Luteinizing hormone responses to luteinizing hormone releasing hormone (LHRH) in acute mania and the effects of lithium on LHRH and thyrotrophin releasing hormone tests in volunteers

The endocrine responses to Luteinizing Hormone Releasing Hormone (LHRH) of eight drug-free males with mania were determined. Basal levels of Luteinizing Hormone (LH) and the plasma levels following injection of LHRH were elevated in patients compared with controls; Follicle Stimulating Hormone (FSH) and testosterone were not different. Elevated levels of LH have been described previously in recovered manic patients and have been suggested to be state-independent features of mania. In order to clarify the status of this finding, the effects of lithium administration upon hormone responses to LHRH in six male volunteers were also investigated, together with the effects upon Thyrotrophin Releasing Hormone (TRH) stimulation of Thyroid Stimulating Hormone (TSH) and prolactin release. Lithium increased the basal levels of LH and levels after injection of LHRH without effect upon FSH and testosterone. Lithium also increased basal and TRH stimulated release of TSH and basal prolactin levels. Lithium was without effect upon prolactin responses to TRH. The results are discussed in relation to current information on the mechanism of lithium's action. The implications for neuroendocrine work on recovered patients taking lithium are also explored.     

PRL,TSH, and thyroid hormones in benign breast diseases

Summary The dynamic secretion of prolactin and TSH as well as the thyroid function were studied in patients with benign breast disease. The study included 13 patients with mastodynia, 15 patients with isolated galactorrhea, 6 patients with breast hypertrophy and 5 patients with fibroadenomata. Eleven healthy women served as controls. Prolactin and TSH were determined before and after TRH stimulation, using 0.2 mg TRH i.v. In addition thyroxine (T₄), trijodthyronine (T₃) and thyroxin-binding-globulin (TBG) were estimated.The following results were obtained: Basal prolactin levels were slightly but not significantly elevated in all patients studied. Maximal prolactin response to TRH was significantly greater as compared to the controls. TSH, T₄, T₃, and TBG-levels in the controls were within the normal range, while mastodynia and galactorrhea patients exhibited hormone patterns as known from endemic goiter (increased T₃- and relatively low T₄-levels). Mean TSH-responses reached the upper limit of the normal range. Mean TBG-levels in mastodynia patients exceeded the levels of the controls. In patients with breast hypertrophy thyroid hormone status indicated borderline hypothyroidism (borderline T₄- and normal T₃-levels, mean TSH-response slightly elevated to TRH). TSH secretion and thyroid function in patients with fibroadenomata did not differ from the controls.The presented data indicate an increased sensitivity of the lactotrophs representing possibly an important factor in the development of these benign breast diseases. The thyroid function tests in these patients revealed patterns known from endemic goiter and borderline hypothyroidism respectively.     

Thyroid hemiagenesis and elevated thyrotropin levels in a child with Williams syndrome.

A girl with Williams syndrome (WS) presented with elevated thyrotropin (TSH) levels (7.0 microU/ml), normal free thyroid hormone concentrations, and absent antithyroid autoantibodies. Thyroid ultrasonography and scintigraphy showed hemiagenesis of the left lobe and no evidence of ectopic tissue. TSH response to thyrotropin-releasing hormone (TRH) injection (200 microg/mq, i.v.) was exaggerated and prolonged, suggesting subclinical hypothyroidism. The biological activity of circulating TSH was slightly below the normal range [TSH bioactivity (B) to immunoreactivity (I) ratio (TSH B/I) = 0.4, normal: 0.6-2.2]. These abnormalities are similar to those seen in patients with hypothalamic hypothyroidism. Thyroid function is not a recognized manifestation of WS and is not routinely investigated. However, abnormalities of the hypothalamic-pituitary-thyroid (HPT) axis and thyroid dysgenesis have been found in other WS cases. Genes mapping at 7q11.23, contiguous to the chromosomal region deleted in most WS patients, may be involved in the development of the thyroid gland, contributing to the complex phenotype of WS.     

