(Acta Paediatr Jpn 1992; 34: 243

- 250)

Combined Human Chorionic GonadotrotGn (HCG) and Human Menopausal Gonaddtropin (HMG) Treatment in Gonadotropin-Deficient Males with Pituitary Dwarfism Toshiaki Tanaka, M.D., ltsuro Hibi, M.D. and Ayako Tanae, M.D. Endocrine Research Laboratory, National Children’s Medical Research Center, Division I Endocrinology & Metabolism, National Children 3 Hospital, Tokyo

The effects of hCG-hMG treatment in 13 boys with pituitary dwarfism associated with gonadotropin deficiency, were assessed. No patients except one showed signs of puberty at a bone age of 13 years or above. The one patient with some signs of puberty did not become fully mature. The hCG-hMG was started at a mean age of 20.4 years. The hCG at a dose of 5,OOOIU was injected intramuscularly twice a week and the hMG at a dose of 75 IU was given once a week at first. During treatment, the frequency of hMG injections was increased to twice a week in six patients who still had not produced normal sperm counts. After a mean duration of 19.23 months, spermatozoa appeared in eight patients, of whom four showed more than 20 X lo6 sperm/ml. Among six patients who did not have normal sperm counts and had increased hMG injections, one produced a pregnancy and four achieved sperm counts of more than 35X 106/ml. One patient had refractory azoospermia. In 13 boys with growth hormone and gonadotropin deficiency, hCG-hMG treatment produced normal spermatogenesis in nine patients, one of whom fathered a girl. Thus, hCG-hMG treatment, especially twice-a-week injections of both hCG and hMG, appears to be effective for gonadotropin deficiency in males. Key Words

Gonadotropin deficiency, Pituitary dwarfism, hCG-hMG treatment, hCG test, Spermatogenesis

Introduction It has been reported that pituitary stalk

Received November 29, 1991 Correspondence address: Toshiaki Tanaka, M.D., Endocrine Research Laboratory, National Children’s Medical Research Center, Division of Endocrinology & Metabolism, National Children’s Hospital, 3-35-3 I , Taishido, Setagaya-ku, Tokyo 154, Japan

transection is often observed by MRI in pituitary dwarfism [I, 21, and may cause other combined pituitary hormone deficiencies. Among these, gonadotropin deficiency is frequently found as well as TSH deficiency in pituitary dwarfism [3]. Male hypogonadism due to gonadtropin deficiency can be treated by replacement of testosterone, gonadotropins or LH-RH. The secondary sexual characteristics may be in-

244 (138) Tanaka el al.

duced by administered testosterone, but the induction of fertility requires stimulation by gonadotropins or LH-RH. LH-RH treatment frequently fails to increase gonadotropin levels and to induce puberty due to pituitary hypoplasia or down-regulation of gonadotropin receptors [4-81. Thus combined replacement therapy with human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG) is still the most common treatment for male hypogonadism. The effects of hCG-hMG treatment in growth hormonedeficient young men with combined gonadotropin deficiency were studied. After treatment at least 70% of patients achieved normal spermatogenesis.

Subjects and Methods The subjects were 13 growth hormonedeficient young men with combined gonadotropin deficiency. All except one were born by breech delivery. The results of growth hormone provocation tests in these patients are summarized in Table 1. In six patients, stanazolol had been administered to differentiate gonadotropin deficiency from delayed puberty, but it did not induce puberty. The diagnosis of gonadotropin deficiency

was based on the clinical findings, namely, that the secondary sexual characteristics had not developed by a bone age of thirteen years, except in one patient (Table 1). This patient (No. 9) was of short stature and had developed secondary sexual characteristics with incresed testosterone levels at nine years six months, when gonadal suppression treatment had been given for four years. One year after the cessation of this treatment, he had not developed further pubertal signs and was diagnosed as having partial gonadotropin deficiency. Before hCG-hMG treatment, four patients were treated with testosterone enanthate by intramuscular injection and one patient was unsuccessfully treated with an LH-RH pump. The hCG-hMG was started after an interval of at least one month after these pretreatments. The hCG-hMG was started at a mean age of 20.4 years (Table 2). At first, hCG was given at a dose of 5,000 IU twice a week and hMG 75IU once a week. During treatment, nine patients who did not achieve a normal sperm count were switched to hCG 5,000 IU twice a week and hMG 75 1U twice a week. All patients recieved hCG and LH-RH

