Expression of gonadotropin-releasing hormone (GnRH) receptor gene is altered by GnRH agonist desensitization in a manner similar to that of gonadotropin beta-subunit genes in normal and castrated rat pituitary.

It was previously established that the administration of a potent GnRH agonist such as triptorelin (D-Trp6-GnRH) induced desensitization of pituitary gonadotropic cells, resulting in decreased expression of gonadotropin beta-subunit genes and the suppression of LH and FSH synthesis and release. Binding of GnRH to the pituitary is also affected by agonist treatment. To examine the desensitizing effects of GnRH agonist on the expression of the pituitary GnRH receptor (GnRH-R) gene, male rats were given triptorelin (long-acting formulation, 300 micrograms/kg), and levels of GnRH-R messenger RNA (mRNA) were determined by Northern and dot blot hybridization to a 32P-labeled rat complementary DNA probe. Abundances of gonadotropin alpha-subunit, LH beta, and FSH beta mRNAs were examined in parallel, using appropriate probes. A rapid time-dependent decrease in the level of GnRH-R mRNA was observed in rats after triptorelin administration. A minimum residual level of mRNA, in the range of 20-25% of the initial value, was attained as early as 5 h after treatment. Levels further stabilized to 25-30% after a small transient increase to 45% on day 5. A single injection was effective for at least 30 days, after which GnRH-R mRNA levels slowly returned to normal, suggesting a progressive abolition of agonist effects. A concomitant acute depletion of mRNA levels was observed for LH beta and FSH beta (50% decrease in about 48 and 3 h, respectively), whereas the alpha-subunit message increased (rapidly reaching a level 1.8-fold that in control rats after 1-2 days). Castration induced a 3.8-fold elevation in the amounts of GnRH-R mRNA after 3 weeks, whereas alpha, LH beta, and FSH beta mRNAs increased by 6.2-, 7.9-, and 4.2-fold, respectively, compared to corresponding values in intact animals. Administration of the GnRH agonist readily prevented, for as long as 3 weeks, the stimulatory effects of castration on the GnRH-R mRNA and mRNAs for the beta-subunit of gonadotropins, but not for the alpha mRNA, which remained at a high level. When triptorelin was administered 3 weeks postoperatively, the castration-induced increase in LH beta and FSH beta was totally abolished, and no significant effect was noted on alpha-subunit mRNA. In conclusion, these data demonstrate that expression of the GnRH-R gene is subject to regulation and depends on GnRH stimulation, in a manner that indicates susceptibility to desensitizing action by the long-acting GnRH analog, triptorelin.(ABSTRACT TRUNCATED AT 400 WORDS)

Testicular tumors in congenital adrenal hyperplasia: steroid measurements from adrenal and spermatic veins.

The present study reports the case of a 25-yr-old man with congenital adrenal hyperplasia due to 21-hydroxylase deficiency in whom bilateral testicular tumors did not regress after suppressive treatment with dexamethasone. Catheterization of left testicular and adrenal veins confirmed the enzyme deficiency in the gonadal lesions. The presence of specific 11 beta-hydroxylated steroids (11 beta-hydroxyandrostenedione, 21-deoxycortisol, and 21-deoxycorticosterone) in the gonadal vein demonstrated the adrenal nature of the testicular tumor. In addition, catheterization allowed further study of the secretion of mineralocorticoids and androgens in the adrenal venous effluent. Plasma levels of deoxycorticosterone were increased in the peripheral vein and decreased in the adrenal vein, confirming the conversion of progesterone by peripheral 21-hydroxylase activity. Plasma levels of delta 5-3 beta-hydroxysteroids, particularly dehydroepiandrosterone and its sulfate, were very low, suggesting a sustained stimulation of 3 beta-hydroxysteroid dehydrogenase activity. This study documents that in patients with congenital adrenal hyperplasia and bilateral testicular tumors, catheterization of a gonadal vein measuring specific 11 beta-hydroxylated steroids confirms the adrenal nature of the gonadal lesions.

Altered balance between thyrotropin-releasing hormone and dopamine in prolactinomas and other pituitary tumors compared to normal pituitaries.

