Correlation Between Integrated LH and FSH Levels and the Response to Luteinizing Hormone Releasing Factor (LRF) R. H. MORTIMER, N. FLEISCHER, M. LEV-GUR, AND R. G. FREEMAN Departments of Medicine and Obstetrics and Gynecology, Albert Einstein College of Medicine, Bronx, New York 10461 ABSTRACT. Integrated blood plasma levels of LH and FSH and their response to the iv administration of 100 fx.g synthetic LRF were studied in 29 normal subjects, 12 women with Stein-Leventhal syndrome, 8 subjects with primary gonadal failure, 7 women with Sheehan's syndrome, 20 subjects with pituitary tumors, 10 subjects with idiopathic gonadotropin deficiency and 5 subjects with hypothalamic tumors. Within each group there was considerable variation in the response of LH and FSH levels to LRF. In each group there was a statistically significant positive correlation between basal integrated gonadotropin levels and the response of the levels to LRF. Both within groups and
T
HE AVAILABILITY of purified synthetic hypothalamic releasing factors for human studies has added a new dimension to the investigation of anterior pituitary function. Administration of a single iv injection of thyrotropin releasing hormone (TRH) to subjects with secondary hypothyroidism results in differential patterns of thyrotropin (TSH) secretory response. In some subjects there is no secretion following TRH administration, but in others TSH release occurs in a normal fashion (1-3). It has been suggested (1,2) that in the first group a lesion at the pituitary level is responsible both for the inadequate TSH secretion and the failure to respond to exogenous TRH whereas in the second group a hypothalamic lesion exists preventing release of endogenous TRH and consequent failure of TSH secretion. Although no definitive evidence Received November 10, 1975. Supported by Giants RR50 from the General Clinical Research Center Program and AM 17326 from the N.I.H. Reprint requests to: Robin Mortimer, MB, FRACP. Division of Endocrinology, Department of Medicine,. Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461.
between groups, the best indicator of the response to LRF was the basal levels of FSH and LH. In subjects with hypogonadotropic hypogonadism there was no significant difference in mean basal LH levels and mean response to LRF between patients with primarily pituitary disease (pituitary tumors or Sheehan's syndrome) and conditions which might represent hypothalamic disease (hypothalamic tumors or idiopathic gonadotropin deficiency). The response to an acute, single, injection of LRF appears to more directly reflect basal gonadotropin levels rather than disease category. (J Clin Endocrinol Metab 43: 1240, 1976)
exists that these interpretations are correct, the latter syndrome has been called hypothalamic hypothyroidism and is seen most commonly in patients with idopathic deficiency of TSH and in some subjects with pituitary tumors (1-3). It was reasonable to expect similar differential patterns of gonadotropin secretory response after the administration of luteinizing hormone releasing factor (LRF) to subjects with hypogonadotropic hypogonadism. Attempts have been made to localize the anatomic site of the lesion in gonadotropin secretion in patients by the response to a single injection of LRF. These include the description of women with secondary amenorrhea who respond normally to LRF and therefore are thought to have a hypothalamic disturbance (4,5). Additionally, subjects with idiopathic gonadotropin deficiency have been classified into those who release substantial amounts of gonadotropin after LRF administration, suggesting a hypothalamic lesion, and those unresponsive to a bolus injection of LRF where it is felt that a pituitary lesion exists (6). In the latter studies, the classification of a hypothalamic versus a pituitary lesion
1240
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LRF EFFECTS ON LH AND FSH LEVELS has been made on the basis of the response to LRF and not on any other independent parameters. Thus, a firm conclusion that LRF testing will differentiate the functionally anatomic lesion is not totally warranted. Indeed, it has been reported by Mortimer et al. that most subjects with gonadotropin deficiency respond to LRF with a variable but definite increase in gonadotropin secretion irrespective of the clinical cause of the gonadotropin deficiency, leading these investigators to conclude that a single dose of LRF, in their hands, offered little help in differentiating the anatomic site of the lesion (7). Our previous experience (8) and the results reported here also suggest that a single iv injection of 100 fxg LRF does not cause a different pattern of LH and FSH secretion in hypogonadotropic subjects with Sheehan's syndrome, pituitary tumors, hypothalamic tumors or idiopathic gonadotropic deficiency. Furthermore, our data show that gonadotropin levels following LRF administration in hypogonadotropic, hypergonadotropic and normal subjects are proportional to basal gonadotropin levels, indicating that a single iv injection of LRF offers little information additional to that derived from measuring basal gonadotropin levels. Materials and Methods The subjects were divided into the following groups. a. Normal controls There were 9 normal potent male laboratory personnel or medical students (aged 23-53 years). Physical examination was normal. Semen analysis was not done. Twenty normally menstruating women (aged 19-35 years) were tested: 7 subjects in the early follicular phase (day 1-4), 8 subjects in the mid-foilicular phase (day 8-10) and 5 subjects in the late follicular phase (day 11-14). h. Pituitary tumors Twelve men (aged 20-54) and 8 women (aged 15-44) were regarded as having hypogonadotropic hypogonadism secondary to a pituitary
