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A primary culture of chicken adenohypophyseal cells has been developed to study the regulation of growth hormone (GH) secretion. Following collagenase dispersion, cells were exposed for 2 hr to vehicle (control) or test agents. Human pancreatic (tumor) growth hormone-releasing factor (hpGRF) and rat hypothalamic growth hormone-releasing factor stimulated GH release to similar levels. GH release was increased by the presence of dibutyryl cyclic AMP. Thyrotropin-releasing hormone (TRH) alone did not influence GH release; however, TRH plus hpGRF together exerted a synergistic (greater than additive) effect, increasing GH release by 100 to 300% over the sum of the values for each secretagogue acting alone. These relationships between TRH and hpGRF were further examined in cultured cells exposed to secretagogues for two consecutive 2-hr incubations. TRH pretreatment enhanced subsequent hpGRF-stimulated GH release by about 80% over that obtained if no secretagogue was present during the first incubation. In other experiments, somatostatin (SRIF) alone did not alter GH secretion. However, SRIF reduced hpGRF-stimulated GH release to levels found in controls. Furthermore, GH release stimulated by the presence of both TRH and hpGRF was lowered to control values by SRIF. The results of these studies demonstrate that a primary culture of chicken adenohypophyseal cells is a useful model for the study of GH secretion. Indeed, these results suggest that TRH and hpGRF regulate GH secretion by mechanisms which are not identical.
Effects of growth hormone-releasing hormone (GRH) and corticotropin-releasing hormone (CRH) on the release of immunoreactive thyrotropin-releasing hormone (ir-TRH) from the rat hypothalamus in vitro were studied. The rat hypothalamus was incubated in medium 199 with 1.0 mg/ml of bacitracin (pH 7.4) for 20 min. The amount of ir-TRH release into the medium was measured by radioimmunoassay. The ir-TRH release from the rat hypothalamus was inhibited significantly in a dose-related manner with the addition of GRH or CRH. These findings suggest that GRH and CRH inhibit ir-TRH release from the rat hypothalamus in vitro.
In 16 patients with metastatic testicular cancer and 10 age matched male control subjects growth hormone (GH) responses to growth hormone releasing hormone (GHRH; 1 microgram/kg body weight iv.) and thyrotropin releasing hormone (TRH; 200 micrograms iv.) were measured. Basal GH levels and GH levels following stimulation with GHRH or TRH were significantly increased in cancer patients compared to control subjects. 9 patients with testicular cancer were studied both in the stage of metastatic disease and after they had reached a complete remission. In complete remission GH responses to GHRH tended to decrease but the differences did not reach statistical significance. Our data suggest an alteration of hypothalamic and/or pituitary regulation of GH secretion in patients with metastatic testicular cancer.
To determine the etiology of male hypogonadism in a newly found mutant rat (hgn/hgn, with a single autosomal recessive trait), concentrations of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured, and the responsiveness of the urogenital organs, hypothalamus, and pituitary gland to testosterone (1 mg/kg s.c. for 7 days), FSH (0.3 AU/kg s.c. for 7 days), human chorionic gonadotropin (hCG) (40 IU/kg s.c. for 7 days), and luteinizing hormone-releasing hormone (LHRH) (0.5 or 5.0 micrograms/kg s.c. for 7 days) were tested. Treatment with testosterone only increased the weights of all of the accessory sex organs, whereas treatment with FSH, hCG, or LHRH did not. Levels of serum FSH and LH were extremely higher and testosterone was lower in hgn/hgn males than in normal males. Serum FSH and LH decreased to levels found in intact animals after treatment with testosterone, suggesting that hypothalamic responsiveness to exogenous testosterone is present in the hgn/hgn males. Thus, the status of the hgn/hgn males was indicated to be due to primary Leydig cell dysfunction.
The effect of intravenous injection of thyrotropin-releasing hormone (TRH) on the plasma concentrations of growth hormone (GH) and growth hormone-releasing hormone (GHRH) was studied in seven patients with acromegaly and in five control subjects. TRH had no effect on plasma GH or GHRH in the five control subjects. A 'paradoxical' increase in plasma GH in response to TRH was observed in four of the seven patients with acromegaly. In these four patients plasma GHRH also increased in response to TRH. No TRH-induced increase in GHRH levels was observed in the other three patients with acromegaly who did not display an increase in GH in response to TRH. The present results imply that GHRH may be involved in the plasma GH response to TRH in patients with acromegaly.
