Pulsatile gonadotrophin releasing hormone versus gonadotrophin treatment of hypothalamic hypogonadism in males

Human Reproduction vol.8 Suppl.2 pp. 175-179, 1993 Pulsatile gonadotrophin releasing hormone versus gonadotrophin treatment of hypothalamic hypogonadism in males Jochen Schopohl Medizinische Klinik, Klinikum Innenstadt, Ziemssenstrasse 1, D-80336 Munchen 2, Germany In this study, pulsatile gonadotrophin releasing hormone () and gonadotrophin were compared for male patients with idiopathic hypothalamic hypogonadism. Thirty-six patients, 19 with this condition, and 17 with Kallmann's syndrome, were included in the study. Their mean age was 21.1 ± 3.0 years (±SD). They were divided into two groups of similar age, number and testicular volume. Pulsatile was started with 4 fig s.c. every 2 h using a portable pump and gonadotrophin with weekly i.m. injections of 3 x 2500 IU human chorionic gonadotrophin (HCG). After 8-12 weeks of HCG treatment, 150 IU human menopausal gonadotrophin (HMG) 2-4 times weekly were added and the dose of HCG reduced if necessary. Testosterone concentrations increased significantly more (P < 0.03) in the gonadotrophin group than in the group (22.5 ± 8.1 versus 16.8 ± 5.5 nmol/1). The rise in oestradiol levels was also significantly higher (P < 0.001) in the gonadotrophin group than in the group (150 ± 70 versus 88 ± 59 pmol/1). Five patients developed gynaecomastia during gonadotrophin. An increased testicular volume (TV) occurred more rapidly (P < 0.001) and was significantly more pronounced (P < 0.001) after (ATV = 8.1 ± 2.0 ml) than with gonadotrophins (ATV = 4.8 ± 1.8 ml). Sperm counts were performed in 14 patients given and in 17 patients given gonadotrophins. Ten patients given had positive sperm counts, ranging from 1.5 to 14 x 10 6 spermatozoa/ml; eight of those given gonadotrophins also developed spermatogenesis (2-26 x 10 6 /ml). The mean time period until spermatogenesis started was significantly shorter (P < 0.02) with than with gonadotrophins (12 ± 1.6 versus 20 ± 2.3 months). These results show how endocrine and exocrine testicular function can be normalized by both forms of. However, gonadotrophin has more sideeffects. Testicular growth is more pronounced with, and this also initiates spermatogenesis more rapidly than gonadotrophin. Key words: gonadotrophin//hypothalamic hypogonadism/ male/ Introduction The treatment of male idiopathic hypothalamic hypogonadism with gonadotrophins leads to good results, especially for the induction of spermatogenesis in a large number of patients (Finkel etal., 1985; Ley and Leonard, 1985; Burris etal., 1988a). Pulsatile gonadotrophin releasing hormone () can also initiate puberty and achieve spermatogenesis in these patients (Hoffman and Crowley, 1982; Morris et al., 1984; Spratt, 1986). Both forms of are effective in the treatment of male idiopathic hypothalamic hypogonadism, but only a few comparative reports exist on their respective clinical value (Liu etal., 1988a,b; Schopohl etal., 1991). The two former studies identified no difference in endocrine or exocrine testicular function after gonadotrophin or, whereas Schopohl et al. (1991) reported that had a considerable advantage over the use of gonadotrophins. The results of the latter study are described in detail here and compared with data in the literature. Materials and methods Patients Eighteen patients were treated with, 10 with idiopathic hypothalamic hypogonadism and eight with Kallmann's syndrome, for 9.3 ± 1.4 months. Their mean (± SD) age at the beginning of was 21.1 ± 3.0 years, and their mean testicular volume was 3.0 ± 2.3 ml. Four patients had previously had orchidopexy because of unilateral cryptorchism. Their mean testosterone concentrations were 1.3 ± 0.6 nmol/1. Their basal and stimulated luteinizing hormone (LH) concentrations were 3.0 ± 1.0 and 12.2 ± 7.8 