Hormone-releasing Hormone Stimulation Research Articles

Graves\u2019 disease coexisted with resistance to thyroid hormone: a case report

BackgroundResistance to thyroid hormone is a rare autosomal dominant disorder characterized by reduced responsiveness to thyroid hormone and can cause syndrome of inappropriate secretion of thyroid stimulating hormone. Although Graves’ disease is a common autoimmune thyroid disorder, the coexistence of these two diseases is extremely rare and makes the diagnosis and treatment complicated, leading to the delayed diagnosis of resistance to thyroid hormone. We describe the case of a Japanese man with resistance to thyroid hormone coexisting with Graves’ disease, in which the correct diagnosis of resistance to thyroid hormone was delayed by masking of the signs of syndrome of inappropriate secretion of thyroid stimulating hormone, with final diagnosis 30 years after the initial treatment for Graves’ disease.Case presentationA 30-year-old Japanese man presented with diffuse goiter and thyrotoxicosis. Anti-thyroid stimulating hormone receptor antibody was positive. He was diagnosed with Graves’ disease. Anti-thyroid medication was chosen as the initial treatment for Graves’ disease. However, this treatment failed to normalize the free triiodothyronine, free thyroxine, and thyroid stimulating hormone levels. His thyroid hormone levels indicated syndrome of inappropriate secretion of thyroid stimulating hormone. After cessation of methimazole treatment by remission of Graves’ disease, his state of syndrome of inappropriate secretion of thyroid stimulating hormone persisted. Magnetic resonance imaging revealed no pituitary tumor lesions. The results of thyroid stimulating hormone-releasing hormone stimulation test showed a normal response of thyroid stimulating hormone. He was suspected to have resistance to thyroid hormone. Direct sequencing analysis of the thyroid hormone receptor β gene identified a heterozygous missense mutation, R282S. Coexistence of resistance to thyroid hormone with Graves’ disease was confirmed. He has no signs of thyrotoxic symptoms, and is capable in activities of daily living at the present time.ConclusionWe described a rare case of resistance to thyroid hormone simultaneously existing with Graves’ disease. This case demonstrated that these diseases can coexist, and indicated some of the difficulties in diagnosis of resistance to thyroid hormone with coexisting Graves’ disease. The diagnosis of resistance to thyroid hormone did not become apparent until after anti-hyperthyroidism treatment. Although rare, careful follow-up after the initial treatment of Graves’ disease is necessary. The coexistence of these two diseases should be considered in patients showing occasional syndrome of inappropriate secretion of thyroid stimulating hormone.

Lntra- and Inter-Individual Variability in Growth Hormone Responses to Growth Hormone-Releasing Hormone

Abstract Normal subjects show a wide range of growth hormone (GH) responses to growth hormone-releasing hormone (GHRH) stimulation, but it is uncertain whether this variability reflects differences among individuals or whether it would also be observed on repeated tests of the same subject. To clarify this, we tested nine normal men repeatedly with iv bolus doses of 1 mug/kg GHRH(1-44)NH(2). Most subjects showed wide variations in their GH responses on repeated testing, and the intra-individual variability was nearly as great as the inter-individual variability in responses, accounting for about two-thirds of the overall variance. A minority of subjects had lower and less variable responses. Ultradian fluctuations in hypothalamic somatostatin secretion may account for this marked intra-individual variability.

Tamoxifen Citrate Therapy in Male Infertility

A prospective, randomized, double-blind study with crossover, using tamoxifen (TAM) (Nolvadex, ici Pharma, Missisauga, Canada) 20 mg/day and placebo (p) for 6 months each, was conducted in 16 infertile men with idiopathic oligozoospermia. Baseline sperm count was 17.092 +/- 3.09 (10(6)/ml). Hormonal profile was performed and included follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), testosterone (T), prolactin (PRL), thyroid-stimulating hormone (TSH), and luteinizing hormone-releasing hormone (LH-RH) stimulation tests. The sperm analysis and hormonal profile were repeated at 6 and 12 months of the study. A sperm penetration assay (SPA) was performed on zona-free hamster egg. Compared with the placebo group, the TAM group showed a significant increase in plasma FSH, LH, E2, and T levels (P less than 0.001), but not in PRL and TSH levels. However, LH-RH stimulation tests and SPA were found to be comparable in the two treatment groups, and there was no significant effect on sperm analysis. Tamoxifen appeared to be no more effective than the placebo in the treatment of idiopathic oligozoospermia.