Melatonin reduces the production and secretion of prolactin and growth hormone from rat pituitary cells in culture

A culture of clonal tumour cells from rat pituitary gland that secrete both prolactin and growth hormone were used to investigate whether the pineal hormone melatonin can act directly on the pituitary gland to control prolactin production. Melatonin inhibition of prolactin and growth hormone production was significant but mild. Concentrations of between 10(-8) M and 10(-6) M reduced both prolactin and growth hormone production and prolactin secretion by 10-50%. 17 beta-oestradiol (OE) and thyrotrophin-releasing hormone (TRH) stimulated prolactin production but had no significant effect on growth hormone production. Melatonin reduced the effects of both of these compounds. Both TRH and vasoactive intestinal peptide (VIP) stimulated secretion of prolactin, and TRH also of growth hormone. Melatonin reduced these effects significantly. TRH and VIP increased cAMP production two- and 12-fold, respectively. Melatonin had no effect on basal or stimulated cAMP production. The melatonin-induced changes in prolactin and growth hormone production and secretion seen here do not approach the magnitude of the fluctuations seen in plasma in vivo. It is concluded that while melatonin does have a direct effect on the lactotroph in the regulation of prolactin production, its main physiological target must be elsewhere.     

Thyroid antoantibodies and the response to thyrotropin releasing hormone in patients with subclinical hypothyroidism.

AIM--To evaluate the clinical usefulness of the thyrotropin releasing hormone (TRH) test and estimation of thyroid autoantibody concentrations in patients with borderline raised thyroid stimulating hormone (TSH). METHODS--The records of 34 consecutive patients with persistent borderline increased TSH (4.4-9.9 mU/l) referred to the Medical Investigation Unit were reviewed. The response of patients with thyroid autoantibodies to the TRH test was compared with that of patients with a negative antibody screen. RESULTS--Eleven (44%) of 25 patients with positive anti-thyroid microsomal and/or thyroglobulin antibody tests and three (33%) of nine patients with a negative antibody screen had hypothyroid responses to TRH. Neither age nor sex affected the response to TRH. Basal TSH alone was poorly correlated with these indices. Twelve (35%) patients who had elevated basal TSH had a normal response to the TRH test. CONCLUSION--Patients with positive or negative thyroid autoantibodies and an exaggerated response to the TRH test should be regarded as hypothyroid and treated with thyroxine. Patients with positive thyroid autoantibodies and normal TSH response may subsequently develop hypothyroidism and should be given long term follow up.     

Screening for thyroid disorders in a working population

Summary Subclinical thyroid disorders have received increasing attention in recent years due to refined laboratory methods and a stronger emphasis on the role of preventive medicine. We performed a screening for thyroid-stimulating hormone (TSH) on 6884 persons in a working population. In cases in which TSH was not within the normal range we also measured the levels of triiodothyronine (T₃), thyroxine (T₄), and thyroxine-binding globulin (TBG). All persons who did not present with exclusion criteria or other nonthyroidal illnesses (n = 59) and the controls (n = 39) were submitted to thyrotropin-releasing hormone (TRH)-testing. Additionally, sonography of the thyroid was performed on 120 persons (59 subjects with abnormal hormone levels and 61 controls) to determine thyroid size and rule out morphological abnormalities. Based on the TRH test and T₃, T₄, and TBG measurements we found a prevalence of 0.03% (2/6884) for overt hyperthyroidism, 0.33% (23/6884) for subclinical hyperthyroidism, 0.09% (6/6884) for subclinical hypothyroidism, and 0.015% (1/6884) for overt hypothyroidism in the healthy population. In subjects with overt or subclinical hyperthyroidism the prevalence of goiters (thyroid volume > 18 ml in women, > 25 ml in men) was 28%. Of this group 48% had structural abnormalities. All persons with goiters and/or structural abnormalities were over 35 years of age. Among the euthyroid, 20% had thyroid enlargement, and the same proportion presented with structural abnormalities. There were no differences between the two age groups. In the group with overt/subclinical hypothyroidism 47% presented with structural abnormalities of the thyroid; however, none presented with thyroid enlargement. Thyroid nodules were found only in older persons (> > 35 years) with euthyroidism or hypothyroidism. These data confirm the relatively high prevalence of functional and morphological abnormalities of the thyroid. An early substitution with iodine is warranted to prevent functional and morphological disorders of the thyroid in older age. People with subclinical hyperthyroid disorders must avoid exposure to iodine, which can cause an exacerbation of the disease.Abbreviations TBG thyroxine-binding globulin - TRH thyrotropin-releasing hormone - TSH thyroid-stimulating hormone - T₃ triiodothyronine - T₄ thyroxine Dedicated to Prof. Dr. N. Zöllner on the occasion of his 70th birthday     

