Clinical and Laboratory Heterogeneity in Idiopathic Hypogonadotropic Hypogonadism ROBERT M. BOYAR,* R. H. K. WU, S. KAPEN, LEON HELLMAN, E. D. WEITZMAN, AND JORDAN W. FINKELSTEIN Departments of Oncology and Neurology, Montefiore Hospital and Medical Center, Bronx, New York 10467 of LH had the highest 24 h mean testosterone concentrations, the best responses to exogenous LH-RH and the most differentiated testicular biopsies. Sleep had no effect on the release of LH or FSH in response to LH-RH. These studies suggest that the clinical and laboratory heterogeneity of idiopathic hypogonadotropic hypogonadism may be the result of differences in the degree of endogenous LH-RH deficiency. (/ Clin Endocrinol Metab 43: 1268, 1976)

ABSTRACT. Six young men with idiopathic hypogonadotropic hypogonadism had 24-h frequent blood sampling studies for measurement of LH, FSH and testosterone. Five of the patients had LH and FSH measured after administration of 100 fig LH-RH during waking and then during sleep. Four of the patients had testicular biopsies performed. The results of the present studies showed that 4 of the patients had no evidence of episodic LH, FSH, or testosterone secretion. The two patients who showed significant sleep related pulses

I

DIOPATHIC hypogonadotropic hypogonadism (IHH) is a genetic disorder that is characterized by the failure to develop normal secondary sexual characteristics at the time of expected puberty. These patients usually show prepubertal levels of LH, FSH and testosterone, but can respond to exogenous hCG with a rise in plasma testosterone (1,2). Since hypothalamic abnormalities have been reported in some anosmic patients with this disorder (3,4), the suggestion has been made that the site of the abnormality resides in the hypothalamic center controlling the synthesis and release of the gonadotropin releasing hormone (Gn-RH or LH-RH). Recent studies with LH-RH have provided additional evidence that these patients have an abnormality in LH-RH synthesis or release resulting in impaired activation of pituitary gonadotropin release. Several reports have shown varied LH and FSH responses to LH-RH in patients Received April 29, 1976. These studies were in part supported by the following NIH grants: CA 07304, HL 14734 and RR-53. * Reprint requests to: Dr. R. M. Boyar, Department of Internal Medicine, University of Texas Health Science Center, Dallas, Texas.

with IHH suggesting a heterogeneous disorder (9-11). In an earlier report, we were similarly impressed by the clinical and laboratory heterogeneity manifested by patients with IHH (1). At that time, we postulated that this heterogeneity may be the result of differences in the 24 h production of the gonadotropins and testosterone, which may not be apparent when measuring a single plasma sample during waking. This suggestion was supported further by the findings that normal puberty is initiated by augmented LH and testosterone secretory activity synchronous with sleep (12,13). In prepubertal subjects, there is no evidence of pulsatile LH secretory activity during sleep or waking, while in adult subjects LH secretory episodes occur randomly throughout the day and night (14). The biologic importance of the augmented LH secretory episodes in pubertal boys was shown by the demonstration of synchronous testosterone secretion during sleep (15). The purpose of this study was threefold: 1) to determine the "maturational" stage of the LH secretory "program" in six patients with IHH, 2) to correlate the 24-h LH and testosterone secretory patterns with the LHRH responses and the clinical findings, and 3) to determine if the response

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IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM

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to LH-RH during sleep was significantly different from the response during waking. Materials and Methods Subjects Six patients with IHH were studied. The clinical characteristics of the patients are shown in Table 1. All six patients presented with delayed puberty. They were 18-7/12 to 31 years of age. Two of the patients had near normal sized testes (Fig. 1A) with differentiation of the seminiferous tubules (Fig. IB) and could be considered examples of the "fertile eunuch" syndrome. They did not have sperm in their ejaculate. They were all chromatin negative and had an XY karyotype. There was no evidence of a hypothalamic or pituitary tumor. Evaluation of the growth hormone response to insulin hypoglycemia, the ACTH-cortisol response to metyrapone and basal T4, T3, TSH and prolactin were all normal. Twenty-four hour frequent sampling studies The patients were admitted to the Clinical Research Center, Montefiore Hospital and Medical Center, Bronx, N.Y. for 20 min interval blood sampling studies according to protocols published previously from this laboratory (16). At TABLE 1. Clinical characteristics of patients with idiopathic hypogonadotropic hypogonadism Testicular size & biopsy

No.