Growth hormone-releasing hormone (GHRH) regulates growth hormone release from the pituitary. However, in addition to this neuroendocrine action, much evidence implies an additional role for GHRH in carcinogenesis in non-pituitary tissues. This role of GHRH in cancer development appears to be due to the operation of several mechanisms, which involve the regulation of the growth hormone-dependent hepatic insulin-like growth factor I (IGFI) production, tumoural IGF-I and IGF-II secretion and direct action of GHRH on tumour cells by autocrine and/or paracrine pathways. This review summarises the available information regarding the role of GHRH in tumorigenesis with special emphasis on the direct action of GHRH in primary and experimental cancers.
Only a proportion of normal men participating in testosterone-based contraceptive trials develop azoospermia (responders). This study analyzed whether serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and sex hormone-binding globulin (SHBG) are qualitatively different between responders and non-responders. Determination of in vitro bioactive FSH after stimulation with gonadotropin-releasing hormone (GnRH) and analysis of molecular heterogeneity of serum FSH, LH and SHBG was carried out by chromatofocusing and concanavalin-A affinity chromatography in eight men who had participated in a previous contraceptive study with testosterone buciclate. Blood was withdrawn at 15-min intervals on two basal occasions and 30, 45 and 60 min after i.v. administration of GnRH (100 micrograms). Pools of sera were separated by chromatofocusing in the pH range 3-6 and by lectin chromatography on concanavalin A. Immunoreactive FSH, LH and SHBG were assayed in the eluates. Bioactive FSH was analyzed by the rat Sertoli cell bioassay. Serum bioactive FSH increased after GnRH stimulation, without significant differences between responders and non-responders. The chromatofocusing profiles of serum FSH showed a significant shift towards the less acidic region after GnRH. The isoform distribution was similar in responders and non-responders. No significant differences were found in the relative proportion of FSH, LH and SHBG retained by concanavalin A. It is concluded that the extent of suppression of sperm production by androgen administration cannot be foreseen either on the basis of the response of bioactive FSH to GnRH administration or from the glycosylation pattern of serum FSH, LH and SHBG.
Growth hormone (GH) responses to growth-hormone-releasing hormone (GRH) and thyrotropin-releasing hormone (TRH) were studied in 17 diabetic patients. Ten patients (group 1) had retinopathy corresponding to stage III-V (Scott's classification), and the remaining seven patients (group 2) had no retinopathy despite longer duration of diabetes in comparison with the patients in group 1. There were no differences in age, percent of ideal body weight, and serum HbA1 levels between the two groups. Basal serum GH levels were 1.9 +/- 0.4 ng/ml (mean +/- SEM) in group 1, and not different from the values in group 2 (1.6 +/- 0.7 ng/ml). However, GH responses to synthetic human GRH-44 (1 micrograms/kg body wt, i.v. bolus) were significantly greater in group 1, as judged by the maximal response or integrated GH secretion after the administration of GRH. There were no differences in serum insulin-like growth factor I (IGF-I) levels between group 1 (262 +/- 35 ng/ml) and group 2 (232 +/- 30 ng/ml), and no significant correlation was found between serum IGF-I levels and GH responses to GRH in either of the two groups. Paradoxical GH responses to TRH (500 micrograms, i.v. bolus) were found in only one patient in each group. We have thus demonstrated that GH responses to GRH are more pronounced in diabetic patients with retinopathy than in patients without this complication, although it remains to be determined whether or not greater GH responses to GRH are causally related to the development of diabetic retinopathy.
We have shown that 4 ng luteinizing hormone releasing hormone (LHRH) pulses induced significantly greater luteinizing hormone (LH) release from proestrous rat superfused anterior pituitary cells with no cycle related differences in follicle stimulating hormone (FSH). Current studies gave 8 ng LHRH in various pulse regimens to study amplitude, duration and frequency effects on LH and FSH secretion from estrous 0800, proestrous 1500 and proestrous 1900 cells. Regimen 1 gave 8 ng LHRH as a single bolus once/h; regimen 2 divided the 8 ng into 3 equal 'minipulses' given at 4 min intervals to extend duration; regimen 3 gave the 3 'minipulses' at 10 min intervals, thereby further extending duration: regimen 4 was the same as regimen 2, except that the 3 'minipulses' were given at a pulse frequency of 2 h rather than 1 h. In experiment 1, all four regimens were employed at proestrus 1900. FSH was significantly elevated by all 8 ng regimens as compared to 4 ng pulses; further, 8 ng divided into 3 equal 'minipulses' separated by 4 min at 1 and 3 h frequencies (regimens 2 and 4) resulted in FSH secretion that was significantly greater than with either a single 8 ng bolus (regimen 1) or when the 'minipulses' were separated by 10 min (regimen 3). In experiment 2, at proestrus 1500, FSH response to the second pulse of regimen 4 was significantly greater than in regimen 2; LH release was significantly suppressed at pulse 2 compared to regimen 2 accentuating divergent FSH secretion. At estrus 0800, FSH response to the second pulse of regimen 4 was significantly stimulated FSH at proestrus 1900, 1500 and estrus 0800, FSH divergence was most marked at proestrus 1500. These data indicate a potential role for hypothalamic LHRH secretory pattern in inducing divergent gonadotropin secretion in the rat.
