Pulsatile luteinizing hormone-releasing hormone treatment of male hypogonadotropic hypogonadism

Pulsatile luteinizing hormone-releasing hormone treatment of male hypogonadotropic hypogonadism

FERTILITY AND STERILITY Vol. 50, No.3, September 1988 Copyright e 1988 The American Fertility Society ; ' Printed in U.S.A. Pulsatile luteinizin...

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FERTILITY AND STERILITY

Vol. 50, No.3, September 1988

Copyright e 1988 The American Fertility Society

;

'

Printed in U.S.A.

Pulsatile luteinizing hormone-releasing hormone treatment of male hypogonadotropic hypogonadism

Wolfgang Aulitzky, M.D.*t Julian Frick, M.D.*t Gunther Galvan, M.D.:j: General Hospital, Salzburg, Austria

Luteinizing hormone-releasing hormone (LH-RH) secretion from the hypothalamus follows a rhythmic pattern, inducing pulsatile luteinizing hormone (LH) and folliclestimulating hormone (FSH) secretion from the pituitary gland. Consideration of this physiologic principle led to the introduction of pulsatile LH-RH therapy via infusion pump for the treatment of different forms of hypogonadotropic hypogonadism. We report on 10 male patients, 16 to 28 years of age, suffering from idiopathic hypogonadotropic hypogonadism (IHH) including Kallman's syndrome (n = 2) and delayed puberty (n = 2). All presented with complete eunuchoidism and had undergone no treatment for their conditions during the previous 2 years. LH-RH was administered in subcutaneous pulses of 4 to 16 J.Lg, with a protable infusion pump (ZYKLOMAT, Ferring Corp., Kiel, FRG); treatment periods ranged from 6 to 24 months. With therapy, the subjects improved secretion of LH, FSH and testosterone. Testicular volumes and penis size increased; all patients developed normal secondary sexual characteristics. Spermatogenesis was induced in all patients. The time to onset of spermatogenesis ranged from 3 to 15 months. No major side effects were observed, and no patient dropped out of the study. The results indicate that pulsatile LH-RH therapy is an highly effective treatment for IHH and delayed puberty. Fertil Steril50:480, 1988

The episodic release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) in males was first reported by Nankin and Troen, 1 Boyar et al., 2 and Santen and Bardin. 3 Knobil et al. 4 were able to show that deviation from the physiologic pattern of LH-RH secretion causes dysregulation or even breakdown of gonadal function in both males and females. It was further demonstrated that the onset of puberty in boys is initiated by nocturnal LH pulses. A clear pulsatile pattern of LH and FSH secretion in healthy boys and young men is then created during sexual maturation. 5- 8 It is hypothesized that normal pulse frequency ranges from 10 to 14 pulses Received September 8, 1987; revised and accepted May 10, 1988. *Department of Urology. t Reprint requests: Wolfgang Aulitzky, M.D., Department of Urology, Salzburg General Hospital, A-5020 Salzburg, Austria. :j: Department of Nuclear Medicine.

480

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Pulsatile LH-RH in male hypogonadism

every 24 hours. The amplitude of the LH pulses is much higher than that of FSH; this may be due to their different half-lives. 9 Idiopathic hypogonadotropic hypogonadism (IHH) is defined as a severe defect in the hypothalamic-pituitary axis. 7 In its most severe form, it causes failure of both sexual maturation and spermatogenesis. However, patients with IHH are characterized by a broad range of pathologic findings, including undescended or incompletely descended testes, micropenis, decreased testicular volume, and lack of mature secondary sexual characteristics. When these findings are associated with anosmia or hyposmia and a defect in the olfactory system, the condition is referred to as Kallman's syndrome. If young patients between 14 and 18 years of age present with these symptoms and spontaneous pubertal development occurs later than usual, they are defined as having delayed puberty. 7 •10 It is Fertility and Sterility