Age (yrs)

Height (cm)

1

24

165

0.5 x 1.0 cm (prepubertal testes)

2

22

177

0.5 x 1.0 cm (prepubertal testes)

3

19

160

4

19

170

5

28

180

6

31

167

Associated abnormality

Hyposmia*

0.5 x 1.0 cm 0.5 x 1.0 cm

Cleft palate

2.5 x 3.0 cm (spermatogenic maturation arrest) 3.0 x 4.0 cm (spermatogenic maturation arrest)

* Unable to detect nitrobenzene at 10 3 M or pyridine at 10"5 M.

FlG. 1A. Clinical appearance of patient 6.

the completion of the 24-h study, 100 /xg of LH-RH (Ayerst) was given iv and plasma samples collected at 15 min intervals for 1 h and 30 min intervals for an additional 2 h for measurement of LH, FSH and testosterone. During the evening of the following day, five of the patients were given a second 100 fig dose of LH-RH

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BOYAR ET AL.

FlG. IB. Testicular biopsy (Original x 100) of patient 6.

that was injected just as the patient entered stage 2 sleep. Plasma samples were collected according to the same protocol as the daytime infusion of LH-RH. The LH and FSH responses to LH-RH were assessed by calculating the increment from baseline to peak, as well as the area under the curve. The latter was determined by planimetry and expressed in arbritary units. Sleep was recorded polygraphically and scored according to standardized criteria (17). Radioimmunoassays Plasma LH (14), FSH (13) and testosterone (15) were measured by radioimmunoassay

methods reported previously from this laboratory. Mean LH, FSH and testosterone levels were calculated during the 24-h period as well as during sleep and the equivalent waking period to determine if significant augmentation occurred during sleep. Student's t test was used to calculate the significance of these differences.

Results

LH, FSH and testosterone (Tables 2 and 3) The 24-h mean plasma LH, FSH and testosterone values were in the prepubertal range in all six patients. In patients 1-4,

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IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM TABLE 2. LH, FSH and testosterone levels

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TABLE 3. Sleep and waking LH and testosterone in IHH T H mTTI/ml

Case no. 1 2 3 4 5 6

LH mlU/ml 1.9 ± 3.7 ± 3.1 ± 2.6 ± 3.6 ± 2.8 ±

0.3 0.7 0.7 0.7 0.5 1.0

FSH mlU/ml 3.6 ±0.7 1.0 ± 0.5 2.4 ± 1.1 1.5 ± 0.7 3.7 ± 0.6 1.1 ± 0.4

(ng/dl) 21.5 6.8 19.6 20.4 70.4 89.6

± 6.4 ± 1.9 ± 3.4 ± 3.8 ± 11.0 ± 28.0

there was no significant difference between the mean LH and testosterone asleep compared to waking (Fig. 2). In patients 5 and 6, there was evidence of episodic LH secretion that resulted in higher mean LH values during sleep compared to waking (Fig. 3). In these two patients, the 24-h mean testosterone values were significantly higher than those found in patients 1-4. These two patients also showed significantly higher mean testosterone levels during sleep compared with waking, (P < 0.001), similar to that found in normal early pubertal boys (15). The plasma FSH values were all in the prepubertal range and showed little evidence of episodic secretion. None of the patients showed higher mean FSH values during sleep compared to waking. LH-RH responses (Table 4) All six patients showed an LH and FSH response to LH-RH. The best LH responses

Case no. 1 2 3 4 5 6

Sleep 1.9 ± 3.4 ± 3.2 ± 2.8 ± 3.9 ± 3.2 ±

0.3 0.5 0.5 0.7

0.5f 1.0*

Waking 1.8 ± 0.2 4.0 ± 0.9 3.2 ± 0.8 2.7 ± 0.7 3.5 ± 0.45 2.2 ± 0.50

Sleep

Waking

19.5 ± 7.0 22.9 ±4.7 6.6 ± 1.7 6.3 ± 1.2 21.7 ± 2.4 19.2 ± 2.8 20.7 ± 3.4 19.8 ±3.9 61.4 ± 4.6 80.1 ±6.3* 117 ± 19.0* 71.7 ± 16