Regularly cycling rhesus monkeys were bilaterally oophorectomized for study of postcastration rise of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The animals were divided in two groups, control animals, which received vehicle, and experimental animals, which received intramuscularly 1 mg of a potent luteinizing hormone-releasing hormone (LHRH) inhibitory analog ([N-Ac-D-Trp1-3,D-p-Cl-phe2,D-Phe6,D-Ala10]-LH-RH) from the day of castration for 10 days. The controls showed significant elevations of FSH and LH 3 to 4 days after castration, but in the experimental animals the rise in gonadotropins was blocked until the LHRH antagonist administration was discontinued. The dynamics of gonadotropin elevation after the discontinuation of [N-Ac-D-Trp1-3,D-p-Cl-phe2,D-Phe6,D-Ala10]-LH-RH administration were similar to those observed in control animals after castration. The availability of a compound that selectively inhibits FSH and LH secretion in primates opens a new approach to contraception and for the treatment of conditions in which gonadotropin inhibition is desired.
In 14 healthy, potentially fertile men, pituitary gonadotropin responses were studied under standardized conditions. Luteinizing hormone-releasing hormone (LH-RH) was given as a continuous infusion of 1 microgram/minute for 4 hours or in a pulsatile fashion with 20 micrograms as an intravenous bolus at intervals of 20 minutes for 4 hours. Blood was collected continuously by means of an integrated sampling technique. The mean serum luteinizing hormone (LH) concentration showed an oscillating pattern around a plateau level reached within 45 minutes during continuous LH-RH administration. During pulsatile infusion, an identical pattern for the first 45 minutes was observed with, thereafter, a continuous increase from 105 minutes until the end of the infusion. The mean increase in the serum LH level during pulsatile administration was significantly higher (P = 0.00001) than the mean increase seen during continuous infusion. The follicle-stimulating hormone concentration revealed a gradual progressive increase after both methods of stimulation, without a significant difference in the mean increase between the two types of administration. This study demonstrates the existence of a self-priming effect of LH after pulsatile LH-RH administration in the man like that in the woman.
Ten ovulatory women were followed with gonadotropin and steroid determinations through two cycles. They were given 500 micrograms of luteinizing hormone-releasing hormone (LH-RH) during the periovulatory period of the second cycle to determine whether ovulation could be facilitated without altering corpus luteum function. Successive cycles demonstrated concordance for patterns of gonadotropin and steroid secretion when studied as group means. Two control cycles and one treatment cycle were consistent with luteal phase defects. The use of a supramaximal dose of LH-RH in these women neither facilitated ovulation nor adversely affected luteal function. A significant linear correlation was noted between peak LH and follicle-stimulating hormone (FSH) values for the spontaneous surges. This same linear relationship was maintained for the LH and FSH responses to 500 micrograms LH-RH. The present data produce further evidence demonstrating that the secretion of LH and FSH appears to be modulated by gonadal steroids and under the permissive control of a single gonadotropin-releasing hormone.
Effects of parathyroidectomy (PTx) in the rat at the 5th day of gestation on the functional development of gonadotrophin secretion in the infantile offspring was examined. A single subcutaneous injection of 10 micrograms/kg of luteinizing hormone-releasing hormone (LHRH) induced a significant increase in serum follicle stimulating hormone (FSH) and luteinizing hormone (LH) in control- and PTx-F1 male and female rats already at 3 days of age. The response in female rats was greater than in males at all ages examined. In the control- and PTx-F1 rats, age-related increase in the responsiveness to LHRH was observed in both sexes for LH but only in females for FSH. However, LH and FSH release by LHRH in the PTx-F1 female rats was significantly lower than that in control females at 14 and 22 days of age. In the PTx-F1 male rats, only FSH response to LHRH showed a tendency to decrease at 22 days of age. Serum calcium levels in 3-day-old PTx-F1 male and female rats were significantly lower than those in controls but only a slight decrease was observed in the PTx-F1 rats at other ages. The present results indicated that a low serum calcium environment during fetal life in the rat affects the functional development of pituitary responsiveness to LHRH, particularly in females.