Table I . Clinical profile of G H D patients with GND

G H peak (ng ml)



*TT L-Dopa ITT


I 2 3 4 5 6

7 8 9 10 II

I? 13

breech breech breech breech breech breech breech

3.0 1.6 0.9 1.0 1.0

breech breech

2.5 4.0 1.3 0.2 0.7

* GND: Gonadotropin


I .4 2.8


breech breech breech cephalic

1.4 2.5



4.4 2.5 I .6 5.1 3.0 1.3


2.2 1.7

0.5 0.3 1.5

Diagnosis of GND* CA BA Tanner T*** (years) (years) stage (ngidl)

16.5 13.5 19.3 14.0 19.8 14.5 18.8 13.9 20.2 > 14.0 17.5 14.0 21.4 14.0 18.0 >14.0 21.5 >14.0 18.5 13.3 19.7 14.5 18.0



deficiency, ** G-P: Glucagon-propranolol test,




27.5 22 31 23 28 26 25 31 43.8 32 20 22 21

Induction or pretreatment Stanazolol Stanazolol

Testosterone enanthate Testosterone enanthate Testosterone enanthate Stanazolol 'Testosterone enanthate Stanazolol, LH-RH pump Stanazolol

*** T: Testosterone.

Acta Paediatr Jpn

HCG- HMG in gonadotropin-deficient pituitary dwarfism (1 39) 245 Table 2. hCGjhMG treatment in GHD males with GND Case No.

CA at start of hCG-hMG (years)

Duration (months)

16.4 19.9 20.2 18.8 25.0 17.7 28.9 18.0 21.5 20.0 20.2 18.0 20.6

16 19 30 33 27 30 27 10 6 14 II 10 17


2 3 4 5

6 7 8 9 I0 I1 12 13 *: biopsy,

**: not done, ***: (

12-15 15 12 15 12 12


7 8

9 10 I1 12 13

50 192 70 1 I6 62 63 72 231 89 98.8 33 I 211 256 181 23

11.1 15.1

356 193

4 (25)

18 15

4,450 1,500 623

54 82 38

pregnancy I 38 ND 9 0

16 0.2 32 36 48

2 (29) 4 (36)


1,930 1,060 2,300 706 I .OoO

17 0 0 0 0

2 (62) 8 (18) 3 (9) 6 (20) 2 (13)


ND** 1,622 2,324 ND** 906

12 15

900 1,940

10 (58)








full* maturation


) total treatment period with hCG-hMG.


LH-RH test

CA* Peak T** CA* Peak LH Peak FSH (years) (mg/dl) (years) (mlU/ml) (mlUjml)

6.0 12.7 12.2 8.2 16.0 10.0 17.5 20.0 7.5 19.0 21.5 10.9 8.1 19.7 9.6


1,437 880 1,462 526 1,380

7 13

hCG test NO.

+ hMG 75U X 2/ w

Testis Testosterone Sperm Duration*** Testis Testosterone Sperm (ml) (ng/dl) ( X 106/ml) (months) (ml) (ng/dl) ( X 10h/ml)

Table 3. hCG test and LH-RH test in GHD males with GND Case

hCG 5,OOOU X 2/ w

hCG 5.000UX2/w+hMG 75UXI/w

6.0 5.3 12.2 6.0 11.3 9.9 17.5 16.5 7.5

11.0 9.0 11.4 3.8 26.0 18.3 4.6 5.0 6.4

11.5 8.0 9.8 1.1 17.0 6.9 1.3 10.0 I .3

6.2 10.9 7.9 19.7 9.6 16.9 11.3

13.2 4.7 21.5 4.9 9.8 3.6 17.5

15.2 3.7 7.6 4.0

2.3 1.9 6.2

* CA: Chronological age, ** T: Testosterone. tests during the prepubertal period (Table 3). Testosterone and gonadotropin levels were measured by radioimmunoassay.