IU/1, respectively, and basal and stimulated concentrations of follicle stimulating hormone (FSH) were 1.2 ± 0.3 and 2.9 ± 1.9 IU/1. Eighteen patients were treated with gonadotrophins, nine with idiopathic hypothalamic hypogonadism and nine with Kallmann's syndrome, for 14.4 ± 7.3 months. Their mean age at the beginning of was 23.6 ± 7.3 years, and their mean testicular volume was 3.6 ± 3.0 ml. Five patients had previously had orchidopexy because of unilateral cryptorchism. Their mean concentrations of testosterone were 1.2 ± 0.8 nmol/1, basal and stimulated LH 2.2 ± 1.1 and 8.2 ±5.1 IU/1 respectively, and basal and stimulated FSH 1.2 ± 0.7 and 2.3 ± 1.0 IU/1 (Schopohl etal., 1991). was performed with a Zyclomat pump or a BT 2 pump (Ferring, Kiel, Germany) as described previously (Schopohl et al., 1991). Therapy was started with 4 jtg /bolus and dosage was increased stepwise up to 16 /tg /bolus if no pituitary response was seen. Gonadotrophin was started with 3 X 2500 IU human chorionic gonadotrophin (HCG) per week i.m. The HCG dose Oxford University Press 175

J.Schopohl 3-18 months n=16 Gonadotrophins 6-27 months n=18 before on before Fig. 1. Testosterone values before and during in each patient of the gonadotrophin releasing hormone ()- and gonadotrophintreated groups. Values before are the mean of two samples, and values on are the means of the last three testosterone values taken during. The shaded area represents the normal range. Closed circles represent the mean value (±SD) in each group. The increase in testosterone was significantly higher with gonadotrophins (P < 0.03). was reduced if oestradiol or testosterone concentrations increased supraphysiologically. The minimal HCG dose needed for maintaining testosterone concentrations within the normal range was 2 X 1000 IU/week. After 2 or 3 months of treatment, 2 x 150 IU weekly doses of human menopausal gonadotrophin (HMG) were added. The HMG dosage was increased up to three and four times per week if testicular growth and the development of sperm count were unsatisfactory. Results Testosterone Concentrations of testosterone increased in all patients of both groups, except in two of them in the group. The mean concentration of testosterone during gonadotrophin was significantly higher (P < 0.03) than during treatment (22.5 ± 8. 1 versus 16.8 ± 5.5 nmol/1). Three patients in the group had values of testosterone between 10.5 and 12 nmol/1, and remained slightly below the normal range (Figure 1). In two patients in the group, no increase in testosterone was observed, due to insufficient compliance, and this was proven by carefully testing pituitary and testicular responses. For this reason, the two patients were excluded from statistical analysis. In the group, testosterone remained in the range seen by Spratt et al. (1986), by whom 22 patients were treated successfully. Mean levels of this steroid in the upper normal range during gonadotrophin were reported by Finkel et al. (1985), Burris et al. (1988b) and Liu et al. (1988a). on Oestradiol An increase in oestradiol concentrations was observed during both treatments (Figure 2). treatment raised the mean value only slightly from 46 ± 22 to 88 ± 59 pmol/1, whereas the increase invoked by the gonadotrophin treatment was significantly more pronounced (P < 0.0005) and rose from 41 ± 11 to 179 ± 102 pmol/1, when the highest oestradiol concentrations during this treatment were compared. Oestradiol concentrations were still significantly higher (P < 0.001) after a reduction in the HCG dose (41 ± 11 to 150 ± 70 pmol/1). Only one patient had a supraphysiological oestradiol value of 292 pmol/1 during. No patient of the group developed gynaecomastia, whereas with gonadotrophins eight patients had an exaggerated rise in oestradiol up to 439 pmol/1 and five of them developed gynaecomastia. Elevated oestradiol concentrations persisted