* Mean LH or testosterone during sleep significantly higher than mean LH or testosterone during waking (P < 0.001). f Mean LH during sleep significantly higher than mean LH during waking (P < 0.01).

were obtained in patients 5 and 6 who had evidence of spontaneous episodic LH secretory activity and the highest 24-h mean plasma testosterone levels. The LH and FSH responses to the morning and sleep onset injections were similar in each of the five patients. In no patient was there a greater release of LH and FSH during sleep compared to waking (Table 4 and Figs. 4 and 5). Testicular size and biopsies (Table 1) The four patients with the most immature testes were those who had no evidence of spontaneous episodic LH release, the lowest plasma testosterone levels and the lowest responses to LH-RH. The two patients who showed evidence of spermatogenic maturation were the two who had spontaneous SL££P STAGE AVMKE-i

mlU/ml LH 15 - i

FIG. 2. The 24-h LH, FSH and testosterone levels before and after 100 fig LH-RH in Case 2. The sleep histogram is depicted above the normal nocturnal sleep period.

mlU/ml FSH 10—I

ng/OOml TESTOSTERONE 100-

1200

OOug LHRH

2000 CLOCK

2400 TIME

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BOYAR ET AL.

1272 SLEEP STAGE AWAKE-i

mIU/ml FIG. 3. The 24-h LH, FSH and testosterone levels before and after 100 /xg LH-RH in Case 6. The sleep histogram is depicted above the normal nocturnal sleep period. TESTOSTERONE ng/IOOml

200n

1200

1600

2000

2400 0400 CLOCK TIME

0800

episodic LH release, significant sleep related increments in the mean plasma testosterone and the best responses to LH-RH. Discussion The 24-h LH and testosterone secretory patterns in these six young men with idiopathic hypogonadotropic hypogonadism appeared to fall into two groups: 1) those with

1200

1600

flat 24-h LH and testosterone secretory patterns and absent augmentation of these hormones during sleep, and 2) those with some episodic LH secretory activity during the nocturnal hours and increased testosterone levels during sleep. In both patients in the latter group, the increased LH secretory activity during the nocturnal hours stimulated testosterone secretion and resulted in higher 24-h mean testosterone concen-

TABLE 4. LH and FSH responses to LH-RH during sleep and waking LH sleep

LH waking Case no.

Basal*

Maximum*

A*f

AreaJ

Basal*

Maximum*

A*f

Area}

1 2 3 4 5 6

2.1 3.1 2.5 1.9 4.0 1.6

14.8 15.5 13.0 14.2 25.6 19.0

12.7 12.4 11.5 12.3 21.6 17.4

260 306 145 234 493 425

1.4 3.4 3.5 3.0

8.0 14.2 9.5 13.4

6.6 10.8 6.0 10.4

154 222 84 155

3.2

19.3

16.1

423

FSH waking

1 2 3 4 5 6

FSH sleep

Basal*

Maximum*

A*f

Area|

Basal*

Maximum*

A*f

Area}

4.2 3.0 2.1 1.2 4.4 1.5

16.7 6.0 8.2 12.5 18 4.5

12.5 3.0 6.1 11.3 13.6 3.0

286 65 156 306 367 50

4.5 3.9 2.4 3.6

12.0 4.5 8.6 13.3

7.5 0.6 6.2 9.7

157 38 136 276

2.3

4.3

2.0

42

* Basal, Maximum and A LH and FSH values expressed as /xIU/ml 2nd IRP-HMG. f A refers to increment from basal to maximum value. t Area under the curve determined by planimetry.

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IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM

0200 0400

0600

1273

0800

1000

FIG. 4. The 24-h LH levels and responses to LH-RH during the day and during sleep in Case 2.

trations. The levels of testosterone were equivalent to those found in early pubertal boys. These data suggest that these two patients had higher intratesticular concentrations of testosterone and that this was responsible for the greater degree of differentiation of the germinal epithelium. The FSH levels within the two groups were

prepubertal and failed to show any significant episodic secretion. The failure of sleep related LH secretion to occur in the patients in group 1 suggests a defect in the CNS "program" controlling the initiation of normal puberty. Since all of our patients responded to LH-RH with a significant rise in LH and FSH, it was clear

f 18-

i i i i i I i r i i i i i i i i i i i i i i i i r i 1300 1500 1700 1900 2100 2300 0100 0300 0500 0700 0900 1100 1300

FIG. 5. The 24-h LH levels and responses to LH-RH during the day and during sleep in Case 6.