Val. 34 No. 2 April 1992

After six to 32 weeks of hCG-hMG treatment by the first method, seven of 12 patients produced sperm and one patient achieved full sperm maturation determined by biopsy (Table 2). Of the seven patients who produced sperm, three achieved a normal sperm count (more than 2 0 X 106/ml). Thus, four patients, including one patient judged by biopsy, achieved normal spermatogenesis at the initial dosage. Testes volumes were 12 to 15ml and serum testosterone levels 526 to 1,462 ng/dl in these four patients. Nine patients who could not produce a normal sperm count at the initial dosage received the second dosage, and fathered a hCG twice a week. One of these patients recived the second dosage, and fathered a normal infant. Of the seven other patients evaluated, four achieved normal sperm counts, two were oligospermic, and one was azoospermic. One patients has not yet been evaluated (Table 2). Serum testosterone did not change significantly after doubling the frequency of hMG administration, but testis volume increased in almost all patients.

246 (140) Tanaka et al, Thus, nine of 13 patients achieved normal sperm counts with hCG-hMG treatment. The relationship between the response to hCG-hMG and the results of the hCG test and peak LH and peak FSH levels in the LH400-



RH test were examined. Fig. 1 shows the peak serum testosterone levels in the hCG tests in patients with various responses to hCG-hMG. The lines join data from the same patients. No relation was found between the responses to hCG-hMG and the hCG test findings. Figs. 2 and 3 show the peak LH and FSH levels after the LH-RH test in patients with various responses to hCG-hMG. No relation was found between the responses to treatment and the LH-RH test findings.



-0 1


E en








E 2000 w m


2 W







Q Normospermia Normospermia with with hCGZ+hMGl hCGZ+hMGZ

Oligofpermia with hCGZ+hMGZ

Azoospermia with hCGlhMG

Fig. I : hCG test in GHD males with GND before hCG hMG treatment.



A 2















LL v)

I :

r W m

x m






















Acta Paediatr Jpn

HCG-HMG in gonadotropin-ejkient pituitary dwarfism (141) 247

Discussion There are some reports of gonadotropin treatment using hCG or hMG alone in male hypogonadism [9-121. MacLeod et a1 [lo, 131 studied the effect of gonadotropins on spermatogenesis in a hypophysectomized male. It was shown that complete hypophysectomy was followed by loss of spermatogenesis down to spermatogonia. Treatment with hMG completely restored spermatogenesis, but the Leydig cells were not stimulated. The addition of hCG to the hMG produced Leydig cell function, with restoration of potency and normal ejaculates. Mancini et a1 [14] also demonstrated that hCG has a stimulating effect on the spermatogonial phase, while hMG stimulated all germinal cell phases. The addition of hCG to hMG resulted in the complete recovery of spermatogenesis, together with full development of Leydig cells, repair of Sertoli cells and disappearance of hyalinization. Thus, to obtain normal spermatogenesis, the combination of hCG and hMG is the therapy of choice [15]. There are many clinical trials [15-231 of hCG-hMG tretment in male patients with isolated hypogonadotropic hypogonadism, but the treatment protocols use different dosages and frequencies. Good results were reported by Finkel et a1 [21] with an approximately 70% success rate in hypogonadotropic hypogonadism without cryptoorchidism with hCG 2,OOOIU and hMG 75IU thrice weekly, and by Saal et a1 [22] with an approximately 67% suczess rate in hypogonadotropic hypogonadism with hCG 3,000-15,000 IU/week and hMG 225450 IU/ week. In contrast, only scanty data are available on hCG-hMG treatment in patients with GH and combined gonadotropin deficiency [24-281. The success rate for normal spermatogenesis does not reach 50% in these reports. We started with hCG 5,000 IU twice a week and hMG 75 IU once a week. Doubling the frequency of hMG administration more effectively produced normal spermatogenesis. We started with the first dosage schedule because of a shortage of hMG at that time.