Molecular economy of nature with two thyrotropins from different parts of the pituitary: pars tuberalis thyroid-stimulating hormone and pars distalis thyroid-stimulating hormone

Thyrotropin (TSH) is classically known to be regulated by negative feedback from thyroid hormones and stimulated by thyrotropin-releasing hormone (TRH) from the hypothalamus. At the end of the 1990s, studies showed that thyrotroph cells from the pars tuberalis (PT) did not have TRH receptors and their TSH regulation was independent from TRH stimulation. Instead, PT-thyrotroph cells were shown to have melatonin-1 (MT-1) receptors and melatonin secretion from the pineal gland stimulates TSH-β subunit formation in PT. Electron microscopy examinations also revealed some important differences between PT and pars distalis (PD) thyrotrophs. PT-TSH also have low bioactivity in the peripheral circulation. Studies showed that they have different glycosylations and PT-TSH forms macro-TSH complexes in the periphery and has a longer half-life. Photoperiodism affects LH levels in animals via decreased melatonin causing increased TSH-β subunit expression and induction of deiodinase-2 (DIO-2) in the brain. Mammals need a light stimulus carried into the suprachiasmatic nucleus (which is a circadian clock) and then transferred to the pineal gland to synthesize melatonin, but birds have deep brain receptors and they are stimulated directly by light stimuli to have increased PT-TSH, without the need for melatonin. Photoperiodic regulations via TSH and DIO 2/3 also have a role in appetite, seasonal immune regulation, food intake and nest-making behaviour in animals. Since humans have no clear seasonal breeding period, such studies as recent ‘’domestication locus’’ studies in poultry are interesting. PT-TSH that works like a neurotransmitter in the brain may become an important target for future studies about humans.     

Thyrotropin response to thyrotropin-releasing hormone in RDC schizodepressed men

Biological tests may help clarify the relationships of schizoaffective disorder to both major depressive disorder and schizophrenia. Thyrotropin-releasing hormone (TRH), 500 micrograms i.v., was administered to 14 schizodepressed, 23 schizophrenics, 41 unipolar major depressives (all by RDC) and 45 healthy controls, all males 20-67 years old with no significant differences in age, body height or weight. Results showed no differences in maximal delta TSH (dTSH max) amongst schizoaffective depressed, schizophrenia and healthy control groups (10.1 +/- 1.3, 9.2 +/- 1.1, 9.7 +/- 0.8 microU/ml, means +/- SEM respectively). Mean major depressives' dTSH max was lower than in each of the other three groups (6.2 +/- 0.4 microU/ml, P less than 0.01 for all). Utilizing a less than or equal to 5.0 microU/ml cut-off criterion for blunting, the schizodepressed had 36%, schizophrenics 44%, healthy controls 22% and major depressed 59% blunters (P less than 0.05 from other three groups). Schizodepressed patients appeared significantly different from major depressed but closer to schizophrenics (and healthy controls) on the TRH test.     

Hypothalamus-pituitary-thyroid axis interactions with pineal gland in the rat.

We examined in the rat several possible relationships between the pineal gland and the hypothalamus-pituitary-thyroid axis. The pineal gland, the retina, and the hypothalamus exhibited a diurnal rhythm in thyrotropin-releasing hormone (TRH) content with peak values occurring around 1200 h. This rhythm in the hypothalamus was abolished by constant light but was not affected by pinealectomy. Nor did pinealectomy affect hypothalamic TRH content, pituitary content of thyroid-stimulating hormone (TSH) or prolactin; serum levels of (TSH), triiodothyronine (T3), or thyroxine (T4), or serum free-thyroxine index; or free-triiodothyronine index. Melatonin did not affect TSH or prolactin release from the anterior pituitary or TRH release from the hypothalamus in vitro. Isoproterenol did not affect the TRH content of pineal glands in vitro; nor did TRH or T3 affect basal or stimulated activities of serotonin N-acetyltransferase, the presumed controlling enzyme in melatonin production. We found no evidence for significant interactions between the pineal gland and the hypothalamus-pituitary-thyroid axis.     