rather difficult to differentiate these patients from IHH since no specific tests are available. One of the most valuable criteria for differential diagnosis is the response to LH-RH or hCG stimulation or both. 10 The goal of successful therapy for IHH should be not only virilization but also fertility. In the past, human gonadotropin (hCG-hMG) therapy has been used for this purpose, but reported results have been contradictory with a response rate ranging from 60% to 90%. 11 Our own experience has resulted in a rather high failure rate (60%), mainly due to the method's inconvenience, side effects, and patient compliance problems. Also unresponsiveness of the tubular compartment of the testis may be involved in treatment failure (e.g., cryptorchidism). According to present hypothesis, pulsatile administration of LH-RH will most closely mimic physiologic stimulation of the pituitary gland. It therefore seems appropriate to administer LH-RH in pulses, on a long-term basis. This should induce a rhythmic pattern of LH and FSH release. 10•12- 18 Ideally, this results in most physiologic stimulation of both compartments of the testis, thereby inducing testosterone (T) secretion and spermatogenesis, the main features of normal pubertal development. The aim of this study was to prove the clinical efficacy of pulsatile LH-RH treatment in patients suffering from hypogonadotropic hypogonadism classified as IHH (including Kallman's syndrome) and delayed puberty. Primarily, we were interested in the individual data of each patient in order to point at the heterogeneity of patient population and the variability of the results concerning hormone secretion, maturation of secondary sexual characteristics, spermatogenesis, and length of therapy. MATERIALS AND METHODS

Ten young men 16 to 28 years of age participated in this study. All showed lack of puberty, present- · ing with complete and incomplete hypogonadotropic hypogonadism. They had been diagnosed as having delayed puberty (nos. 1 and 2), and idiopathic hypogonadotropic hypogonadism (IHH) (nos. 3 to 8) including Kallman's syndrome (nos. 9 and 10). Diagnoses were established from the results of the following: clinical investigation according to the Tanner Score; pooled plasma values for LH, FSH, and T; endogenous secretional patterns of LH, FSH, and T for 12 to 24 hours by frequent Vol. 50, No.3, September 1988

blood sampling (every 10 minutes = 1 PM to 1 AM); bolus and pulsatile (48 hours) LH-RH stimulation tests to investigate pituitary response on a short- and long-term basis; computed tomography of the brain and sella; chronologie age; bone age; investigation of olfaction and sight; karyogram; and, in some instance, testicular biopsy. Hormone fluctuations were identified by visual inspection and a method described by Clifton and Steiner.19 Family history, chronologie age, endogenous secretion of LH, FSH, and T response to LH-RH bolus test were used to distinguish between delayed puberty and IHH. An additional attempt was made to discriminate between these two groups of patients by using the test scores of an 48 hours pulsatile LH-RH test. 15•20 If a normal secretional pattern of LH and FSH developed after the 48-hour stimulation test period, the diagnosis of delayed puberty was confirmed. All other results were indicative of IHH (including Kallman's syndrome). Both Kallman patients suffered from anosmia and were therefore classified as complete Kallman's syndrome. Patient no. 7 also suffered from cryptorchidism on his left side. Plasma hormones were determined by standard radioimmunologic methods. In our laboratory, the sensitivity of the intraassay and interassay coefficients of variations were as follows: LH, 0.5 mU/ ml, 6.4% and 9.9%; FSH, 0.6 mU/ml, 9.8% and 9.9%; and T, 0.3 ng/ml, 6.6% and 4.3%. Testicular volume was measured with a Prader's orchidometer and by sonography. LH-RH therapy was performed with a computerized, portable infusion pump (ZYKLOMAT, Ferring Corp., Kiel, FRG). The small and lightweight pump (140 g) was carried in a body belt; the drug was administered subcutaneously. The patients changed the injection side themselves every third day in order to assure rapid and complete LH-RH absorption by the subcutaneous tissue. LH-RH doses were administered in regular pulses every 120 minutes, both day and night. The dosage was increased (4 to 16 ~g/pulse) until normal levels ofT were achieved. Treatment period varied from 6 to 24months. The patients were seen in our outpatient clinic every other week throughout the observation period for refilling of the pump, clinical checkups, and endocrine evaluations. Pulse response studies were performed every third month. Semen analyses were done as described elsewhere21 every sixth week from the time a patient was able to deliver a Aulitzky et al.