CLOCK

i v \ 000 1700

TIME

AWAKE

20 15 -

i = 10 SLEEP LH-RH

i 2100

i i r 2300 0*00

T

i i i i i 0300 0500 0700

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that these patients' pituitary glands were capable of synthesizing and releasing LH and FSH. Since the responses in patients 1-4 were similar to normal prepubertal boys, they could not be considered inappropriate for the degree of sexual maturation, although they were below normal age matched subjects. It is of interest that the LH response to LH-RH was greatest in patients 5 and 6, most probably reflecting the self-priming effect of these patients' endogenous LH-RH. This correlation would be expected if the response to a single bolus injection of LH-RH reflects prior exposure of the gonadotroph cell to endogenous LH-RH. The similarity between the LH and FSH responses to LH-RH during sleep and waking probably reflects the absence of a sensitizing effect of sleep per se on the pituitary in response to LH-RH. These findings suggest that the onset of augmented LH secretion during sleep in early puberty probably reflects increased secretion of LHRH during sleep, rather than a change in the pituitary's sensitivity to LH-RH during this state. The results of this study suggest that the heterogeneity in the clinical presentation and LH-RH responsiveness in isolated hypogonadotropic hypogonadism probably results from differences in the degree of endogenous LH-RH deficiency. This difference is probably a quantitative one with patients 5 and 6 having a less severe deficiency of LH-RH. The finding of a failure of initiation or progression of the normal pubertal LH secretory "program" in these patients suggests that the normal pubertal mechanism that is heralded by augmented LH secretion synchronous with sleep fails to occur or is arrested at an early pubertal stage in this disorder. Since the pituitary is equally responsive during sleep and waking periods, the defect is probably the result of an absolute or relative deficiency of LH-RH. It is possible that varying degrees of IHH exist with varying maturational stages of the pubertal "program."

Finally, the "fertile eunuch" syndrome has been described in men who showed evidence of sperm maturation on testicular biopsy and incomplete masculinzation at the time of normal puberty. Selective pituitary failure involving only LH secretion has been suggested as the cause of the deficient masculinization in this disorder. More recently, however, with the use of sensitive and specific radioimmunoassay, normal isolated plasma LH (18) as well as urinary LH (19,20) values have been reported. Patients 5 and 6 may be classified as examples of the "fertile eunuch" syndrome. They showed a more mature pubertal LH secretory "program" associated with higher plasma testosterone levels than the more typical patients with IHH. These findings suggest that the "fertile eunuch" syndrome may represent a less severe deficiency of LH-RH, rather than a distinct disorder. Further studies in similar patients will be required before this can be established firmly. Acknowledgments The authors would like to thank Nate Katz, Ed Rosario, Mira Fein and Ken Tucker for their able technical assistance. The secretarial assistance of Abbie G. Willis and Marilyn Hurler is appreciated. The authors express their appreciation to Dr. Arthur Bauman, who referred patients 3 and 4 for study.

References 1. Boyar, R. M., J. W. Finkelstein, M. Witkin, S. Kapen, E. Weitzman, and L. Hellman, Studies of endocrine function in isolated gonadotropin deficiency, J Clin Endocrinol Metab 36: 64, 1973. 2. Santen, R., and C. Paulsen, Hypogonadotropic eunuchoidism. II. Gonadal responsiveness to exogenous gonadotropins, J Clin Endocrinol Metab 36: 55, 1973. 3. De Morsier, G., and G. Gauthier, La dysplasia olfacto-genitale, Path Biol (Paris) 11: 1267, 1963. 4. Gauthier, G., Olfacto-genital dysplasia, Ada Neuroveg 21: 345, 1960. 5. Marshall, J. C., P. Harsoulis, D. C. Anderson, A. S. McNeilly, G. M. Besser, and R. Hall, Isolated pituitary gonadotrophin deficiency: Gonadotrophin secretion after synthetic luteinizing hormone and follicle stimulating hormonereleasing hormone, Br MedJ 4: 643, 1972. 6. Reitano, J. F., R. Caminos-Torres, and P. J. Snyder, Serum LH and FSH responses to the

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IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM

7.