Anthology of the first clinical studies with hypothalamic hormones: a story of successful international cooperation

Our early pioneering clinical trials in Mexico with natural and synthetic thyrotropin-releasing hormone (TRH) and luteinizing hormone releasing hormone (LH-RH) also known as gonadotropin releasing hormone (Gn-RH), were reviewed. Highly purified TRH of porcine origin was shown to stimulate Thyrotropin (TSH) release in hypothyroid cretins. Subsequent tests with synthetic TRH also demonstrated significant increases in plasma TSH in normal men and women as well as in patients with primary hypothyroidism and other endocrine disorders. Even more extensive clinical studies were carried out with highly purified natural porcine LH-RH. Subjects with normal basal serum levels of gonadotropins, low levels (men and women pretreated with steroids) and high levels (e.g. post menopausal women) all responded to LH-RH with a release of LH and FSH. The results of these early studies with the natural LH-RH were confirmed by the use of synthetic LH-RH. These investigations made in Mexico with TRH and LH-RH preceded all other clinical studies by a wide margin. Subsequently various clinical investigations with LH-RH agonists and antagonists were also carried out. All these studies played a major role in introducing hypothalamic-releasing hormones into clinical medicine.     

Effects of growth hormone treatment on thyroid function in pediatric patients with Prader–Willi syndrome

It is unclear whether hypothyroidism is present in patients with Prader–Willi syndrome (PWS). This study aimed to clarify the state of the hypothalamic–pituitary–thyroid axis and the effects of growth hormone (GH) treatment on thyroid function in pediatric patients with PWS. We retrospectively evaluated thyroid function in 51 patients with PWS before GH treatment using a thyroid‐releasing hormone (TRH) stimulation test (29 males and 22 females; median age, 22 months). We also evaluated the effect of GH therapy on thyroid function by comparing serum free triiodothyronine (fT3), free thyroxine (fT4), and thyroid stimulating hormone (TSH) levels at baseline, 1 year, and 2 years after GH therapy. TSH, fT4, and fT3 levels were 2.28 μU/ml (interquartile range [IQR]; 1.19–3.61), 1.18 ng/dl (IQR; 1.02–1.24), and 4.02 pg/dl (IQR; 3.54–4.40) at baseline, respectively. In 49 of 51 patients, the TSH response to TRH administration showed a physiologically normal pattern; in two patients (4.0%), the pattern suggested hypothalamic hypothyroidism (delayed and prolonged TSH peak after TRH administration). TSH, fT4, and fT3 levels did not change significantly during 1 or 2 years after GH treatment. The TSH response to TRH showed a normal pattern in most patients, and thyroid function did not change significantly during the 2 years after initiating GH treatment.     

Value of endometrial biopsies and serum hormone determinations in women with infertility

Premenstrual endometrial biopsies were performed in 324 infertile women. Their hormonal status was established in the early follicular phase of the same cycle (FSH, LH, oestradiol-17 beta, testosterone, DHEAS, TSH and prolactin, the latter two both basally and following TRH stimulation). In the luteal phase, oestradiol-17 beta and progesterone concentrations were determined three times between the fifth and tenth hyperthermic days, as was prolactin, both basally and following metoclopramide stimulation. All pregnancies occurring before January 1986 were recorded. Seventy-five per cent of the biopsies were evaluated on the expected ovulation date from the basal temperature charts, 77% according to the next onset of menstruation. Twenty-six per cent of the biopsies were out of phase, and 7% displayed abortive secretion. A significant correlation existed between endometrial profiles and the characteristics of the cycle, stimulated TSH and prolactin levels, and with testosterone and FSH concentrations. No correlation of the endometrial status with midluteal oestradiol or progesterone concentrations was found. While various hormones of both the follicular and luteal phases correlated significantly with the pregnancy rate, the same was not demonstrated for the state of endometrial biopsy. Therefore, following exclusion of organic explanations of infertility in women with biphasic cycles, the determination of progesterone and oestradiol-17 beta in the luteal phase was considered. In women with reduced concentrations of these hormones, androgens, gonadotrophins, prolactin and TSH should be determined. Endometrial biopsy is valuable only if pregnancy fails to occur, despite therapeutically normalized hormone concentrations.     