in six of these patients after reducing the HCG dosage (Figure 2), and further reduction normalized this steroid but led to a decrease of testosterone to <7 nmol/1. Gynaecomastia improved and oestradiol concentrations declined, but disappeared only when these levels were normalized. Levels of testosterone were > 35 nmol/1 in all patients during the time period involving the highest concentration levels of oestradiol. There are limited amounts of data on changes in oestradiol during in men. Liu et al. (1988a) observed a supraphysiological increase in two out of five patients after 12 months of using a median dose of 30 fig /pulse, which also led to elevated LH levels that were probably responsible for the elevated oestradiol. Spratt et al. 176

550 3-18 months n = 16 Highest increase Treatment of hypothalamic hypogonadism in males Gonadotrophins After dose reduction 6-27 months n=18 before before on before on Fig. 2. Oestradiol levels before and on from each patient on gonadotrophin releasing hormone () and on gonadotrophin. Values before are the means of two samples. Values in the middle section represent the highest levels of each patient in the gonadotrophin group during. Values during in the left and right sections respectively are the means of the last three concentrations of oestradiol obtained during the of each patient in the and gonadotrophin groups. The shaded area represents the normal range. Closed circles are the mean value in each group (±SD). The increase in oestradiol was significantly higher with gonadotrophins (P < 0.001). Two patients with lack of compliance (Schopohl etal., 1991). 0) E vol lar 3.O CO 12" 10 8 6 3-18 months n = 16 (n) patients Gonadotrophins 6-27 months n = 18 r12 10 - h8 1 6.i *o Qi V) «J ere 4 2 (0-2 fe L o before on before on Fig. 3. Individual increases in testicular volume of each patient of both groups. Numbers in parentheses give patients with the indicated testicular increase. Testicular increase was significantly higher in the gonadotrophin releasing hormone () group (P < 0.001). Two patients with lack of compliance (Schopohl et al., 1991). 177

J.Scbopohl 1.5 16., o E 1.0-0.5" O O 12. 2 8. u «4. '5 CO 0" 6 9 Months 12 15 Fig. 4. Monthly testicular growth (ATV/month) in the patients treated with gonadotrophin releasing hormone () and gonadotrophins (Gn). The numbers above the curve and below the gonadotrophin curve represent the number of patients treated at the indicated time points. Testicular growth occurred significantly faster in the group. (1986) described a small increase, not exceeding the normal range in any patient. In three out of 11 patients treated with gonadotrophins, Liu et al. (1988a) described elevated concentrations of oestradiol in some men, although mean levels were only slightly elevated when compared to the five patients treated with. Bums et al. (1988b) observed supraphysiological oestradiol concentrations in seven out of 22 patients treated with HCG. The cause of the higher oestradiol and testosterone concentrations during gonadotrophin is probably testicular overstimulation. This might be an equivalent to the ovarian overstimulation that is observed in women after gonadotrophin, although it has less clinical importance in men than in women. Testicular volume and testicular growth Testicular size increased significantly in both groups (Figure 3). The increase of testicular volume in the -treated patients (the mean increase was 8.1 ± 2.0 ml) was significantly higher (P < 0.001) than in patients treated with gonadotrophins (mean increase of 4.8 ± 1.8 ml) (Figure 3). With, an increase in testicular volume of 8 ml or more occurred in ten patients, whereas only one patient given gonadotrophin showed an enlargement of 8 ml. All others had smaller increases in testicular size (Figure 3). Similar increases of testicular growth were reported by Spratt et