Insulin Hypoglycemia Test and Releasing Hormone (Corticotropin-Releasing Hormone and Growth Hormone-Releasing Hormone) Stimulation in Patients with Pituitary Failure of Different Origin

To investigate the efficacy of endocrine evaluation in diagnosing and localizing the cause of anterior pituitary failure, 17 patients with suprasellar space-occupying lesions, 4 patients with intrasellar tumors, 8 patients with no detectable anatomical lesion, 1 patient with posttraumatic failure and 1 patient with septooptical dysplasia were investigated. Endocrine evaluation consisted of measuring adrenocorticotropic hormone (ACTH), cortisol, and growth hormone (GH) levels during insulin hypoglycemia test (IHT) and after administration of corticotropin-releasing hormone (CRH) and growth hormone-releasing hormone (GRH). In addition, basal prolactin levels, gonadal and thyroid function were evaluated. The results showed that 4 of 17 patients with suprasellar tumors had normal ACTH and GH responses during IHT and after releasing hormone (RH) administration. Five of these patients had a normal ACTH or cortisol rise but no GH response during IHT. All 5 had a normal ACTH and 3 had normal GH rise after RH. Seven patients with suprasellar tumors had no ACTH or GH response during IHT, but all had an ACTH response to CRH. Only 3 of this group had a GH response to GRH. There was one exception of a patient who showed a GH and ACTH rise during IHT but only a blunted ACTH and no GH rise after RH administration. Four patients with pituitary failure and no demonstrable lesion had an ACTH rise after CRH but no GH rise after GRH, whereas in 3 patients with isolated ACTH deficiency no ACTH rise after CRH was seen. In 4 patients with nonsecreting pituitary tumors normal ACTH responses to IHT and CRH were seen, whereas GH rose during IHT only in 1 patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypogonadism in Idiopathic Hemochromatosis

The mechanism of hypogonadism was studied in a 63-year-old man with idiopathic hemochromatosis. Basal levels of thyroid, prolactin, cortisol, and growth hormones were normal and responded normally to appropriate provocative stimuli. Basal testosterone and gonadotropin levels were low. There was inadequate gonadotropin response to luteinizing hormone-releasing hormone and clomiphene citrate stimulation. Testosterone response to human chorionic gonadotropin was normal. Hypothalamic-pituitary dysfunction resulting in impaired gonadotropin secretion appears to be the cause of hypogonadism in hemochromatosis.

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.

Studies on the follicle stimulating hormone releasing hormone by radioimmunoassays and by bioassays

An entity (in fractions), separated from the luteinizing hormone-releasing hormone (LHRH), <Glu-OH, and N-Ac-Asp-OH, which released both FSH and LH appeared to show immunoreactivity in the RIA for LHRH. This entity was destroyed by trypsin, but did not yield LHRH, under conditions which (1) converted a synthetic model, [Arg-Lys-Gln 1]-LHRH, of a pro-LHRH to LHRH; (2) did not destroy LHRH. This entity may not be a pro-LHRH, but may be the follicle stimulating hormone-releasing hormone (FSHRH) on the basis of all these data. A second immunoreactive entity had negligible, if any, releasing activity for FSH and LH, and did not yield LHRH on trypsin digestion.

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.

Disappearance of LHRH and D-Leu6-Des Gly NH210 LHRM Ethylamide in Ewes

The in vivo disappearance of biological activity of luteinizing hormone-releasing hormone/follicle stimulating hormone-releasing hormone (LHRH) and a structural analog, D-Leu6-des Gly NH210 LHRH ethylamide (D-Leu6) were compared in intact ewes. Nine ewes were in the luteal phase of an estrus cycle when randomly divided into three equal treatment groups. Ewes were infused with either saline (5 ml/hr), LHRH (1 mg/5 ml/hr), or D-Leu6 (.1 mg/5 ml/hr) for 16.5 hours. Jugular blood was drawn every 30 min during infusion and for 6 hr thereafter to determine serum luteinizing hormone (LH). One milliliter of each blood sample collected following cessation of infusion was injected (iv, within 5 to 10 sec of collection) into an estrogen-progesterone treated ovariectomized (EPO) rat. The EPO rats were bled at 0, 15, 30, 60, 120, 240, 360 min after injection of sheep blood. LH released from each rat was used as an index of biologically active LHRH or D-Leu6 remaining in sheep blood at the time of collection. Mean serum LH concentrations in ewes treated with D-Leu6 or LHRH were not different (P>.05) indicating similar bioactivities of the two different doses of peptide used. Ewes had serum LH concentrations of less than 5 ng/ml at the time their blood was injected into the bioassay rats. Serum LH was not increased in blood of rats compared to pretreatment levels when injected with blood from sheep given saline (P>.05). Regression lines were fit to the means of the disappearance curves of each treatment. Analysis of regression coefficients showed the LH-releasing activity of LHRH and the D-Leu6 treated ewes decreased at a similar rate (P>.05). Since the two treatments were not different, they were pooled and a half-life of 185 min or 3.07 hr was calculated. Biological activity of LHRH and D-Leu6 was not detectable after 4.0 hr post-infusion. These data indicate that the greater biological potency of the analog D-Leu6 relative to synthetic LHRH is not attributable to a longer circulating time in the blood.

