Luteinizing Hormone/follicle Stimulating Hormone-releasing Hormone Research Articles

Anterior pituitary responsiveness to hypothalamic hormones in anorexia nervosa.

7 women and 3 men with anorexia nervosa were tested with thyrotropin-releasing hormone (TRH) and luteinizing hormone-follicle stimulating hormone-releasing hormone (LH-RH) and the growth hormone (GH), prolactin (PRL), gonadotropin (FSH-LH) and thyrotropin (TSH) responsiveness of their anterior pituitaries (AP) to the two hypothalamic neurohormones were determined. Administration of TRH (500 microgram i.v.) induced rises in plasma GH in 4 patients, while in 4 patients it induced rises in plasma FSH and/or LH. LH-RH (150 microgram i.v.) induced rises in plasma GH in 3 patients, increased plasma PRL in 3 patients and plasma TSH in 1 patient. Collectively, in only 1 patient, who was in a phase of initial nutritional rehabilitation, was there conventional AP responsiveness to hypothalamic neurohormones. This demonstrates that there is a profound derangement of AP responsiveness to hypothalamic neurohormones in patients with anorexia nervosa, probably reflecting a primary alteration in brain neurotransmitter function.

Deranged anterior pituitary responsiveness to hypothalamic hormones in depressed patients.

Abnormal anterior pituitary (AP) responsiveness to acute administration of thyrotropin-releasing hormone (TRH) and luteinizing hormone-follicle stimulating hormone-releasing hormone (LH-RH) was investigated in 14 patients (two men and 12 women) suffering from primary affective disorders. In ten, TRH, 500 microgram given intravenously, induced a rise in plasma growth hormone (GH) level, while in eight patients it induced a rise in plasma levels of FSH or LH or both. When LH-RH, 150 microgram was administered intravenously to ten patients, it induced a rise in plasma GH level in one patient and increased plasma prolactin level in three patients. Collectively, in only three of 14 patients was conventional AP responsiveness to hypothalamic neurohormones present. These findings demonstrate the existence of a profound derangement of AP responsiveness to hypothalamic neurohormones in depressed patients and suggest that a primary alteration in the physiologic links between the central nervous system and the AP may be at the origin of the neuroendocrine disturbance.

AN ELECTROENCEPHALOGRAPHIC INVESTIGATION OF SHORT‐TERM EFFECTS OF THREE HYPOTHALAMIC HORMONES (TRH, LH/FSH‐RH, GH‐RIH) IN NORMAL SUBJECTS

Three hypothalamic regulatory hormones, thyrotrophin-releasing hormone (TRH), luteinizing hormone/follicle-stimulating hormone-releasing hormone (LH/FSH-RH) and growth hormone-release inhibiting hormone (GH-RIH) given intravenously had no effect on the electroencephalographic response known as the contingent negative variation (CNV) in normal subjects. TRH was given as a 10 ml infusion of 600 microg over 8 min to six subjects. This produced subjective sensations and a rise in heart rate but no significant alteration of CNV magnitude. LH/FSH-RH was given in a dose of 200 microg in 10 ml over 2 min to six subjects. This had no effect on CNV magnitude or heart rate and produced no subjective effects. GH-RIH was given as a 10 ml infusion of 250 microg over 10 min to six subjects. Again there was no alteration in the magnitude of the CNV; the heart rate was slowed.

Luteinizing Hormone-Releasing Hormone for Induction of Follicular Maturation and Ovulation in Women with Infertility and Amenorrhea

Five patients with primary infertility and secondary amenorrhea who did not respond to clomiphene with a gonadotropin or estrogen surge were treated with 500 mug of luteinizing hormone, follicle-stimulating hormone-releasing hormone (LH-RH), self-administered subcutaneously every 8 hours for 14 days. Of four patients who responded to this treatment, three showed follicular maturation, ovulation, and menses, although the luteal phase was deficient; in the fourth patient, follicular maturation and menses occurred without evidence of ovulation. For their second course of treatment these four patients were given LH-RH with the addition of human chorionic gonadotropin when the urinary estrogen levels indicated follicular maturation. All four patients responded with ovulation, an adequate luteal phase, and menses, without clinical indication of ovarian hyperstimulation. These results suggest that LH-RH may be a better alternative to human menopausal gonadotropin in the treatment of anovulatory infertility.