The induction of hyperprolactinaemia in the male rat following chronic high-dose oestrogen administration over 3 months was associated with a significant inhibition of the secretion of growth hormone (GH) (P less than 0.02) thyroid stimulating hormone (TSH) (p less than 0.0025), luteinizing hormone (LH) and follicle stimulating hormone (FSH) (both P less than 0.01). Acute, but not chronic, administration of bromocriptine (1 mg/kg) to these hyperprolactinaemic animals had the effect of normalizing the serum levels of GH and TSH but not those of LH or FSH. While the effects observed on GH, TSH, LH and FSH following induction of hyperprolactinaemia are likely to be consequential to brain actions of prolactin, the present data do not exclude the possibility of direct actions of oestrogen itself.
The responses of anesthetised fetal pigs (n=95) and chronically catheterized fetal pigs (n=10) to luteinizing hormone releasing hormone (LHRH) administration (2 micrograms/kg estimated fetal body weight) was investigated. Fetuses were studied at 55, 70, 85, 100, 106 (chronic) and 113 days. Plasma concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were measured by radioimmunoassay. Blood samples were taken from the umbilical artery (anesthetised fetuses) or carotid artery (catheterized fetuses) every 10 min for 1 h except in the youngest age group. No significant sex difference in the LH response to LHRH treatment was observed. The LH response increased with gestational age; average pretreatment plasma concentrations were below 1.1 ng/ml. No response was observed at 55 days, and the highest response was seen at 113 days when plasma LH concentrations rose to 4.3 +/- 0.7 (mean +/- SEM) ng/ml 40 min after treatment. Pretreatment plasma FSH concentrations at 55 days were 1.6 +/- 0.1 ng/ml and gradually rose in males to 3.2 +/- 0.4 ng/ml at 113 days, which was significantly lower than in females where concentrations averaged 8.1 +/- 2.0 ng/ml. LHRH did not significantly affect FSH concentrations in males, while in females a gradually increasing response was observed; at 113 days plasma FSH was 12.5 +/- 2.9 ng/ml 40 min after treatment. The increase in response to LHRH with age of plasma LH concentrations in both sexes, and of plasma FSH concentrations in females indicates the maturation of the hypothalamo-pituitary system.
We examined the kinetically distinct characteristics of estradiol's effects upon pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release in response to pulses of exogenous gonadotropin-releasing hormone (GnRH) in healthy postmenopausal individuals. The putative self-priming actions of GnRH on LH and FSH release were tested by intravenous injections of equal paired doses of GnRH (10 micrograms) before and after 1, 5, 10, and 30 d of pure estradiol-17 beta delivery via an intravaginal silastic ring. Self-priming actions of GnRH, as defined by heightened gonadotropin release in response to the second pulse of GnRH compared with the first, were completely absent in the hypoestrogenemic state. However, estradiol administration unmasked GnRH self-priming in a time-dependent fashion, with maximal expression after 5 and 10 d of steroid replacement, followed by attenuation by 30 d. Since estradiol's modulation of GnRH action was expressed differentially on LH and FSH release, we suggest that such facilitation of GnRH-stimulated pituitary LH and FSH release may provide an additional mechanism for dissociated secretion of gonadotropic hormones in health or disease.
Four families with growth hormone (GH) deficiency, either isolated or with other pituitary hormonal deficits are described. Members of each underwent pharmacological testing for GH secretion and infusions of GH releasing hormone (GHRH) to determine the locus of the defect in GH secretion. In addition, we have extracted DNA from white blood cells to characterize the GHRH and GH genes. All members tested had the normal complement of GH and GHRH genes. Four generations of one family with isolated GH deficiency, autosomal dominant were studied. The younger members showed minimal GH responsiveness to a single infusion of GHRH. However, the older members did not respond even after 30 doses of GHRH given intravenously every 3 h. Two members of a family with the autosomal recessive type of isolated GH deficiency had large GH increases after GHRH infusion. Thus in these families the GH secretory defect lies within the hypothalamus. Members of two families with pituitary deficiency (GH and other tropic hormones) of the autosomal recessive type had variable responses to GHRH and varying amounts of pituitary tissue seen on high resolution CT scans. Although it is not possible to delineate the precise location of the secretory defects in these latter two families, a hypothalamic defect is probable based on the responses to multiple trophic stimuli. Heterogeneity of structure and function exists within and between families with isolated GH deficiency and within and among families with pituitary deficiency. It is from the study of such families in which all members presumably have the same underlying defect that one can more readily decide on a pathogenetic mechanism.