Some notes on the background of the isolation, determination of structure, synthesis, and early clinical trials of the luteinizing hormone- and follicle-stimulating hormone-releasing hormone

Some notes on the background of the isolation determination of structure synthesis and early clinical trials of the luteinizing hormone (LH)- and follicle stimulating hormone-releasing hormone (FSH-RH) are presented. The solving of the thyrotropin releasing hormone structure made the work on the hypothalamus easier. After establishing that the 11 types of estrogen-progesterone combinations used in contraceptive pills did not suppress the stimulatory effects of LH-RH on the release of LH it was postulated that contraceptive steroids act mainly on the hypothalamus. And later it was shown that these steroids also act on the pituitary gland. This helped postulate that sex steroids may cause differential release of LH and FSH in response to LH-RH/FSH-RH. Immunologic studies led to the production of antisera to LH-RH and development of a radioimmunoassay for LH-RH. It was then shown that such antisera caused gonadal atrophy in male animals and blocked the release of LH and FSH and ovulation in cycling rats. The synthesis of various analogs of LH-RH enabled 2 classes of these compounds to be established: 1) stimulatory superactive analogs causing prolonged liberation of LH and FSH and 2) inhibitory analogs which block LH and FSH release and ovulation.

Re-examination of porcine and bovine hypothalamic fractions for additional luteinizing hormone and follicle stimulating hormone-releasing activities.

More than 150 hypothalamic fractions were reassayed for luteinizing hormone-releasing hormone (LHRH) and follicle stimulating hormone-releasing hormone (FSHRH) activities in search for LHRH and FSHRH which differ from the decapeptide (pyro)Glu-His-Trp-Ser-Try-Gly-Leu-Arg-Pro-Gly-NH2 (I). Among the porcine fractions tested were those obtained: 1) from the isolation of thyrotropin-releasing hormone; 2) from two isolation procedures for LHRH; and 3) from methanolic and aqueous 2N acetic acid extracts which were subjected to Biogel P-2 filtration and partition chromatography. Some bovine hypothalamic fractions were also tested. Both in vivo and in vitro assays were used for measuring LHRH and FSHRH activities. The values obtained were in each case compared with those resulting from the administration of pure natural or synthetic LHRH decapeptide I. A radioimmunoassay for LHRH (I) was also utilized for some fractions. In all the purification steps the location of LHRH and FSHRH activity, as determined by in vivo assays, corresponded to that of the decapeptide I. Purification of hypothalamic extracts on Biogel P-2 and by partition chromatography separated a fraction from the decapeptide I, which released more FSH than LH in vitro from the pituitaries of immature female rats. However, this material was inactive in vivo and in other in vitro systems, so that its significance is obscure. The results suggest that if material with LHRH and FSHRH activity other than the decapeptide I is present in acid extracts of porcine hypothalami, then its FSHRH and LHRH activity would be a minor part of the total LHRH/FSHRH activity in the extracts. (Pyro)-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 appears to account for most of all of the LHRH and FSHRH activity found.

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.

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.

17] Methods for estimating the biologic activity of the luteinizing hormone- and follicle stimulating hormone-releasing hormone

Both in vitro and in vivo methods are used for estimating biologic activities of the substance, which probably is the physiological luteinizing hormone–releasing hormone (LH-RH), and follicle stimulating hormone-releasing hormone (FSH-RH), and its analogues. These methods involve the measurements of LH and FSH released from rat pituitaries into the incubation medium or into blood. These assays may be performed according to designs that permit statistical treatment of data and calculation of the relative potency, with 95% confidence limits of the material being tested with respect to the standard reference LH-RH/FSH-RH preparation. LH in incubation medium or blood is determined by a double antibody radioimmunoassay method for rat LH. FSH is determined either by the bioassay of Steelman and Pohley or a double antibody radioimmunoassay method for rat FSH.

