear to be between 2 and 5 times the inidene of varioele in the general young male population. I -6 It is unlear whether the above finding of a 39% inidene of varioele in infertile men is representative of the male subfertile population as a whole or is biased beause of the authors' reognized interest in this problem. The latter would appear to be a likely possibility. The ausal relationship between varioeles and infertility has been suggested by the observations of several investigators that spermiograms often improve after internal spermati vein ligation9-13 and that the postsurgial pregnany rate seems to be greater than that antiipated without surgery.12, 13 Unfortunately, none of these studies has been adequately ontrolled, and, in the present study, semen analyses were not obtained following spermati vein ligation. Spermatogenesis is hormonally ontrolled. Both FSH and LH are required for initiation of spermatogenesis, but the effets of the latter hormone are probably mediated by the stimulation of inreased onentrations of intra testiular testosterone.23 Serum gonadotropin onentrations are in turn ontrolled by hormonal seretions from the testis. Both testosterone and estradiol have inhibitory feedbak effets on LH and FSH seretion. Removal of these feedbak effets, suh as ours after astration, results in inreased LH and FSH levels.24 There is general agreement that testosterone is the primary inhibitor of the seretion of LH, probably ating both at the hypothalami and pituitary levels.25,26 The seretion of FSH is also inhibited by gonadal steroids suh as testosterone, dihydrotestosterone, and estradiol. 24, 27-3 In addition, there is evidene to suggest that the spermatogeni tubules may produe a substane(s) that also ontrols the seretion of FSH. The latter onept is based on observations indiating that spermatogeni tubular abnormalities may result in isolated inreases of serum FSH.3-34 Thus, patients with idiopathi oligospermia may present with normal serum testosterone and LH onentrations but elevated serum FSH levels. Little is known about the reprodutive hormonal parameters in patients with a varioele. Rabah and Starka 18 reported in 1971 that serum testosterone levels in

6 Vol. 26, No. 1 PITUITARY AND GONADAL HORMONES IN VARICOCELE 111 a group of men with varioeles were lower than those in a ontrolled group of normally fertile men. In their study, serum testosterone levels were measured by using the protein-binding method of Horton et aj.35 While these authors found a signifiant differene between the two groups, it is somewhat surprising that the peripheral serum testosterone levels in their ontrol group were onsiderably higher than those reported by other authors. To our knowledge, no previous data are available on gonadotropin levels in patients with variooeles. The present study fails to demonstrate abnormalities in the peripheral venous LH, FSH, testosterone, or estradiol levels in patients with variooeles. In order to assess gonadal seretion of sex steroids more diretly, spermati vein testosterone and estradiol onentrations were also measured in all subjets. No differenes were found between the steroid onentrations from the spermati veins of those subjets with varioeles and the ontrol patients in whom the blood samples were taken from the same anatomial loation. In the present study, testosterone onentrations in spermati vein blood samples obtained from or near the inguinalligament were similar to those reported earlier by other authors The observation that spermati vein testosterone levels were lower in the small group of ontrol patients (srotal surgery) in whih blood was sampled from the pampiniform plexus (rather than from the spermati vein near the inguinal ligament) was surprising to us. Sine these same patients had normal peripheral testosterone onentrations, it seemed unlikely that they were sereting less hormone from the testis than the other ontrol subjets. The explanation for the differene in onentration is unlear but may be related to inreased shunting of blood from nontestiular soures produed by the aspiration of blood from an area of low blood flow (pampiniform plexus). Five additional patients with idiopathi infertility were studied. Peripheral serum LH, testosterone, and estradiol levels were normal in these subjets. Serum FSH levels were elevated in two patients with oligospermia. The spermati vein testosterone and estradiol levels were not different from those of the ontrol group in whom samples were obtained from the same anatomial level of spermati vein. SUMMARY Peripheral vein luteinizing hormone, follile-stimulating hormone, testosterone, and estradiol, and spermati vein testosterone and estradiol levels were determined in 13 subfertile men with linially diagnosed varioeles, 5 patients with idiopathi infertility, and 13 ontrol patients. Testis biopsies and semen analyses were also performed on most of the infertile patients and some of the ontrols. Seretion of both gonadal steroids and pituitary gonadotropins was normal in the subfertile men with varioeles. It appears likely that mehanisms other than abnormal reprodutive hormonal fators are responsible for the altered spermiograms and dereased fertility of suh patients. REFERENCES 1. Johnson DE, Pohl DR, Rivera-Correa H: Varioele: an innouous ondition? South Med J 63:34, Oster J: Varioele in hildren and adolesents. Sand J Urol Nephrol 5:27, Lewis EL: The Ivanissevith operation. J Urol 63:165, Clark BG: The inidene of varioele in normal men and among men of different age. JAMA 198:1121, Appleby GS: Variooeles, a problem in military personnel. W Va Med J 51:76, Brodny NL, Robins SA, Hershman HA, De Nuio A: Epididymography, varioeleography and testiular angiography: their uses in the study of the infertile male. Fertil Steril 6:158, MaLeod J: Seminal ytology in the presene of varioele. Fertil Steril 16:735, 1965

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