Pulsatile LH-RH in male hypogonadism

481

'i

Table 1

Hormone Values, Testis Size, and Sperm Counts During LH-RH Therapy

No

Age (yr) life/bone

1"

16/14

2"

19/13

3b

28/13

4b

18/14

5b

19/14

6b

20/13

7b

19/14

8b

17/14

9c

20/14

1o·

21/16

Therapy duration/ results

T (ng/ml) Before

After

Before

After

Before

After

Before

After

Sperm density (mill/ml)

0.7

2.0

4.1

7.8

3.2

5.1

6/6

18/18

29.7

44.5

0.1

3.7

0.3

2.3

0.4

4.9

4/4

15/12

24.0

48.0

0.2

2.1

0

6.9

0.5

2.7

6/4

16/20

32.0

64.0

0.5

4.9

0.5

4.2

0.6

1.3

6/6

20/20

20.4

20.4

0.1

3.8

0.1

9.5

0.7

6.2

6/6

14/14

1.0

2.0

0.2

4.8

0

7.6

0.3

7.8

2/2

10/11

4.0

10.0

0.3

4.6

0

8.6

0

0.5

4/3

12/10

1.0

1.0

0.1

2.4

0.3

4.1

0.4

5.7

4/4

16/14

24.3

24.3

0.1

0.8

0

4.7

0.4

2.1

4/4

13/15

4.8

9.6

0.3

1.4

0.3

9.3

0.2

5.3

1/1

12/11

12.8

19.2

9months persistent 9months persistent 15months nonpersistent 12months persistent 12months persistent 9months persistent 12months nonpersistent 12months persistent 15months nonpersistent 24months nonpersistent

LH (mU/ml)

• Delayed puberty. b Idiopathic hypogonadotropic hypogonadism.

semen sample. Pulsatile LH-RH therapy was administered until normal sperm counts were observed or until at least 3 months after the establishment of spermatogenesis. In order to prove the persistence of the results a final checkup was performed three months after termination of treatment. If sufficient endogenous hormone secretion did not persist without LH-RH therapy, continuation or androgen replacement therapy was offered to the patients. This result of therapy was defined as "non persisting".

RESULTS

Pooled plasma hormone values (LH, FSH, and T) were extremely low or under the detection limit in all patients, as shown in Table 1. No clear gonadotropin pulses could be identified in any of our patients during the 12 to 24 hours preceding therapy, either. This confirms the existence of a substantial defect in their hypothalamic-pituitary-gonadal axis. Uncharacteristic fluctuations of LH and FSH secretion on somewhat higher levels were seen in subjects no. 1 and 2 only. Highly pathologic or subnormal responses to bolus LH-RH stimulation (100 ,.,g) were seen in patients no. 3 to 10 being classified as IHH (including Kallman's syndrome). When they were treated with pulsatile LH-RH administration for 48 hours Aulitzky et al.

Testis vol. (r/1)

Total sperm output (mill)

• Kallman's syndrome.

(pulsatile LH-RH test), only slight and irregular gonadotropin secretion with plasma levels below the normal range could be induced (negative test score). Patients no. 1 and 2 were the only ones to show normal LH response to bolus LH-RH administration and a pulsatile secretional pattern (positive test score) could be induced by chronic intermittent LH-RH stimulation. They were classified as delayed puberty. The testicular biopsies performed in 7 of 10 patients prior to therapy revealed juvenile tubules in 6 patients and a cryptorchid testis in 1 patient (no. 7). Three patients refused biopsies. During Treatment

Pretreatment

482

FSH (mU/ml)

Pulsatile LH-RH in male hypogonadism

Delayed Puberty

The clinical course of the two patients classified as having delayed puberty (nos. 1 and 2) are shown in Figure 1. During treatment, both patients exhibited normal pubertal development in all respects (stage G4 to G5 according to Tanner). Spermatogenesis occurred after 3 and 6 months of therapy; normal sperm density and a total output of 20 million sperms were measured in both patients by the end of treatment after 9 months. Serum levels of LH, FSH, and T reached the normal range. The success of therapy was persistent, and T values measured 3 months after termination of therapy were in the normal range (3.5 to 4.2 ng/ml). Fertility and Sterility

15

PIt 1 0 n t

1

IS

10

0

Complete and Incomplete IHH

Pltlent 2

10

r

~

LH IIIU/oll •

~

FSH IIIU/oll.O.