Unchanged response to stimulation of pituitary hormone release after serial UV irradiation in men

A group of 24 healthy young men were evaluated before and after serial suberythematous ultraviolet (UV) radiation: group I, control (no irradiation); groups II and III, 12 radiations in 4 weeks with two different spectra (both containing UV-B). Before the first and 2 days after the last exposure all the volunteers were given an intravenous injection of thyrotropin releasing hormone (TRH, protirelin 0.2 mg) and luteinizing hormone releasing hormone (LH-RH, gonadorelin 0.1 mg). The serum concentrations of TSH, follicle stimulating hormone, LH and prolactin were measured at 0, 20, 30, 45 and 60 min by radioimmunoassay. Neither basal nor stimulated levels of the pituitary hormones showed significant changes after UV radiation. The results showed that exposure to suberythematous doses of UV did not influence the regulation of pituitary hormones in these healthy individuals.     

In vitro TSH and PRL secretion from eutopic and heterotopic rat pituitaries: effects of hypothyroidism

Five adenohypophyses from donors of the same strain, age, and sex were transplanted under the renal capsule of young adult female rats. At least 3 wk later, enzymatically dispersed cells from eutopic or heterotopic adenohypophyses from the same rat were perifused in vitro in a small chamber. Thyrotropin (TSH) and prolactin (PRL) secretion per 10(6) cells were significantly less from heterotopic than from eutopic cells under all conditions. In cells from euthyroid animals, TRH induced TSH secretion only in the eutopic cells but induced PRL secretion in both eutopic and heterotopic cells. Hypothyroidism increased TRH-induced TSH secretion and content in the cell lysate in both eutopic and heterotopic cells but increased TRH-induced PRL secretion only in the eutopic cells. The increase in TSH secretion induced by hypothyroidism in the heterotopic cells was of borderline statistical significance. The inability of TRH to induce TSH secretion in heterotopic pituitary cells from euthyroid rats may be due to a lower set point for thyroid hormone inhibition of TSH secretion in the heterotopic thyrotrophs. Heterotopic pituitary TSH secretion is probably suppressed by the normal plasma thyroid hormone concentration maintained by the eutopic pituitary and may be stimulated by TRH only in the presence of a subnormal plasma thyroid hormone concentration.     

Thyrotropin-releasing hormone levels decrease in hypothalamus of aging rats

Because hypothalamic and extrahypothalamic levels of thyrotropin-releasing hormone immunoreactivity (TRH-IR) undergo profound changes during the prenatal and early postnatal period in rats, similar effects with advanced aging were anticipated. For this reason we measured hypothalamic and reproductive tissue levels of TRH-IR, hypothalamic levels of somatostatin (SRIF), and beta-endorphin (EP), serum levels of prolactin (Prl), growth hormone (GH), thyrotropin (TSH), and thyroxine (T4) in young, sexually mature and 24-28 month-old male Long-Evans and Sprague-Dawley rats. Hypothalamic and prostatic levels of TRH-IR were consistently reduced as were the levels of T4 in old rats compared to young controls. Aging did not change the ratio of TRH to the major TRH-like peptide in prostates, as determined by high pressure liquid chromatography (HPLC) or the levels of hypothalamic SRIF and EP. All of the hypothalamic TRH-IR in both old and young male rats consisted of TRH by HPLC. Falling hypothalamic TRH levels and TRH secretory capacity may play a role in the blunted TSH response to cold stress in old rats.     