al. (1986) after treatment, and by Ley and Leonard (1985) and Burns et al. (1988b) after gonadotrophin treatment. Liu et al. (1988b) observed an important further rise in testicular growth in four patients previously treated with gonadotrophins. In another report, Liu et al. (1988a) reported no significant difference in testicular volume after or gonadotrophins after 2 years of treatment; this was probably due to lack of compliance in some patients given. The testes grew more rapidly during the first 6 months of. During, the growth rate was maximal in the second month of treatment, at 1.5 ± 0.9 ml per month, 178 I 12j "o 8. o «(0 'I. 2 4 8 10 12 Gonadotrophin 2 4 6 8 10 Initial testicular volume (ml) Fig. 5. Correlation of the initial testicular volume and maximal testicular volume during (above) and gonadotrophin treatment (below). 100-, Vo 80-60- 40-20- (n=14) Gonadotrophins (n = 17) 9 12 15 18 21 24 27 Fig. 6. Percentage of positive sperm counts during treatment. The mean time to the initiation of spermatogenesis was significantly shorter (P < 0.02) in the gonadotrophin releasing hormone () group as compared to the gonadotrophin group (12 ± 1.6 versus 20 ± 2.3 months) (Schopohl et al., 1991). 12

and in the fourth month of gonadotrophin treatment at 0.7 ± 0.5 ml per month (Figure 4). Comparisons of growth rates over 15 months showed a significantly faster growth in the group (P < 0.001). Significant correlations were found between the initial testicular volume and the maximal testicular volume in both groups. The correlation coefficient in the group was 0.65 (P < 0.01) and in the gonadotrophin group 0.82 (P < 0.001) (Figure 5). This observation confirms the findings of Spratt et al. (1986) and Burris et al. (1988b). Sperm count Sperm counts were performed in 14 patients of the group and in 17 patients of the gonadotrophin group. During pulsatile, sperm counts ranging from 1.5 to 14 X 10 6 spermatozoa/ml were achieved after 9.7 ± 5.6 months (range 4 18 months) in ten patients (71 %). During gonadotrophin treatment, eight patients (47%) reached a positive sperm count ranging from 2 to 26 x 10 6 /ml after 14.9 ± 7.2 months (range 4-27 months). No correlation was found between the elevated concentrations of oestradiol and a failure to induce spermatogenesis. Spratt et al. (1986) reported sperm counts > 1 X 10 6 /ml in 55 % of their patients treated with, with a treatment period ranging from 4 to 21 months (mean 16 ± 2.7 months). In addition, the remaining 45% of patients had sperm counts of < 1 X 10 6 /ml with a period of ranging from 4 to 33 months. Only 42% of their patients with a pre-therapeutic testicular volume of < 3 ml had sperm counts >1 X 10 6 /ml. Burris et al. (1988b) reported positive sperm counts in 68% of their HCG-treated patients, but only 32% had sperm values > 1 X 10 6 /ml; the duration of treatment ranged from 6 to 78 months (mean 20.1 ± 4.4 months). None of their patients with a pre-therapeutic testicular volume of < 3 ml achieved sperm counts of > 1 X 10 6 /ml. However, this limit may be arbitrary because the same authors published data (Burris et al., 1988a) showing that sperm counts had been < 1 x 10 6 /ml in 16% of men who later succeeded in establishing pregnancy. Ley and Leonard (1985) observed positive sperm counts in seven out of eight patients, of whom only one had a pre-therapeutic testicular volume >3 ml. In five patients, sperm counts were > 1 x 10 6 /ml with a period of ranging from 5 to 24 months (mean 13.6 ± 1.8 months). The mean duration of treatment until positive sperm counts were achieved was 12 ± 1.6 months for -treated patients, and 20 ± 2.3 months in those given gonadotrophins; this difference was significant (P < 0.02) (Figure 6). In the group, seven out of 10 (70%) patients with an initial testicular volume <3 ml had a positive sperm count, whereas only three out of 10 (30%) given gonadotrophins had evidence of spermatogenesis. The mean time until the development of a positive sperm count was 13.5 ± 1.8 (±SE) months in the group and 25.8 ± 0.8 months in the gonadotrophin group (P < 0.001). Two patients achieved pregnancy with their spouses, and two children were delivered. In the other patients, pregnancy was not a desired goal at the time of. Liu et al. (1988a) did not observe a more rapid initiation of spermatogenesis during when compared with gonadotrophin treatment. This observation may have arisen due Treatment of hypothalamic hypogonadism in males to the small number of patients treated with for > 1 year (four patients), and due to a significant age difference between their and gonadotrophin-treated patients. Conclusion produces a more rapid initiation of spermatogenesis than gonadotrophin treatment, especially in patients with a testicular volume of 3 ml or less before. No differences occurred in induction of spermatogenesis using either form of. does not lead to elevated concentrations of oestradiol and gynaecomastia, which are frequently observed during gonadotrophin. Patients treated with require good compliance and technical understanding, because they have to manage most of the technical part of the by themselves. This is not necessary when patients are treated with gonadotrophins. Gonadotrophin remains therefore an effective alternative treatment when patients with idiopathic hypothalamic hypogonadism are not able or willing to carry an infusion pump for a year or more. References Burris,A.S., Clark,R.V., Vantman,D.J. and Sherins.R.J. (1988a) A low sperm concentration does not preclude fertility in men with isolated hypogonadotropic hypogonadism after gonadotropin. Fertil. Steril., 50, 343-347. Burris,A.S., Rodbard,J.W., Winters,S.J. and Sherins,R.J. (1988b) Gonadotropic in men with isolated hypogonadotropic hypogonadism: the response to human chorionic gonadotropin is predicted by initial testicular size. J. Clin. Endocrinol. Metab., 66, 1144-1151. Finkel.D.M., Phillips,J.L. and Snyder,PJ. (1985) Stimulation of spermatogenesis by gonadotropins in men with hypogonadotropic hypogonadism. N. Engl. J. Med., 313, 651 655. Hofrrnan,A.R. and Crowley,W.F. (1982) Induction of puberty in men by long-term pulsatile administration of low-dose gonadotropinreleasing hormone. N. Engl. J. Med., 307, 1237-1241. Ley.S.B. and Leonard,J.M. (1985) Male hypogonadotropic hypogonadism: factors influencing response to human chorionic gonadotropin and human menopausal gonadotropin, including prior exogenous androgens. J. Clin. Endocrinol. Metab., 61, 746 752. Liu.L., Banks,M., Barnes,K.M. and Sherins.R.J. (1988a) Two-year comparison of testicular responses to pulsatile gonadotropin-releasing hormone and exogenous gonadotropins from the inception of in men with isolated hypo-gonadotropic hypogonadism. J. Clin. Endocrinol. Metab., 67, 1140-1145. Liu,L., Chaudhari.N., Corle.D. and Sherins,R.J. (1988b) Comparison of pulsatile subcutaneous gonadotropin-releasing hormone and exogenous gonadotropins in the treatment of men with isolated hypogonadotropic hypogonadism. Fertil. Steril, 49, 302 306. Morris,D.V., Adeniyi-Jones,R., Wheeler,M., Sonksen.P. and Jacobs,H.S. (1984) The treatment of hypogonadotrophic hypogonadism in men by the pulsatile infusion of luteinising hormonereleasing hormone. Clin. Endocrinol., 21, 189 200. Schopohl,J., Mehltretter,G., von Zumbusch,R., Eversmann,T. and von Werder,K. (1991) Comparison of gonadotropin-releasing hormone and gonadotropin in male patients with idiopathic hypothalamic hypogonadism. Fertil. Steril, 56, 1143-1150. Spratt,D., Finkelstein,J.S., O'Dea,L.S.L., Badger.T.M., Rao.P.N., Campbell,J.D. and Crowley.W.F. (1986) Long-term administration of gonadotropin-releasing hormone in men with idiopathic hypogonadotropic hypogonadism. Ann. Intern. Med., 105, 848 855. 179