1241
tumor by one or more of the following criteria: an enlarged and/or eroded sella turcica, bitemporal hemianopsia or angiographic, pneumoencephalographic or surgical evidence of pituitary tumor. All of these patients with pituitary tumors were hypogonadal as judged by lower than normal plasma levels of FSH, LH and estrogen or testosterone. c. Sheehan's syndrome This diagnosis was made in 7 women (aged 48-69) based on the demonstration of deficiency of gonadotropins with or without the absence of other pituitary hormones, the absence of sella turcica enlargement or visual field defects and a history of traumatic delivery followed by the failure to lactate and resume menstruation. d. Hypothalamic tumors Two men and 2 women (aged 21-32) had operative evidence of a suprasellar craniopharyngioma and a 17-year-old girl had an operatively documented third ventricular tumor invading the hypothalamus. All five were hypogonadal. e. Idiopathic gonadotropin deficiency The diagnosis of idiopathic gonadotropin deficiency was made in 5 men and 5 women (aged 23-37). This diagnosis was based on the absence of puberty and presence of hypogonadotropic hypogonadism with no evidence of a pituitary tumor. One man and 1 woman were anosmia /. Stein-Leventhal
syndrome
Twelve women (aged 18-37) with oligoamenorrhea, hirsutism, enlarged ovaries and infertility were regarded as having SteinLeventhal syndrome. g. Primary gonadal insufficiency Eight subjects (aged 8-77) with primary gonadal insufficiency were studied. Four women had been oophorectomized and 1 woman, aged 77, was 26 years postmenopausal. All had elevated gonadotropin levels. Three males (aged 4-9) had congenital anorchia as judged by absence of scrotal or inguinal testes, high gonadotropin levels relative to their age and failure of low testosterone levels to rise after the intramuscular injection of 3000IU of human chorionic gonadotropin (A.P.L. Ayerst) daily for three days.
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50
T
HE AVAILABILITY of purified synthetic hypothalamic releasing factors for human studies has added a new dimension to the investigation of anterior pituitary function. Administration of a single iv injection of thyrotropin releasing hormone (TRH) to subjects with secondary hypothyroidism results in differential patterns of thyrotropin (TSH) secretory response. In some subjects there is no secretion following TRH administration, but in others TSH release occurs in a normal fashion (1-3). It has been suggested (1,2) that in the first group a lesion at the pituitary level is responsible both for the inadequate TSH secretion and the failure to respond to exogenous TRH whereas in the second group a hypothalamic lesion exists preventing release of endogenous TRH and consequent failure of TSH secretion. Although no definitive evidence Received November 10, 1975. Supported by Giants RR50 from the General Clinical Research Center Program and AM 17326 from the N.I.H. Reprint requests to: Robin Mortimer, MB, FRACP. Division of Endocrinology, Department of Medicine,. Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461.
between groups, the best indicator of the response to LRF was the basal levels of FSH and LH. In subjects with hypogonadotropic hypogonadism there was no significant difference in mean basal LH levels and mean response to LRF between patients with primarily pituitary disease (pituitary tumors or Sheehan's syndrome) and conditions which might represent hypothalamic disease (hypothalamic tumors or idiopathic gonadotropin deficiency). The response to an acute, single, injection of LRF appears to more directly reflect basal gonadotropin levels rather than disease category. (J Clin Endocrinol Metab 43: 1240, 1976)
exists that these interpretations are correct, the latter syndrome has been called hypothalamic hypothyroidism and is seen most commonly in patients with idopathic deficiency of TSH and in some subjects with pituitary tumors (1-3). It was reasonable to expect similar differential patterns of gonadotropin secretory response after the administration of luteinizing hormone releasing factor (LRF) to subjects with hypogonadotropic hypogonadism. Attempts have been made to localize the anatomic site of the lesion in gonadotropin secretion in patients by the response to a single injection of LRF. These include the description of women with secondary amenorrhea who respond normally to LRF and therefore are thought to have a hypothalamic disturbance (4,5). Additionally, subjects with idiopathic gonadotropin deficiency have been classified into those who release substantial amounts of gonadotropin after LRF administration, suggesting a hypothalamic lesion, and those unresponsive to a bolus injection of LRF where it is felt that a pituitary lesion exists (6). In the latter studies, the classification of a hypothalamic versus a pituitary lesion
1240
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 16 November 2015. at 05:48 For personal use only. No other uses without permission. . All rights reserved.