Thyroid hemiagenesis and elevated thyrotropin levels in a child with Williams syndrome

A girl with Williams syndrome (WS) presented with elevated thyrotropin (TSH) levels (7.0 μU/ml), normal free thyroid hormone concentrations, and absent antithyroid autoantibodies. Thyroid ultrasonography and scintigraphy showed hemiagenesis of the left lobe and no evidence of ectopic tissue. TSH response to thyrotropin-releasing hormone (TRH) injection (200 μg/mq, i.v.) was exaggerated and prolonged, suggesting subclinical hypothyroidism. The biological activity of circulating TSH was slightly below the normal range [TSH bioactivity (B) to immunoreactivity (I) ratio (TSH B/I) = 0.4, normal: 0.6–2.2]. These abnormalities are similar to those seen in patients with hypothalamic hypothyroidism. Thyroid function is not a recognized manifestation of WS and is not routinely investigated. However, abnormalities of the hypothalamic-pituitary-thyroid (HPT) axis and thyroid dysgenesis have been found in other WS cases. Genes mapping at 7q11.23, contiguous to the chromosomal region deleted in most WS patients, may be involved in the development of the thyroid gland, contributing to the complex phenotype of WS. Am. J. Med. Genet. 85:491–494, 1999. © 1999 Wiley-Liss, Inc.     

Effects of atrial natriuretic factor on anterior pituitary hormone secretion in normal man

Summary The effects of intravenous human atrial natriuretic factor ANF(99-126) administration on anterior pituitary hormone secretion have not been extensively investigated in humans. We repeatedly studied 10 healthy volunteers (5 female, 5 male, aged 28±2 years) on 2 occasions, 3 days apart. In randomized, single blind order, subjects received pretreatment with either placebo or intravenous ANF(99–126) (bolus 100 g/kg, 30-min infusion of 0.1 g/kg-min). Subsequently, on both occasions subjects received a combined intravenous bolus injection of pituitary releasing hormones (200 pg thyrotropin releasing hormone, 100 g gonadotropin releasing hormone, 50 g growth hormone releasing hormone and 100 g human adrenocorticotropin releasing hormone; Bissendorf, Hannover, FRG). Plasma concentrations of adrenocorticotropic hormone (ACTH), cortisol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), thyrotropin (TSH), prolactin, ANF and cyclic guanosine monophosphate (GMP) were determined by radioimmunoassay. ANF(99–126) treatment induced a significant reduction in basal ACTH plasma concentrations and tended to decrease basal plasma cortisol. The TSH response to combined releasing hormone administration was significantly diminished after ANF(99-126) pretreatment. In women, the releasing hormone induced prolactin increase was reduced after ANF(99–126) pretreatment. With the present study design, ANF(99–126) did not alter the basal or releasing hormone stimulated plasma concentrations of cortisol, LH, FSH and GH. Releasing hormone administration did not affect ANF and cyclic GMP plasma levels. In humans, effects of natriuretic peptides on anterior pituitary hormone secretion may have to be considered with investigational or therapeutic administration of ANF analogues or agents interfering with the ANF metabolism.Abbreviations ANF(99–126) human atrial natriuretic factor - ACTH adrenocorticotropic hormone - LH luteinizing hormone - FSH follicle-stimulating hormone - GH growth hormone - TSH thyrotropin - PRL prolactin - cyclic GMP cyclic guanosine monophosphate - TRH thyrotropin releasing hormone - GnRH gonadotropin releasing hormone - GHRH growth hormone releasing hormone - CRH adrenocorticotropin releasing hormone     

Transdifferentiation of pituitary thyrotrophs to lactothyrotrophs in primary hypothyroidism: case report

Primary hypothyroidism causes adenohypophysial hyperplasia via stimulation by hypothalamic thyrotropin-releasing hormone (TRH). The effect was long thought to simply result in thyroid-stimulating hormone (TSH) and prolactin (PRL) cell hyperplasia, an increase in TSH and PRL blood levels with resultant pituitary enlargement, often mimicking adenoma. Recently, it was shown that transformation of growth hormone (GH) cells into TSH cells takes place in both clinical and experimental primary hypothyroidism. Such shifts from one cell to another with a concomitant change in hormone production are termed "transdifferentiation" and involve the gradual acquisition of morphologic features of thyrotrophs ("somatothyrotrophs"). We recently encountered a unique case of pituitary hyperplasia in a 40-year-old female with primary hypothyroidism wherein increased TSH production was by way of PRL cell recruitment. The resultant "lactothyrotrophs" maintained TSH cell morphology (cellular elongation and prominence of PAS-positive lysosomes) but expressed immunoreactivity for both hormones. No co-expression of GH was noted nor was thyroidectomy cells seen. This form of transdifferentiation has not previously been described.     

