Hypothalamic-Pituitary-Gonadal Function in Patients with Myotonic Dystrophy FREDDY FEBRES, 1 HUGO SCAGLIA, RUB&N LISKER, JORGE ESPINOSA,1 TOMAS MORATO, MARIO SHKUROVICH, AND GREGORIO P&REZ-PALACIOS Departments of Reproductive Biology and Genetics, Instituto National de la Nutrition, Mexico 22, D. F., and Department of Neurophysiology, Hospital del niho, IMAN, Mexico characteristics. In the same family, hypothalamic amenorrhea was observed in the female patient, and hypothalamic eunuchoidism and hypergonadotropic hypogonadism with marked tubular and leydig cells failure in the male patients. The non-related male patient had hypergonadotropic hypogonadism with tubular failure but with a compensatory leydig-cell hyperplasia. These data are interpreted as demonstrating different expressivity of the hypogonadism associated with the same inherited muscle disease. (J Clin Endocrinol Metab 41: 833, 1975)
ABSTRACT. Gonadal function was studied in three post-pubertal siblings (two male and one female) and one unrelated male patient with myotonic dystrophy. The diagnosis was confirmed in all cases by electromyography and muscle biopsy. Basal levels of plasma immunoreactive LH, FSH, testosterone, and estradiol were measured. Hypothalamic, pituitary, and gonadal reserve and responsiveness were evaluated by clomiphene, LHRH, and hCG tests. Histologic examination of gonadal biopsies was also performed. The results showed that gonadal failure present in the four patients had different
T
HE clinical features of the hypogonadism frequently associated with myotonic dystrophy (MD) have been well established (1-4). Steinert (5) in 1909 was the first to report the finding of atrophic testes and baldness in patients with MD. Druckeret al. (6) presented evidence of the primary nature of tubular atrophy and demonstrated that the testicular lesion in patients with this inherited disease differs morphologically and clinically from that observed in patients with Klinefelter's Syndrome. Several reports on the urinary gonadotropin excretion in MD have shown a wide range of variability from undetectable to normal and some time-elevated titers (1,6-8). However, recently Harper et al. (9) studied the hormone profile of many of these patients and demonstrated that the mean radioimmunoassayable serum FSH and LH Received December 30, 1974. Supported by grants from the Ford Foundation, the Population Council, and the International Development Research Center. 1 Graduate student. The Reproductive Biology training Program. Instituto Nacional de la Nutricion. Reprints and correspondence: Dr. Gregorio PerezPalacios, Associate Professor, Department of Reproductive Biology, Instituto Nacional de la Nutricion, Viaducto Tlalpan y San Fernando, Mexico 22, D. F.
levels were significantly greater than those observed in normal men, indicating that primary gonadal failure accounted for the hypogonadism in most of the male patients. Although menstrual disorders have been reported to occur in female patients with MD (10), little information is available regarding the nature of the gonadal failure if any. This paper reports studies of pituitary and gonadal function in three post-pubertal siblings and one unrelated patient with hypogonadism associated to MD. Materials and Methods 1) Clinical summaries Figure 1 shows the pedigrees of the two families studied. Family T R.T. The propositus (Fig. 1, III-4) is a 36-yrold man referred to the Endocrine Outpatient Clinic because of hypogenitalism. The patient was the second child in a family of 6, born by normal full-term delivery after an uneventful pregnancy. Muscle function was normal during early childhood. Mental retardation was noted at 7 years of age and he was unable to attend school. Muscle weakness with a moderate degree of myotonia was first observed at 12 years of age.
833
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 August 2016. at 00:32 For personal use only. No other uses without permission. . All rights reserved.
834
FEBRES ETAL.
JCE & M • 1975 V o U l . No 5
FAMILY : T
* kkkkk M
FAMILY: M
FIG. 1. Pedigrees of the two families with myotonic dystrophy included in this study.