LRF EFFECTS ON LH AND FSH LEVELS has been made on the basis of the response to LRF and not on any other independent parameters. Thus, a firm conclusion that LRF testing will differentiate the functionally anatomic lesion is not totally warranted. Indeed, it has been reported by Mortimer et al. that most subjects with gonadotropin deficiency respond to LRF with a variable but definite increase in gonadotropin secretion irrespective of the clinical cause of the gonadotropin deficiency, leading these investigators to conclude that a single dose of LRF, in their hands, offered little help in differentiating the anatomic site of the lesion (7). Our previous experience (8) and the results reported here also suggest that a single iv injection of 100 fxg LRF does not cause a different pattern of LH and FSH secretion in hypogonadotropic subjects with Sheehan's syndrome, pituitary tumors, hypothalamic tumors or idiopathic gonadotropic deficiency. Furthermore, our data show that gonadotropin levels following LRF administration in hypogonadotropic, hypergonadotropic and normal subjects are proportional to basal gonadotropin levels, indicating that a single iv injection of LRF offers little information additional to that derived from measuring basal gonadotropin levels. Materials and Methods The subjects were divided into the following groups. a. Normal controls There were 9 normal potent male laboratory personnel or medical students (aged 23-53 years). Physical examination was normal. Semen analysis was not done. Twenty normally menstruating women (aged 19-35 years) were tested: 7 subjects in the early follicular phase (day 1-4), 8 subjects in the mid-foilicular phase (day 8-10) and 5 subjects in the late follicular phase (day 11-14). h. Pituitary tumors Twelve men (aged 20-54) and 8 women (aged 15-44) were regarded as having hypogonadotropic hypogonadism secondary to a pituitary
1241
tumor by one or more of the following criteria: an enlarged and/or eroded sella turcica, bitemporal hemianopsia or angiographic, pneumoencephalographic or surgical evidence of pituitary tumor. All of these patients with pituitary tumors were hypogonadal as judged by lower than normal plasma levels of FSH, LH and estrogen or testosterone. c. Sheehan's syndrome This diagnosis was made in 7 women (aged 48-69) based on the demonstration of deficiency of gonadotropins with or without the absence of other pituitary hormones, the absence of sella turcica enlargement or visual field defects and a history of traumatic delivery followed by the failure to lactate and resume menstruation. d. Hypothalamic tumors Two men and 2 women (aged 21-32) had operative evidence of a suprasellar craniopharyngioma and a 17-year-old girl had an operatively documented third ventricular tumor invading the hypothalamus. All five were hypogonadal. e. Idiopathic gonadotropin deficiency The diagnosis of idiopathic gonadotropin deficiency was made in 5 men and 5 women (aged 23-37). This diagnosis was based on the absence of puberty and presence of hypogonadotropic hypogonadism with no evidence of a pituitary tumor. One man and 1 woman were anosmia /. Stein-Leventhal
syndrome
Twelve women (aged 18-37) with oligoamenorrhea, hirsutism, enlarged ovaries and infertility were regarded as having SteinLeventhal syndrome. g. Primary gonadal insufficiency Eight subjects (aged 8-77) with primary gonadal insufficiency were studied. Four women had been oophorectomized and 1 woman, aged 77, was 26 years postmenopausal. All had elevated gonadotropin levels. Three males (aged 4-9) had congenital anorchia as judged by absence of scrotal or inguinal testes, high gonadotropin levels relative to their age and failure of low testosterone levels to rise after the intramuscular injection of 3000IU of human chorionic gonadotropin (A.P.L. Ayerst) daily for three days.
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