••

20

20

rest. vol toll

10

10

rO

0 29.7

0 2.5

6.1

0



oe

Figure 2 illustrates the patterns that developed in the six subjects with complete and incomplete IHH (nos. 3, 4, 5, 6, 7, 8). Pubertal development was observed in all six patients (stage G4 to G5 according to Tanner) by the end of treatment. A distinct increase or normalization of plasma levels of LH, FSH, and T was reached after 3 months of therapy in all patients. LH and FSH levels reached normal limits in all six, whereas the T response was subnormal in two (nos. 3 and 8). Testicular volumes increased, and production of semen was also observed after this period. Spermatogenesis was induced in all six patients; the time of achievement ranged from 6 to 12 months. However, normal sperm density and a total sperm output> 20 million was achieved in only three subjects (patients 3, 4, and 8), whereas the three others remained oli-

lng/olle

0

oontns

2-.0

••

0

Sllero count lolll~ll

oontns

Figure 1 Hormone values, testicular volumes, and incidence of spermatogenesis during pulsatile LH-RH treatment in patients 1 and 2 (delayed puberty). Normal pubertal development was induced in all respects, including normal sperm counts.

I~

Dltltnt

1

I~

Dl I I ~n I

Ill

I~

Plllent

~

10 (OQ/111

LH

J.

III(Jt•l I •

FSH I Mit• II A

20

20

10

10

0

0

1.1

0.1

• • '·'• •

S2.0

12

0

0

0

0

D• t I t n I

6

10

zo .•

0

0

0

0

0

0

IZ

oat lent

I .0



•ol (1111 I



<:.pe.r• coun! f•lllt•l I

11

IIOntr'IS

II

10

lrc;t

'0

• •

IS

OPntlls

IS

19.6

20

IIOOU'IS

'

IS

10

Dl I I In

t I

,...

10 LN

~,,.

1-.Jt•ll

e

fSM I.U/•116

20

20

10

10

o 0

0.1



•.o •

0

1.0

0



1.0

• 11

.:w1tns

21t J

0

0





~,. ..

covnr

,.11111111

11

IIOf'ltrtl

Figure 2 Hormone values, testicular volumes, and incidence of spermatogenesis during pulsatile LH-RH treatment in patients 3 to 8 (IHH, not Kallman's syndrome). Normal plasma hormone levels were reached after 3 months of therapy, and spermatogenesis was induced in all patients. Normal sperm density was observed in patients 3, 4, and 8. Vol. 50, No.3, September 1988

Aulitzky et al.

Pulsatile LH-RH in male hypogonadism

483

J\.8 15

15

10

10

patient 10

T

Cng/ml J •

LH

CIIU/rnll •

FSH IIIU/1111

J t::.

20

20

Test. vol 1111

10

10

rO

0

0

0

0

0.1

0

0

0

0

1.2

0

0

0

0



0

0

0

0



12

15

12

15

~~ontns

O.l

12.8

21

2•

• •

18

I

J



Sper111 count 111111/ml J

110nti'IS

Figure 3 Hormone values, testicular volumes, and incidence of spermatogenesis during pulsatile LH-RH treatment in patients 9 and 10 (Kallman's syndrome). Normal plasma LH and FSH values were reached after 3 months of therapy, butT values remained in the lower limit until after 6 months. Spermatogenesis was induced in both patients after month 15. ·

gospermic (no. 5, 6, and 7). These results correlated with the final testicular volumes reaching 16 to 20 ml in patients with normal sperm counts compared to 11 to 14 ml in the oligospermic group. The success of therapy was persistent in 4/6 patients (no. 4, 5, 6, and 8). Their T values 3 months after therapy were in the lower normal limits (2.1 to 5.7 ng/ml). IHH-Kallman's Syndrome

The two patients with Kallman's syndrome (nos. 9 and 10; Fig. 3), both ofwhom had presented with complete anosmia, were treated with LH-RH for 15 and 24 months, respectively. After the third month of therapy, a marked increase of serum levels of LH and FSH was observed, whereas T serum levels remained in the lower limit throughout the observation period. In addition, testes growth was comparatively slower in these two patients. Before treatment, testicular volumes were 1 and 4 ml; after 15 and 24 months of therapy, they now have increased to a maximum of 12 and 15 ml, respectively. Both Kallman's syndrome subjects began semen output in the third month of treatment, and both produced sperms after 15 months. Sperms densities were 1.2 and 0.8 million/ml, respectively, at the onset of spermatogenesis. At month 24, patient no. 10 showed a sperm density of 12.8 million/mi. The total sperm output was 19.2 million, and the sperm motility was normal at this time. Patient no. 9 is still under treatment and his last sperm density was 4.8 million/ml (total sperm output 9.6 million). Pubic hair, penis growth, and normal male sexual behaviour were induced in both patients. However, 484