I
m
on
CATARACTS
/
DECEASED
AFFECTED
E
EXAMINED
SAID TO BE AFFECTED
/
PROPOSITI
He remained sexually immature. Cryptorchid testes required orchiopexy when the patient was 23 years old. Physical examination revealed eunochoidal body proportions (upper/lower segment ratio = 0.7). Vital signs were normal. A left cataract and a cleft palate were noted. Normal olfactory function was demonstrated. Generalized distal muscle atrophy with myotonia were found. Scarce axillary, facial, and pubic hair were noted. The external genitalia were infantile. The testes were extremely small (1.5 x 2 x 1.5 cm) and soft. Buccal mucosal cells did not show the Barr body and the cytogenetic examination of leukocytes revealed a 46 XY chromosome constitution. X-ray films revealed an internal frontal hyperostosis and a normal sella turcica. Plasma levels of LH, FSH, and T were undetectable (Table 1) while plasma TSH, T3, and T4 were within normal levels. TRH injection induced a significant increase of plasma TSH. The 24-h
urinary excretion of 17-OH corticosteroids were normal and psychological examination revealed anl.Q. of 49. L.T. A 34-yr-old man (Fig. 1, III-5), brother of the propositus, had muscle weakness, mental retardation, and a decrease of libido which started when the patient was 16 years of age. His childhood and adolescence was apparently normal and puberty began at 12 years of age. Physical examination revealed a phenotypic normal male with normal body proportions and severe muscular dystrophy. Myotonia was more evident than in his older sibling. Vital signs were normal. Normal sexual hair and lack of cataracts were observed. The penis was of a normal size (9 cm length) and the testes were small (3.5 x 2 x 1 cm) and firm. X-ray films showed a normal bone age, and internal frontal hyperostosis. The chromosome complement was 46 XY and his I.Q. was 61. E.T. A 26-yr-old female (Fig. 1, III-7) sister of
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 August 2016. at 00:32 For personal use only. No other uses without permission. . All rights reserved.
ENDOCRINE FUNCTION IN MYOTONIC DYSTROPHY TABLE
835
1. Basal levels of pituitary and sex steroid honnones in patients with myotonic dystrophy Plasma
Patients
Sex
Age
LH ng/ml
RT LT ET JM
Male Male Female Male
36 34 26 21
20.0 124.5 45.1 105.6
TSH
FSH ng/ml
li\J/m 1
50.0 640.0 100.0 1000.0
3.7 4.2 3.8 4.5
the propositus, presented muscle weakness, mental retardation, and amenorrhea. Her childhood was normal until age 6 when mental retardation was noted; she was unable to perform school work. She started breast development, menstrual bleeding, and sexual hair growth at 12 years of age. Muscle weakness and myotonia were evident two years later, and menstrual disorders began at the same time. She experienced periods of amenorrhea of 6-months duration. Neither hirsutism nor virilization were noted. Vaginal smears demonstrated estrogenic activity, and a pneumopelvigraphy showed ovaries of normal size and shape. Chromosome complement was 46 XX. X-rays films revealed normal bone age and frontal hyperostosis. Family M. J.M. (Fig. 1, Family M IV-2). The propositus, a 21-yr-old man presented muscle weakness and dystrophy. His childhood and adolescence were normal. External genitalia and sexual characteristics developed in a normal fashion at the expected time. His muscle weakness started when he was 17 years of age, and a decrease in libido was recently noted. Physical examination revealed normal body proportions and normal sexual hair growth. The penis (8.5 cm length) and testes (4 x 3.5 x 2 cm) were of normal size although both testes were slightly hard. Lack of ejaculation precluded sperm examination. Vital signs were normal and no gross somatic alterations were noted. His I.Q. was within the normal range and he has been able to attend university successfully. The electromyograms and muscle biopsies in several muscle groups performed in the four patients were consistent with the diagnosis of myotonic dystrophy (11-14). In addition, measurement of esophageal muscular activity in the four subjects revealed dystrophic alterations as
T ng/ml
E2 pg/ml
0.1 1.2 400.0 4.8