VoE. 34 No. 2 April 1992

We recommend starting with the second dosage schedule to obtain early spermatogenesis. Nine out of 13 growth hormonedeficient young men with gonadotropin deficiency, approximately 70% of the patients, achieved normal spermatogenesis after hCGhMG treatment. To achieve normal sperm counts, it seems necessary to obtain normal testosterone levels and a testicular volume of more than 12ml with hCG-hMG treatment. Compared with previous reports our dose of hCG of 5,000 IU twice a week is higher. This would produce higher testosterone levels to stimulate spermatogenesis. Three of four patients who had received previous testosterone therapy achieved normal spermatogenesis by hCG-hMG treatment. Therefore it appears that previous androgen therapy does not cause irreversible testicular damage in hypogonadotropic patients. This agrees with the conclusion drawn by Ley and Leonard [23]. There was no relation between the responses to hCG-hMG treatment and hCG or LH-RH test results; neither test has predictive value for spermatogenesis with hCG-hMG treatment. References I.


3. 4.



Fujiwara I, Kikuchi K, Nishimura K et al. Transection of the pituitary stalk; Development of an ectopic posterior lobe assessed with MRI imaging. Radiology 1987; 165: 487489. Kikuchi K, Fujisawa 1, Momoi T et al. Hypothalamic-pituitary function in growth hormone-deficient patients with pituitary stalk transection. J Clin Endocrinol Metab 1988; 67: 817-823. Hibi I, Tanae A. Kouda N et al. Diagnosis and treatment in pituitary dwarfism. Clinical Endocrinology (Tokyo) 1984; 32: 9-14 (in Jpn). Mortimer CH, McNeilly AS, Fisher RA et al. Gonadotrophin-releasing hormone therapy in hypogonadal males with hypothalamic or pituitary dysfunction. Br Med J 1974; 4: 617421. Jaramillo CJ, Charro-Salgado AL. Perezinfante V et al. Clinical studies with D-Trp-luteinizing hormone-releasing hormone in men with hypogonadotropic hypogonadism. Fertil Steril 1978; 30: 430435. Zarete A, Kastin AJ. Soria J et al. Effect of synthetic luteinizing hormone releasing hormone (LH-RH) in two brothers with hypogonadotropic hypogonadism and anosmia. J Clin Enodcrinol Metab 1973; 36: 612-614.

248 ( 142) Tanaka et al. 7. Auclair C. Kelly PA. Labrie F et al. Inhibition of testicular luteinking hormone receptor level by treatment with a potent luteinizing hormonereleasing hormone agonist or human chorionic gonadotropin. Biochem Biophys Res Commun 1977: 76: 855 862. 8. Laron 2. Dickerman Z. Zeev ZE et al. Long-term elfect of D-Trp-luteini7ing hormone-releasing hormone on testicular size and luteinizing hormone, follicle-stimulating hormone. and testosterone levels in hypothalamic hypogonadotropic males. Fertil Steril 1981: 35: 328 331. 9. Gem~ellC. Kjessler B. Treatment of infertility after partial hypophysectomy with human pituitarygonadotrophins. Lancet 1964; I : 644. 10. MacLeod J. Pazianos A. Ray BS. Restoration of human spermatogenesis by menopausal gonadotrophins. Lancet 1964; 1: 1196. 1 1 . Gulizia S et al. Abnormal germinal exfoliation in semen of hypogonadotropic patients during an hCG treatment. Andrologia 1980: 13: 7477. 12. Luboshitzky R. Dickstein G, Barzilai D. Induction of spermatogenesis in isolated hypogonadotropic hypogonadism with exogenous human chorionic gonadotropin. J Endocrinol Invest 1981; 4: 217-219. 13. MacLeod J, Pazianos A, Ray BS. The relation of human spermatogenesis and of the reproductive tract with urinary gonadotropins following hypophysectomy. Fertil Steril 1966; 17: 7. 14. Mancini RE, Seiguer AC, Lloret AP. Effect of gonadotropins on the recovery of spermatogenesis in hypophysectomized patients. J CIin Endocr 1969; 29: 467478. 15. Johnsen SG. A study of human testicular function by the use of human menopausal gonadotrophin and chorionic gonadotrophin in male hypogonadotrophic eunuchoidism and infantilism. Acta Endocrinol 1966: 53: 315~-341. 16. Schirren C. Heinenberg H-D. Control observations on andrological patients treated with HCG' HMG under special reference to spermatogram and somatic development. Andrologia 1981: 13: 198 206. 17. Okuyama A, Nakamura M. Aono T et al. Testicular responsiveness to long-tcrm administration of hCG and h M C in patients with hypogonadotrophic hypogonadism. Hormone Res 1986: 23: 21-30. 18. lsurugi K. Effect of hCGihMG combination therapy in patients with male hypogonadism due to