Aulitzky et al. Pulsatile LH-RH in male hypogonadism

the time needed to achieve these goals was much longer than for the other eight patients, which is most likely due to their severe form of hypothalamic-pituitary function disorder. According to the cause of their defect, the result of pulsatile LH-RH treatment was not persistent and further treatment was required. None of the 10 patients dropped out of the study, and no serious side effects were observed during the course of drug therapy. DISCUSSION

These promising results prove the efficacy of low-dose pulsatile LH-RH therapy in men with delayed puberty and IHH. Similar results were described by several groups in the past. Comparisons are difficult due to the different patient population described. Still, the data presented by Hoffmann et al./ 3 Crowley et al., 18 Morris et al., 16 and Klingmiiller et al. 14 provide rather similar results. They were able to induce normal puberty in patients suffering from IHH and delayed puberty. The patients presented by Shargil et al. 17 are classified as having incomplete IHH or severe forms of delayed puberty which represent only a minor proportion of our group of patients (nos. 1 and 2). The selection of his patients seems to be the main reason for his excellent rate of success concerning pregnancies. According to the literature discussed and our data, the duration of treatment varies in a broad range. The two patients classified as delayed puberty in our study exhibited fast progress of pubertal development within 9 months and induction of Fertility and Sterility

spermatogenesis within 3 to 6 months of therapy. These positive results were persistent in both and give further support to the hypothesis that these two patients were diagnosed correctly as having delayed puberty. The other six patients with IHH showed marked differences during their course of therapy. The duration of treatment ranged from 9 to 15 months, and only three patients developed normal sperm counts (nos. 3, 4, and 8). This success of therapy was persistent in two of them only (nos. 4 and 8). Even their sperm counts were normal at the end of therapy; the T response was subnormal, which might be due to a persistent organic defect in their hypothalamic-pituitary region. These findings present evidence that normal spermatogenesis can be achieved even when T responses were subnormal. This might be due to the positive effect of the physiologic-like stimulation by pulsatile LH-RH administration. Patient no. 3 returned to pretreatment values after termination of treatment; even he had developed normal hormone secretion and normal sperm counts during therapy. The other three patients (nos. 5, 6, and 7) remained oligospermic even when treatment was extended to 12 months. The reason why these patients remained oligospermic is unknown; cryptorchidism may be the cause in at least one patient (no. 7). The two patients diagnosed as having Kallman's syndrome showed a much slower and nonpersisting response to therapy. Spermatogenesis did not occur earlier than 15 months after onset of therapy, and the T responses were less pronounced compared to most other patients. These findings again correlate with results published in the pase3 •15•22 and is most likely due to the severity of the defect of their hypothalamic-pituitary function. There was also a close correlation between final testis. volumes and sperm density or total sperm output. The difference of the mean testicular volumes found in patients with normal sperm counts (mean 16.9 ± 2.8 ml SD) compared with those with oligospermia (mean 12.2 ± 1.6 ml SD) was highly significant (P < 0.003). No significant correlation was found between pretreatment testis volumes and final sperm production. Fertility has not yet been proven in any of our patients. This fact must not be interpreted as a negative result since most of our patients were rather young and all unmarried. They further suffered total loss of libido due to their state of eunuchoidism and were not at all interested in impregnation. Although all our patients who particiVol. 50, No.3, September 1988