8.

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10.

11.

12.

repetitive administration of gonadotropin-releasing hormone in patients with idiopathic hypogonadotropic hypogonadism, J Clin Endocrinol Metab 4: 1035, 1975. Job, J. C , P. E. Gamier, J. L. Chaussain, and G. Milhand, Elevation of serum gonadotropins (LH and FSH) after releasing hormone injection in normal children and in patients with disorders of puberty, J Clin Endocrinol Metab 35: 473, 1972. Roth, J. C., R. P. Kelch, S. L. Kaplan, and M. M. Grumbach, FSH and LH response to luteinizing hormone-releasing factor in prepubertal and pubertal children, adult males and patients with hypogonadotropic and hypergonadotropic hypogonadism, J Clin Endocrinol Metab 35: 926, 1972. Bell, J., I. Spitz, A. Slonim, A. Perlman, S. Segal, Z. Palti, and D. Rabinowitz, Heterogeneity of gonadotropin response to LH-RH in hypogonadotropin hypogonadism, J Clin Endocrinol Metab 36: 791, 1973. Zarate, A., A. J. Kastin, J. Soria, E. Canales, and A. V. Schally, Effect of synthetic luteinizing hormone releasing hormone (LH-RH) in two brothers with hypogonadotropic hypogonadism and anosmia, J Clin Endocrinol Metab 36: 612, 1973. Spitz, I. M., C. Rosen, J. Bell, M. Ben-David, W. Polishuk, and D. Rabinowitz, Isolated gonadotropin deficiency: A heterogeneous syndrome, N Engl J Med 290: 10, 1974. Boyar, R., J. Finkelstein, H. Roffwarg, S. Kapen, E. Weitzman, and L. Hellman, Synchronization of augmented luteinizing hormone secretion with sleep during puberty, N Engl J Med 287: 582, 1972.

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13. Boyar, R., J. W. Finkelstein, R. David, H. Roffwarg, S. Kapen, E. D. Weitzman, and L. Hellman, Twenty-four hour patterns of plasma luteinizing hormone and follicle stimulating hormone in sexual precocity, N Engl J Med 289: 282, 1973. 14. Boyar, R. M., M. Perlow, L. Hellman, S. Kapen, and E. Weitzman, Twenty-four hour pattern of luteinizing hormone secretion in normal men with sleep stage recording, J Clin Endocrinol Metab 35: 73, 1972. 15. Boyar, R., R. S. Rosenfeld, S. Kapen, J. W. Finkelstein, E. D. Weitzman, and Leon Hellman, Human puberty: Simultaneous augmented secretion of luteinizing hormone and testosterone during sleep, J Clin Invest 54: 609, 1974. 16. Weitzman, E. D., D. Fukushima, C. Nogeire, H. Roffwarg, T. F. Gallagher, and L. Hellman, Twenty-four hour pattern of the episodic secretion of cortisol in normal subjects, J Clin Endocrinol Metab 33: 14, 1971. 17. Rechtschaffen, A., and A. Kales (eds.), A Manual of Standardized Terminology. Techniques and Scoring System for Sleep Stages of Human Subjects (NIH Publication No. 204), National Institute of Neurological Diseases and Blindness, Bethesda, Maryland, 1968. 18. Santen, R. J., J. M. Leonard, R. T. Sherins, H. M. Gandy, and C. A. Paulsen, Short and long effects of clomiphene citrate on the pituitary-testicular axis,./ Clin Endocrinol Metab 33: 970, 1971. 19. Christiansen, P. Urinary gonadotrophins in nine fertile eunuchs, Ada Endocrinol (Kbh) 71: 454, 1972. 20. del Pozo, E., E. Bolte, and M. Very, Suprasellar disturbance in the syndrome of fertile eunuchoidism: Case report, Ada Endocrinol (Kbh) 80: 165, 1975.

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Clinical and laboratory heterogeneity in idiopathic hypogonadotropic hypogonadism.

Clinical and Laboratory Heterogeneity in Idiopathic Hypogonadotropic Hypogonadism ROBERT M. BOYAR,* R. H. K. WU, S. KAPEN, LEON HELLMAN, E. D. WEITZMA...
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