Secretion of growth hormone and thyroid-stimulating hormone in patients with dementia

We studied the growth hormone (GH) response to GH-releasing hormone (GHRH) and the thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) in four groups of patients with dementia and examined whether GH and TSH secretion is altered in patients with Alzheimer's disease. The four groups included those with Alzheimer's disease (n=28), parkinsonism with dementia (n=10), progressive supranuclear palsy with dementia (n=10), and dementia of vascular origin (n=28). The results showed no differences among the four groups in GH response to GHRH (12.2 ± 2, 10.7 ± 2, 8.9 ±1.1, and 9.9 ± 1.9 g/ml, respectively); there was no correlation between GH response to GHRH and sex, stage of the disease, or cerebral atrophy. The proportion of patients with exaggerated, normal, or lower GH response was similar in the four groups. There were also no differences among the groups in terms of TSH response to TRH (9.2 ±0.9, 11.1 ± 1, 11.1 ± 1, and 10.3 ± 1 mU/ml, respectively), nor was there a correlation between TSH response to TRH and sex, stage of the disease, cerebral atrophy, or GH response to GHRH. The proportion of those with exaggerated, normal, or lower TSH response was similar in the four groups. Cerebrospinal somatostatin levels were similar in Alzheimer's disease and vascular dementia patients. These findings indicate that neither GH response to GHRH nor TSH response to TRH provides a useful diagnostic adjunt in Alzheimer's disease patients.Abbreviations AD Alzheimer's disease - PD parkinsonism with dementia - PSP progressive supranuclear palsy - VD dementia of vascular origin - GH growth hormone - GHRH growth hormone releasing hormone - TRH thyrotropin releasing hormone - TSH thyroid stimulating hormone Correspondence to: J.M. Gomez     

Initiation of high dose gonadotrophin-releasing hormone antagonist treatment during the late follicular phase in the macaque abolishes luteal function irrespective of effects upon the luteinizing hormone surge

The determination of the efficacy of gonadotrophin-releasing hormone (GnRH) antagonists in blocking the luteinizing hormone (LH) surge and luteal function is important for our understanding of the control of the menstrual cycle and for clinical application. GnRH antagonists have failed to block the LH surge reliably in the non-human primate. The aim of the study was to utilize high dose GnRH antagonist treatment administered during the late follicular phase of the menstrual cycle to block the pre-ovulatory LH surge. It was postulated that the LH surge would be prevented in all animals, but if this failed subsequent luteal function would be blocked by continued suppression of LH, since the early corpus luteum is susceptible to inhibition by GnRH antagonist treatment. A group of 16 adult female stumptailed macaques (Macaca arctoides) with regular menstrual cycles were selected. The GnRH antagonist [N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Pal(3)3,D-(Hci)6, Lys(iPr)8,D- Ala10]GnRH (Antarelix) (concentration 10 mg/ml) was administered as three daily s.c. injections, at a dose of 1 mg/kg on days 11, 12 and 13 of the follicular phase of the menstrual cycle. Of nine macaques in which it was judged that the treatment was commenced within 1 day of the expected LH surge (serum oestradiol >400 pmol/l), six demonstrated a decline in serum oestradiol concentrations, a total block of the LH/follicle stimulating hormone (FSH) surge and inhibition of ovulation as judged by an absence of a rise in progesterone concentrations. In the three other animals in this category, a partial LH surge occurred, but this failed to result in a functional corpus luteum. In a further three animals treatment was initiated on the day of the LH surge, and again there was absence of a subsequently functional corpus luteum. These results show that GnRH is involved at the time of the mid-cycle LH/FSH surge in the non-human primate. Initiation of high dose GnRH antagonist treatment during the periovulatory period abolishes luteal function irrespective of its effects upon the LH surge because of its long-term action and resultant withdrawal of luteal support.