26 27


gonadotropin deficiency. Jap J Fert Ster 1983; 28: 189--196(in Jpn). Furukawa M, Ohashi T. Ohashi Y et al. Clinical studies on hCG-hMG therapy for male patients with hypogonadotropic hypogonadism. Nishi Nihon Hinyouki Gakkai Zasshi 1987; 49: 1321-1326 (in Jpn). Mizutani M, Moriyama H, Sanda N et al. Combined administration of human chorionic gonadotropin and human menopausal gonadotropin to idiopathic male infertility. Hinyou Kiyou 1987: 33: 51 -54 (in Jpn). Finkel DM, Phillips JL. Snyder PJ. Stimulation of spermatogenesis by gonadotropins in men with hypogonadotropic hypogonadism. N Eng J Med 1985; 313: 651-655. Saal W. Happ J. Cordes U et al. Subcutaneous gonadotropin therapy in male patients with hypogonadotropic hypogonadism. Fertil Steril 1991; 56: 3 19-324. Ley SB. Leonard JM. Male hypogonadotropic hypogonadism: Factors influencing response to human chorionic gonadotropin and human menopausal gonadotropin, including prior exogenous androgens. J Clin Endocrinol Metab 1985; 61: 746752. Miwa K, Tsukidate K, Mori 0. Gonadotropin therapy in pituitary dwarfism with hypogonadotropic hypogonadism. J J a p Pediatr SOC 1983; 87: 1692I702 (in Jpn). Ogawa M, Mori 0, Kamijo T et al. Successful induction of spermatogenesis by HCG-HMG therapy in pituitary dwarfism with gonadotropin deficiency. Clin Endocrinol (Tokyo) 1990; 38: 135-141 (in Jpn). Ishihara M. A combined therapy with HCG and HMG in nine gonadotropindeficient men. Tottori lgaku Zasshi 1981; 9: 326-334 (in Jpn). Vandeweghe M. Complete viriluation and spermatogenesis with combined HCG/HMG treatment in gonadotropin and growth-hormone deficient patients. In H. Frisch & M.O. Thorner eds: Hormonal Regulation of Growth, Serono Symposia Publications vol 58. New York, 1989. Raven Press, p283 287. Trygstad 0, Foss 1. Gonadotropins in the tratment of multiple pituitary hormone deficiency. In H. Frisch & Z. Zaron eds: Induction of Puberty in Hypopituitarism, Serono Symposia Review vol 16. Rome. 1988, Ares-Serono. p103-110.