/xg/100ml
Urine 17-OH CS mg/24 h
9.7 9.3 10.1 10.0
3.2 4.1 3.9 5.0
has been previously described in this inherited disease (15). 2) Methods Assays. Plasma LH and FSH were measured by double-antibody radioimmunoassays (RIA) as previously described (16). Results were expressed as ng/ml of the LER-907 preparation. Samples were assayed in duplicate at two different dilutions to ascertain parallelism with the standard curves. The inter-assay coefficients of variation for LH and FSH were 11.5% and 10.1%, respectively, whereas the LH and FSH intraassay coefficients of variation were 9.1% and 5.0%. The limits of LH and FSH levels in normal men were 54.7 ± 27.5 ng/ml and 172.0 ± 76.5 ng/ml. Cyclic variations in normal women have been previously published (17). Steroid hormone determinations were carried out by RIA as has been described (18-20) with some modifications. Plasma concentrations of progesterone (P4) were measured by hapten-RIA using antisera against P 4 -lla-bovine serum albumin (BSA) complex at 1:1000 dilution. A high specificity with no cross-reactivity with related C2i or Cj 9 steroids permitted the assay to be performed without chromatography. The interand intra-assay coefficients of variation were 9% and 5%, respectively, and the assay sensitivity was 50 pg/ml. The range of values obtained throughout the normal menstrual cycle (n = 12) were in follicular phase (FP) 50-1000 pg/ml and in luteal phase (LP) 2-18 ng/ml. Plasma testosterone (T) determinations were carried out by a direct hapten-RIA using antisera against T-17 /3-BSA at a dilution of 1:3500. The only steroid which showed significant crossreactivity was 5a-dihydrotestosterone (17%). The intra- and inter-assay coefficients of variation were 15% and 12%, respectively, and the assay sensitivity was 50 pg/ml. Values in normal men
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 August 2016. at 00:32 For personal use only. No other uses without permission. . All rights reserved.
FEBRES ETAL.
836
(n = 20) were 3-7 ng/ml and in normal women 0.2-0.8 ng/ml. Plasma estradiol (E2) was assayed by a direct hapten-RIA using antisera against E2-17/-J-BSA at a dilution of 1:50,000. At that dilution the only phenolic steroid that showed cross-reactivity with the antisera was estrone and that to a very limited extent (
ABSTRACT. Gonadal function was studied in three post-pubertal siblings (two male and one female) and one unrelated male patient with myotonic dystrophy. The diagnosis was confirmed in all cases by electromyography and muscle biopsy. Basal levels of plasma immunoreactive LH, FSH, testosterone, and estradiol were measured. Hypothalamic, pituitary, and gonadal reserve and responsiveness were evaluated by clomiphene, LHRH, and hCG tests. Histologic examination of gonadal biopsies was also performed. The results showed that gonadal failure present in the four patients had different
T
HE clinical features of the hypogonadism frequently associated with myotonic dystrophy (MD) have been well established (1-4). Steinert (5) in 1909 was the first to report the finding of atrophic testes and baldness in patients with MD. Druckeret al. (6) presented evidence of the primary nature of tubular atrophy and demonstrated that the testicular lesion in patients with this inherited disease differs morphologically and clinically from that observed in patients with Klinefelter's Syndrome. Several reports on the urinary gonadotropin excretion in MD have shown a wide range of variability from undetectable to normal and some time-elevated titers (1,6-8). However, recently Harper et al. (9) studied the hormone profile of many of these patients and demonstrated that the mean radioimmunoassayable serum FSH and LH Received December 30, 1974. Supported by grants from the Ford Foundation, the Population Council, and the International Development Research Center. 1 Graduate student. The Reproductive Biology training Program. Instituto Nacional de la Nutricion. Reprints and correspondence: Dr. Gregorio PerezPalacios, Associate Professor, Department of Reproductive Biology, Instituto Nacional de la Nutricion, Viaducto Tlalpan y San Fernando, Mexico 22, D. F.