Combined test for assessment of anterior pituitary function.

A combined test consisting of the simultaneous administration of insulin, thyrotrophin-releasing hormone (TRH), and luteinizing hormone and follicle stimulating hormone-releasing hormone (LH/FSH-RH) was performed in 24 people. Eleven of these also had the three individual tests performed separately, and the remaining 13 had a separate test of either LH/FSH-RH and TRH together or singly at a later date. In both normal people and patients, whether the tests were performed alone or in combination, no difference was found between the hormone responses (growth hormone, cortisol, LH, FSH, thyroid-stimulating hormone) seen to these stimuli.It is proposed that combined administration of insulin and the hypothalamic releasing hormones may be used as a single test for the assessment of anterior pituitary function. The test is convenient and time saving, and with care can be performed in outpatients.

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.

Effect of synthetic luteinizing hormone- and follicle stimulating hormone-releasing hormone (LH-FSH-RH) on serum levels of LH, FSH, thyrotrophin (TSH) and growth hormone (HGH) in normal male subjects.

ABSTRACT Four normal male subjects received iv injections of synthetic luteinizing hormone- and follicle stimulating hormone-releasing hormone (LH/FSH-RH) in doses of 12.5, 25, 100, 200 and 400 μg, respectively. A dose of 12.5 μg of LH/FSH-RH caused a significant increase in serum FSH, and 25 μg significantly increased the serum LH. The peak responses occurred 15 to 30 min after the LH/FSH-RH injections in most of the experiments. The increase in the mean maximum serum LH and FSH levels was 2 to 4 fold. There was great variation in response between the subjects, but when tested repeatedly with the same dose of LH/FSH-RH a given individual responded in a consistent manner. The log dose-response curve between LH/FSH-RH and serum LH, and between LH/FSH-RH and serum FSH was approximately linear. A small but significant (P &lt; 0.05) rise in serum thyrotrophin (TSH) was found after LH/FSH-RH in doses ranging from 25 to 400 μg. There was no significant rise in serum growth hormone (HGH). On the basis of the present study a standard 100 μg iv LH/FSH-RH test is suggested.

Post-Pill Amenorrheea [Abridged

24 cases of postpill amenorrhea are presented. The patients were 17-34 years of age and the length of amenorrhea was 6-60 months with a mean of 13.4 months. There was no relationship between the type of contraceptive pill, length of usage, and the incidence of amenorrhea which suggests that the mechanism of action is general rather than due to a specific combination of steroid hormones. The basal endocrine status of the thyroid and adrenal was normal. 14 of the patients had low estrogen and gonadotropins and of these only 4 had a positive clomiphene pituitary reserve test. These 4 patients subsequently restarted normal cycles and luteinizing hormone/follicle stimulating hormone-releasing hormone tests showed normal pituitary function, indicating that the others probably had some derangement of hypothalamic pituitary function.

Serum LH levels in prepubertal female pigs chronically treated with synthetic luteinizing hormone-releasing hormone-follicle stimulating hormone-releasing hormone (LH-RH-FSH-RH).

A double—antibody radioimmunoassay utilizing a heterologous system specific for porcine luteinizing hormone (PLH) has been developed with rabbit antibovine LH serum as a first antibody. Porcine LH (LER-786-3) was used for iodination and as a reference standard. Reliable estimates of LH could be obtained in 200 pi of serum from immature pigs at any time. Porcine follicle-stimulating hormone (FSH), porcine thyroid- stimulating hormone, porcine adrenocorticotropic hormone or serum components per se did not affect measurements of LH. Ten prepubertal female pigs (mean wt 12.8 kg) were assigned randomly in equal numbers to a treated or control group. Treatment consisted of 16 im injections of 25 ng of pure synthetic LH and FSH releasing hormone (LH-RH/FSH-RH) in one ml of acidified saline or acidified saline only at 6–hr intervals over a period of 96 hr for treated and control animals respectively. Blood samples were collected via indwelling jugular catheters, at various times following each injection. Serum LH...