Acta Paediatr Jpn

HCG- HMG in gonadotropin-deficient pituitary dwai$sm ( 143) 249

DISCUSSION Dr. Hibi Dr. Hasegawa from Tokyo: Did the patients you studied show a difference in initial testicular volume, and if there was a difference how did it relate to the treatment response? Dr. Hibi: Except for the patient No. 9, all patients had less than 3 ml testicular volume. However, the variation of testicular volume among them is not specifically studied. Dr. Yamanaka from Kyoto University: What was the testosterone level after treatment? I don’t know the normal variation among your subjects but I think in many of your subjects it was higher than the adult normal. You gave 5,OOOU twice a week of HCG. We use 3,OOOU HCG and its long-term use probably maintains a high testosterone level for a long time. What is the long-term effect of that high testosterone level? In order to achieve normal spermatogenesis is it important to maintain a high testosterone level for a long period of time? Dr. Hibi: I don’t have a clear answer about the testosterone level. I agree that it might too high. Whether it was a good thing in terms of the treatment outcome I don’t know. Our results were superior to other results which used a lower dosage. Until it is shown that the dose in our study is too high, I will continue to use this regimen. As you know, testosterone has a negative effect on the spermatogenesis and it is mediated by gonadotropin suppression, so if we give exogenous gonadotropin, a high testosterone level does not inhibit spermatogenesis. Dr. Yamana from Yamanashi: With your method, how long did it take to achieve the full development of secondary sex characteristics since stanozolol has been given at high doses in order to tell whether there is delayed puberty or true hypogonadal tropic hypogonadism. It was about 4mg and it was given for about six months for differential diagnosis. Dr. Hibi: We have used enanthate for four years in some other patients so because of this

Vol. 34 No. 2 April 1992

kind of intervention we could not determine how long it took for the full development of secondary characteristics. In order for the testicular volume to increase from 3cc to 15cc, it took about one year. We started with the first step method. I think it takes longer than two years. Dr. Totani from Nagoya: Out of 13 subjects, 12 were breech delivery. In the case of a female with pituitary dwarfism, breech delivery is as common as that or is there a high incidence of breech delivery just by chance? If not by chance, is it related to the intra-uterine position of the fetus, or was it caused by hypoxia during delivery? Dr. Hibi: You are a gynecologist so this question is particularly interesting for you I guess. I have reported on classical pituitary dwarfism cases, and there was an incidence of 45-7595 of breech delivery, so this is much higher than that of the general population. However, growth hormone deficiency reported now in Japan is associated with 7% of breech delivery. In other words, this is not a typical incidence in treated cases but it is typical in cases of the classical pituitary dwarfism, I think the etiology is related to birth injury due to breech delivery. 1 think there is sufficient data to support this idea but it would take a while now for me to explain the supportive data. The point is that pituitary dwarfism is the result of breech delivery because I have looked at the incidence of pituitary dwarfism in siblings and I didn’t find any, but more than 50% of the siblings had had a breech delivery and I believe that the first child in breech delivery-prone mothers tends to produce pituitary dwarfism. Another cause is probably pituitary anatomical dysgenesis and some had the canalization of the spinal cord, probably because of the breech delivery, which sometimes caused death from asphyxia, and this often causes, for example, transverse amputation of the spinal cord. Therefore I think this is also related. In any case, the incidence of breech delivery among these children is very high but only some of the babies with breech delivery develop pituitary dwarfism and the reason is not yet explained,

250 (144) Tanaka et al. but I think it is because of the angle of the head of in the uterus. A “star-gazing” baby has a hyperextented position of the head and this may predispose to pituitary dwarfism or injury to the pituitary. Dr. Totani: Thank you very much for presenting these interesting results. Basically you have used the same methodology as ours. We have given for six months the HCG and Later followed it by HCG plus HMG. 1s 3,000 units better than 5.000 units? We used 3.000U. The question as to whether this succeeds depends on the patient’s compliance. I think you have encouraged the patients by education. Dr. Hibi: During the first 2-3 months we only test the ejaculate in order to confirm the treatment response.

Dr. Totani: Do you believe that 5,OOOU are necessary? Dr. Hibi: 1 have no idea. Our dose is higher than yours but I believe by improving compliance we can ensure a comparable response even with 3,OOOU. Dr. Totani: Testicular biopsy was performed to confirm spermatogenesis in your study. Do you believe testicular biopsy is necessary? Dr. Hibi: No, my policy is not to perform biopsy but this particular patient had mental retardation and the patient did not know what masturbation was. The question was whether to teach him masturbation or to perform the biopsy. I was very hesitant in teaching him masturbation so finally I had no choice but to perform a testicular biopsy.

Acta Paediatr Jpn

Combined human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG) treatment in gonadotropin-deficient males with pituitary dwarfism.

The effects of hCG-hMG treatment in 13 boys with pituitary dwarfism associated with gonadotropin deficiency, were assessed. No patients except one sho...
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