levels were significantly greater than those observed in normal men, indicating that primary gonadal failure accounted for the hypogonadism in most of the male patients. Although menstrual disorders have been reported to occur in female patients with MD (10), little information is available regarding the nature of the gonadal failure if any. This paper reports studies of pituitary and gonadal function in three post-pubertal siblings and one unrelated patient with hypogonadism associated to MD. Materials and Methods 1) Clinical summaries Figure 1 shows the pedigrees of the two families studied. Family T R.T. The propositus (Fig. 1, III-4) is a 36-yrold man referred to the Endocrine Outpatient Clinic because of hypogenitalism. The patient was the second child in a family of 6, born by normal full-term delivery after an uneventful pregnancy. Muscle function was normal during early childhood. Mental retardation was noted at 7 years of age and he was unable to attend school. Muscle weakness with a moderate degree of myotonia was first observed at 12 years of age.
833
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 August 2016. at 00:32 For personal use only. No other uses without permission. . All rights reserved.
834
FEBRES ETAL.
JCE & M • 1975 V o U l . No 5
FAMILY : T
* kkkkk M
FAMILY: M
FIG. 1. Pedigrees of the two families with myotonic dystrophy included in this study.
I
m
on
CATARACTS
/
DECEASED
AFFECTED
E
EXAMINED
SAID TO BE AFFECTED
/
PROPOSITI
He remained sexually immature. Cryptorchid testes required orchiopexy when the patient was 23 years old. Physical examination revealed eunochoidal body proportions (upper/lower segment ratio = 0.7). Vital signs were normal. A left cataract and a cleft palate were noted. Normal olfactory function was demonstrated. Generalized distal muscle atrophy with myotonia were found. Scarce axillary, facial, and pubic hair were noted. The external genitalia were infantile. The testes were extremely small (1.5 x 2 x 1.5 cm) and soft. Buccal mucosal cells did not show the Barr body and the cytogenetic examination of leukocytes revealed a 46 XY chromosome constitution. X-ray films revealed an internal frontal hyperostosis and a normal sella turcica. Plasma levels of LH, FSH, and T were undetectable (Table 1) while plasma TSH, T3, and T4 were within normal levels. TRH injection induced a significant increase of plasma TSH. The 24-h
urinary excretion of 17-OH corticosteroids were normal and psychological examination revealed anl.Q. of 49. L.T. A 34-yr-old man (Fig. 1, III-5), brother of the propositus, had muscle weakness, mental retardation, and a decrease of libido which started when the patient was 16 years of age. His childhood and adolescence was apparently normal and puberty began at 12 years of age. Physical examination revealed a phenotypic normal male with normal body proportions and severe muscular dystrophy. Myotonia was more evident than in his older sibling. Vital signs were normal. Normal sexual hair and lack of cataracts were observed. The penis was of a normal size (9 cm length) and the testes were small (3.5 x 2 x 1 cm) and firm. X-ray films showed a normal bone age, and internal frontal hyperostosis. The chromosome complement was 46 XY and his I.Q. was 61. E.T. A 26-yr-old female (Fig. 1, III-7) sister of
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 August 2016. at 00:32 For personal use only. No other uses without permission. . All rights reserved.