pated in the study had presented with complete eunuchoidism, the time needed for the induction of pubertal development and spermatogenesis with LH-RH treatment proved to be equal to or shorter than that needed with hCG/hMG therapy. 17•23 - 25 As with the combined therapy, Kallman's syndrome patients took longer to achieve spermatogenesis (15 months), but this was expected due to the severity of their condition. 6 •13- 15 •17 These results correspond to those observed after conventional therapy, again indicating that pulsatile LH-RH therapy is at least comparable to HCG/hMG therapy. After termination of pulsatile LH-RH therapy, androgen replacement of hCG/hMG therapy was offered to those patients who did not achieve persistent success. Since none of our patients who required further treatment accepted daily intramuscular injections, two were treated by androgen replacement and the other two were put on the pump again. It is a well known fact that adolescents or adults undergoing late puberty may suffer from severe psychologic problems. 7 We associate the sense of well-being our patients experienced with the pulsatile, physiologic-like stimulation of the pituitary gland and subsequent rhythmic hormonal pattern, not merely increased T levels. This benefit is underlined by the fact that our patients exhibited no psychologic problems during drug-induced puberty and did not need the psychologic counseling we offered. The excellent patients cooperation rate may be due in part to the minimal discomfort caused by self-controlled subcutaneous administration via minipump, in contrast to the daily injections given intramuscularly in combination with daily counselings of their physicians. Finally the costs of the drug administered is less in case of LH-RH in comparison to hCG/hMG. The cost of the pump is usually taken over by hospitals or insurance companies in our countries. Both, patients and insurance companies save further expenses by avoiding multiple counseling of the physicians. The only potential drawback we can foresee is that operation of a minipump requires a skilled hand, and in the event that a patient is unwilling to handle it correctly, successful treatment can be jeopardized. However, all of our patients have been easily trained to use the pump. hCG/hMG is still the treatment of choice in cases of isolated pituitary failure (e.g., due to total hypophysectomy). But for the reasons stated above, long-term pulsatile LH-RH administration Aulitzky et al.

Pulsatile LH-RH in male hypogonadism

485

appears to be the more desirable treatment for most other cases of delayed puberty and IHH. Due to its high success rate and low rate of side effects and attrition, pulsatile LH-RH therapy represents a true alternative to hCG/hMG. In conclusion, pulsatile LH-RH therapy is a well-tolerated and effective treatment for the induction of pubertal development and spermatogenesis in patients with various forms of hypogonadotropic hypogonadism. The broad variety of results concerning hormone secretion, sperm production, length of therapy, and persistence of the success is mainly due to the heterogeneity of the patient population. Patients classified as delayed puberty and incomplete IHH seem to respond best, but also complete IHH (including Kallman's syndrome) can be treated successfully by pulsatile LH-RH therapy. Acknowledgments. The authors express their appreciation to the Ferring Corporation for the generous gift of the pump and the drug, to Ms. Amy Segal for editorial assistance, to the staff of the Department of Nuclear Medicine for their technical assistance, and especially to Dr. Helmut Joos and Ms. Andrea Schrattenecker for their valuable help in managing the patients.

REFERENCES 1. Nankin HR, Troen P: Repetitive luteinizing hormone elevations in serum of normal men. J Clin Endocrinol Metab 33:558, 1971 2. Boyar R, Finkelstein J, Roffwarg H, Kapen S, Witzman E, Hellmann L: Synchronization of augmented luteinizing hormone secretion with sleep during puberty. N Eng! J Med 287:582, 1972 3. Santen RJ, Bardin CW: Episodic luteinizing hormone secretion in man. Pulse analysis, clinical interpretation, physiologic mechanisms. J Clin Invest 52:2617, 1973 4. Knobil E, Plant TM, Wildt L, Belchetz PE, Marshall G: Control of the rhesus monkey menstrual cycle: permissive role of hypothalamic gonadotropin -releasing hormone. Science 207:1371, 1980 5. Von Werder K, Eversmann T: Therapy of male hypogonadotropic hypogonadism by pulsatile GnRH application. Dtsch Med Wochenschr 109:432, 1984 6. Aulitzky W, Frick J: Pulsatile LH-RH treatment in 2 men with "IHH" (idiopathic hypogonadotropic hypogonadism) and 2 men with "delayed puberty" (constitutiona1 delay). (Abstract) IIIrd International Congress of Andrology 1985. J Androl6:2, P-91, 1985 7. Styne DM: Puberty. In Basic and Clinical Endocrinology, Edited by Greenspan FS, Forsham PH. Lange Medical Publications, Los Altos, California, 1986, p 456 8. Boyar RM, Rosenfeld RS, Kapen S, Finkelstein JW, Roffwarg HP, Weitzmann ED, Hellmann L: Human puberty: simultaneous segmented secretion of luteinizing hormone and testosterone during sleep. J Clin Invest 54:609, 1974 9. Pasqualini JR, Kincl FA: Hormones and the Fetus, volume 1. New York, Pergamon Press, 1985, p 15