Suppression of gonadotropin release and ovulation in animals by inhibitory analogs of luteinizing hormone-releasing hormone.

The basic assumption in developing competitive inhibitors of luteinizing hormone/follicle stimulating hormone-releasing hormone (LH/FSH-RH), the structure of which is shown in Figure 1, was that analogs could be designed which could retain the ability to bind to pituitary receptor sites whilst being devoid of gonadotropin-releasing activity. The first indication that this approach was valid came out of work by Vale et al. (1972) who found that removal of histidine from the peptide chain gave a nonapeptide of very low LH-RH activity which was capable of inhibiting the action of LH-RH on cultures of anterior pituitary cells. This inhibition was, however, weak and subsequently could not be demonstrated in vivo in rats (Vilchez-Martinez et al., 1974a). Other inhibitors based on the original decapeptide sequence were shown (Vilchez-Martinez et al., 1974a) to be active in vivo; however, these were also too weak to be of practical value. It became obvious, therefore, that ways must be found to substantially raise the binding affinity of an inhibitor, again without increasing agonistic activity to any great extent.

The Hypothalamic Regulatory Hormones and Their Clinical Applications

The chapter discusses three hypothalamic regulatory hormones. The three hypothalamic regulatory hormones are thyrotrophin-releasing hormone (TRH), luteinizing hormone/follicle-stimulating hormone-releasing hormone (LH/FSH-RH), and growth hormone-release inhibiting hormone (GH-RIH). These three hormones are produced by the anterior pituitary gland whose function is controlled by hypothalamus. They are stored in the median eminence, from which they are released in response to certain stimuli, passing in the portal venous system down the pituitary stalk to the anterior lobe, where they affect the synthesis and release of the pituitary hormones. Since they may either stimulate or inhibit the release and synthesis of the anterior lobe hormones, they are better referred to as regulatory hormones than as releasing hormones. The hypothalamic-pituitary system is a “cascading amplifier.” The hypothalamic signal causes the release of larger amounts of anterior pituitary hormones, which in turn leads to the production of even greater amounts of target gland hormones. The chapter discusses location, mechanism of action, specificity, duration of action, side effects, and toxicity of these hormones. Clinical applications of these hormones are also discussed in the chapter.

HYPOTHALAMIC HORMONE INTERACTION IN ACROMEGALY

The growth hormone response to the administration of the currently available synthetic hypothalamic hormones was assessed in eleven patients with acromegaly. Eight of them showed a positive GH response to thyrotrophin releasing hormone and three showed no response. The GH response to TRH was shown to be unrelated to the thyrotrophin response to TRH. The GH response to TRH was inhibited by the administration of growth hormone release inhibiting hormone. Luteinizing hormone/follicle stimulating hormone releasing hormone (LHRH) caused a positive GH response in four patients, but this was trivial in three. The TRH mediated GH release in acromegaly is not mediated via TSH and appears to be attributable to loss of specificity of the receptor sites on the somatotroph to the hypothalamic hormones.

Use of clomiphene and luteinizing hormone/follicle stimulating hormone-releasing hormone in investigation of ovulatory failure.

A luteinizing hormone/follicle-stimulating hormone-releasing hormone (LH/FSH-RH) test was performed in 70 women with amenorrhoea or anovulatory infertility, or both, and a clomiphene stimulation test was also performed in 24 of these patients. Most patients responded to LH/FSH-RH with significant increases in LH and FSH. In women with gonadal dysgenesis or premature ovarian failure exaggerated responses were observed after LH/FSH-RH and there was no change in high basal LH levels after clomiphene. Patients with absent or impaired responses to LH/FSH-RH failed to respond to clomiphene. All patients with anovulatory menstrual cycles responded to both LH/FSH-RH and clomiphene, while seven out of 13 amenorrhoeic patients with a normal LH/FSH-RH response showed an early LH rise during clomiphene treatment and six were unresponsive. These results suggest a difference between the two groups at hypothalamic level with consequent therapeutic implications.