ENDOCRINE FUNCTION IN MYOTONIC DYSTROPHY TABLE
835
1. Basal levels of pituitary and sex steroid honnones in patients with myotonic dystrophy Plasma
Patients
Sex
Age
LH ng/ml
RT LT ET JM
Male Male Female Male
36 34 26 21
20.0 124.5 45.1 105.6
TSH
FSH ng/ml
li\J/m 1
50.0 640.0 100.0 1000.0
3.7 4.2 3.8 4.5
the propositus, presented muscle weakness, mental retardation, and amenorrhea. Her childhood was normal until age 6 when mental retardation was noted; she was unable to perform school work. She started breast development, menstrual bleeding, and sexual hair growth at 12 years of age. Muscle weakness and myotonia were evident two years later, and menstrual disorders began at the same time. She experienced periods of amenorrhea of 6-months duration. Neither hirsutism nor virilization were noted. Vaginal smears demonstrated estrogenic activity, and a pneumopelvigraphy showed ovaries of normal size and shape. Chromosome complement was 46 XX. X-rays films revealed normal bone age and frontal hyperostosis. Family M. J.M. (Fig. 1, Family M IV-2). The propositus, a 21-yr-old man presented muscle weakness and dystrophy. His childhood and adolescence were normal. External genitalia and sexual characteristics developed in a normal fashion at the expected time. His muscle weakness started when he was 17 years of age, and a decrease in libido was recently noted. Physical examination revealed normal body proportions and normal sexual hair growth. The penis (8.5 cm length) and testes (4 x 3.5 x 2 cm) were of normal size although both testes were slightly hard. Lack of ejaculation precluded sperm examination. Vital signs were normal and no gross somatic alterations were noted. His I.Q. was within the normal range and he has been able to attend university successfully. The electromyograms and muscle biopsies in several muscle groups performed in the four patients were consistent with the diagnosis of myotonic dystrophy (11-14). In addition, measurement of esophageal muscular activity in the four subjects revealed dystrophic alterations as
T ng/ml
E2 pg/ml
0.1 1.2 400.0 4.8
/xg/100ml
Urine 17-OH CS mg/24 h
9.7 9.3 10.1 10.0
3.2 4.1 3.9 5.0
has been previously described in this inherited disease (15). 2) Methods Assays. Plasma LH and FSH were measured by double-antibody radioimmunoassays (RIA) as previously described (16). Results were expressed as ng/ml of the LER-907 preparation. Samples were assayed in duplicate at two different dilutions to ascertain parallelism with the standard curves. The inter-assay coefficients of variation for LH and FSH were 11.5% and 10.1%, respectively, whereas the LH and FSH intraassay coefficients of variation were 9.1% and 5.0%. The limits of LH and FSH levels in normal men were 54.7 ± 27.5 ng/ml and 172.0 ± 76.5 ng/ml. Cyclic variations in normal women have been previously published (17). Steroid hormone determinations were carried out by RIA as has been described (18-20) with some modifications. Plasma concentrations of progesterone (P4) were measured by hapten-RIA using antisera against P 4 -lla-bovine serum albumin (BSA) complex at 1:1000 dilution. A high specificity with no cross-reactivity with related C2i or Cj 9 steroids permitted the assay to be performed without chromatography. The interand intra-assay coefficients of variation were 9% and 5%, respectively, and the assay sensitivity was 50 pg/ml. The range of values obtained throughout the normal menstrual cycle (n = 12) were in follicular phase (FP) 50-1000 pg/ml and in luteal phase (LP) 2-18 ng/ml. Plasma testosterone (T) determinations were carried out by a direct hapten-RIA using antisera against T-17 /3-BSA at a dilution of 1:3500. The only steroid which showed significant crossreactivity was 5a-dihydrotestosterone (17%). The intra- and inter-assay coefficients of variation were 15% and 12%, respectively, and the assay sensitivity was 50 pg/ml. Values in normal men
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 August 2016. at 00:32 For personal use only. No other uses without permission. . All rights reserved.
FEBRES ETAL.
836
(n = 20) were 3-7 ng/ml and in normal women 0.2-0.8 ng/ml. Plasma estradiol (E2) was assayed by a direct hapten-RIA using antisera against E2-17/-J-BSA at a dilution of 1:50,000. At that dilution the only phenolic steroid that showed cross-reactivity with the antisera was estrone and that to a very limited extent (