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10. Wagner TOF, Brabant G, Warsch F, Hesch RD, Miihlen A: Pulsatile gonadotropin-releasing hormone treatment in idiopathic delayed puberty. J Clin Endocrinol Metab 62:95, 1986 11. Lunenfeld B, Glezerman M: Zur Therapie der miinnlichen Infertilitiit. In Sterilitiit-Diangose und Therapie miinnlicher Fertilitiitsstiirungen, Edited by Lunenfeld B, Glezerman M. Grosse Verlag Berlin, 1981, p 110 12. Jacobson RI, Seyler E Jr, Ramborlane WV Jr, Gertner JM, Gene! M: Pulsatile subcutaneous nocturnal administration of GnRH by portable infusion pump in hypogonadotropic hypogonadism: initiation of gonadotropin in responsiveness. J Clin Endocrinol Metab 49:652, 1979 13. Hoffman AR, Crowley WF: Induction of puberty in men by long-term pulsatile administration oflow-dose gonadotropin-releasing hormone. N Eng! J Med 307:1237, 1982 14. Klingmiiller D, Menger D, Wildt L, Leyendecker F, Kriick K, Schweikert HU: Induction of puberty in a patient with hypogonadotropic hypogonadism: effect of sequentially applied hCG and pulsatile GnRH administration. Hormones Metab Res 17:358, 1985 15. Aulitzky W, Kunit G, Frick J: Pulsatile LHRH treatment in two patients with delayed puberty and one patient with idiopathic hypogonadotropic hypogonadism (IHH). In Pulsatile Therapy of the Male, Edited by TOF Wagner. Hameln, TM-Verlag, 1985, p 99 16. Morris DV, Adeniyi-Jones R, Wheeler M, Sonksen P, Jacobs HS: The treatment of hypogonadotropic hypogonadism in men with the pulsatile infusion of luteinizing hormone-releasing hormone. Clin Endocrinol21:189, 1984 17. Shargil AA: Treatment of idiopathic hypogonadotropic hypogonadism in men with luteinizing hormone-releasing hormone: a comparison of treatment with daily injections and with pulsatile infusion pump. Fertil Steril4 7:492, 1987 18. Crowley WF, Spratt D Jr: The results of long-term GnRH administration in idiopathic hypogonadotropic hypogonadism. In Pulsatile Therapy of the Male, Edited by TOF Wagner. Hameln, TM-Verlag, 1985, p 69 19. Clifton DK, Steiner RA: Cycle detection: A technique for estimating the frequency and amplitude of episodic fluctuations in blood hormone and substrate concentrations. Endocrinology 112:1057, 1983 20. Partsch CJ, Hermanussen M, Sippell WG: Differentiation of male hypogonadotropic hypogonadism and constitutional delay of puberty by pulsatile administration of gonadotropin-releasing hormone. J Clin Endocrinol Metab 60: 1196, 1985 21. Frick J, Danner CH, Joos H, Kunit G, Luukkainen T: Spermatogenesis in men treated with subcutaneous application oflevonorgestrel and estrone rods. J Androl2:331, 1981 22. Lunenfeld B, Olchovsky D, Tadir Y, Glezerman M: Treatment of male infertility with human menopausal gonadotropins: selection of cases, management, and results. Andrologia 11:331, 1979 23. Davies AG: Eunuchoid treated with gonadotropins. Proc Soc Med 58:580, 1965 24. Johnsen SG: A study of human testicular function by the use of human menopausal gonadotropin and human chorionic gonadotropin in male hypogonadotropic eunuchoidism and infantilism. Acta Endocrinol (Copenh) 53:315, 1966 25. Sherins RJ, Winters SJ, Wachslicht H: Physiologic studies of the role of FSH in stimulation of spermatogenesis in the hypogonadotropic male. (Abstr.) Symposium Recent Progress in Andrology. L'Aquila, Italy, April21 to 23, 1977

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