Pituitary sensitivity to 50 micro g LH/FSH-RH in subjects with anorexia nervosa in acute and recovery stages.

Gonadotrophic output was measured in response to a 50-mug dose of luteinizing hormone/follicle stimulating hormone-releasing hormone (LH/FSH-RH) in subjects with anorexia nervosa. A diminished response was found in subjects of low body weight, and in some a response occurred with increments of plasma FSH greater than those of LH. With restoration of body weight the response to the releasing factor was similar to that usually observed in healthy men and women.

Luteinizing hormone and follicle stimulating hormone-releasing hormone test in patients with hypothalamic-pituitary-gonadal dysfunction.

A standard intravenous 100 mug luteinizing hormone/follicle stimulating hormone-releasing hormone (LH/FSH-RH) test was used to assess the pituitary gonadotrophin responses in 155 patients with a variety of diseases of the hypothalamic-pituitary-gonadal axis. In all but nine patients there was an increase in circulating levels of either LH or FSH in response to the releasing hormone though 137 (88%) were clinically hypogonadal. It was not possible with this test to distinguish between hypothalamic and pituitary causes of hypogonadotrophic hypogonadism, since a variety of LH and FSH responses emerged within the disease groups. However, primary gonadal failure characteristically resulted in exaggerated gonadotrophin response. The potential therapeutic use of the gonadotrophin releasing decapeptide is suggested in certain patients with hypogonadotrophic hypogonadism.

Hormonal responses to synthetic luteinizing hormone and follicle stimulating hormone-releasing hormone in man.

The effects of the gonadotrophin-releasing hormone, synthetic decapeptide luteinizing hormone/follicle stimulating hormone-releasing hormone (LH/FSH-RH), have been studied in 18 normal men and five women in the follicular phase of their menstrual cycle. Rapid and dose-dependent (25 to 100 mug) increases in serum immunoreactive LH were seen, which reached a peak 20 to 30 minutes after a rapid intravenous injection. Similar but much smaller increases in serum immunoreactive FSH were seen. These conclusions have been validated by using two different immunoassay systems for each hormone. The LH/FSH-RH therefore causes both LH and FSH release in man as in animals but does not affect growth hormone, thyrotrophin, or ACTH. The gonadotrophin responses were the same in the women as in the men but were insufficient in the men to cause statistically significant changes in the serum levels of the gonadal steroid hormones, testosterone or oestradiol, or in their precursors 17 alpha-hydroxyprogesterone or progesterone. In the women, however, there was a rise in oestradiol after the 100-mug doses. The use of LH/FSH-RH will provide an important test to define the level of the lesion in hypogonadal patients and also should be valuable in the treatment of some types of male and female infertility. A simple and clinically useful LH/FSH-RH test of pituitary function is described (100 mug given intravenously), and the provisional normal responses of LH and FSH at 20 and 60 minutes are given.

Effect of synthetic luteinizing hormone releasing hormone (LH/FSH-RH) in women with menstrual disorders.

Synthetic luteinizing hormone/follicle stimulating hormone-releasing hormone (LH/FSH-RH) (50 mug) was given intravenously to six women with oligomenorrhoea and to four women with secondary amenorrhoea. Peripheral venous blood was withdrawn at regular intervals over a 24-hour period. The concentrations of LH, FSH, and oestradiol-17beta were determined by radioimmunoassay. In all subjects there was a variable rise in LH (3-16 times the mean basal level): in six a small rise in FSH (two to three times the mean basal level) and in seven a twofold to threefold rise in oestradiol three to eight hours after the rise in gonadotrophins.