We measured TRH and dopamine (DA) concentrations in prolactinomas and other pituitary tumors in order to further understand the roles of these two factors in the hormone hypersecretion and growth of these tumors. The mean TRH concentration (by RIA) in 16 prolactinomas was 247 +/- 92 (+/- SE) fmol/mg cell protein (range, 10-1297), near that found in normal pituitary tissue. The prolactinoma TRH content did not correlate with the patient's tumor size or plasma PRL level. By contrast, DA assayed by high pressure liquid chromatography was present in normal pituitary tissue (7.3 +/- 3.5 pmol/mg cell protein), but was very low or undetectable in the prolactinomas (23 fmol/mg cell protein or less). 3,4-Dihydroxyphenylacetic acid, also assayed by high pressure liquid chromatography, was undetectable in both normal pituitary tissue and prolactinomas. This imbalance between TRH and DA content also was found in GH-secreting and nonsecreting adenomas. The TRH content in 18 GH-secreting tumors (24 +/- 6 fmol/mg) was considerably lower than that in the prolactinomas (P less than 0.001). In 8 nonsecreting adenomas, the mean TRH concentration was 109 +/- 28 fmol/mg, about half of that in the prolactinomas. In those 2 types of adenomas, DA also was nearly undetectable (less than or equal to 73 fmol/mg cell protein). We conclude that the imbalance between TRH and DA contents in prolactinomas compared to those in normal pituitary tissue might participate in the mechanisms leading to hypersecretion of PRL and the growth of all types of pituitary adenomas.

Effect of Decapeptyl (a GnRH analogue) and of transforming growth factor-alpha (TGF-alpha), in the presence of heparin, on the sulfatase activity of human breast cancer cells.

The effects of the polypeptide Decapeptyl (a gonadotropin-releasing hormone (GnRH) agonist analogue) and of transforming growth factor-alpha (TGF-alpha), on estrone sulfate-sulfatase activities in the homogenates of various breast cancer cell lines were studied in the presence of heparin. In hormone-dependent MCF-7 breast cancer cells, Decapeptyl can inhibit sulfatase activity, and this effect is significantly augmented in the presence of heparin. In the other hormone-dependent T-47D breast cancer cell line, the decrease of sulfatase activity was only significant when Decapeptyl was associated with heparin. No significant effect on sulfatase activity elicited by heparin, Decapeptyl or a mixture of both was found in the hormone-independent MDA-MB-231 breast cancer cells. TGF-alpha stimulates sulfatase activity in the MDA-MB-231 cells but has no effect in the MCF-7 cells; in contrast, TGF-alpha combined with heparin provokes a decrease of the sulfatase activity in both cell lines. It is concluded that the sulfatase activity in some types of breast cancer cell can be inhibited by heparin combined with the polypeptides Decapeptyl or TGF-alpha.

Administration of a gonadotropin-releasing hormone agonist during pregnancy: follow-up of 28 pregnancies exposed to triptoreline.

OBJECTIVE: To evaluate the teratogenic or fetal risk of a long-acting GnRH agonist (GnRH-a) triptoreline acetate (Decapeptyl; Ipsen-Biotech, Inc., Paris, France), inadvertently administrated in the first weeks of pregnancy. DESIGN: Prospective follow-up of exposed pregnancies and case reports. SETTING: Teratology information service of a public hospital and pharmacovigilance department of the firm. PATIENTS: Inadvertent pregnant women receiving a treatment, mainly for endometriosis or IVF. INTERVENTIONS: Case by case, individual estimations of the risks have been provided. MAIN OUTCOME MEASURE: Each pregnancy issue has been analyzed. RESULTS: No teratogenic or fetal toxic effect has been noted. CONCLUSION: No specific hazard has been observed among newborns after inadvertent exposures to a GnRH-a during the first 20 weeks of pregnancy.

[Treatment of central precocious puberty with sustained-release triptorelin]. / Le traitement des pubertés précoces centrales par la triptoréline à libération prolongée.

Central precocious puberty is defined as the appearance of morphological and biological changes induced by the early maturation of the hypothalamic-pituitary-gonadal system before eight years of age in girls and ten years of age in boys. This early onset of the gonadotropin-releasing hormone pulse generator activation leads to secretion of gonadal steroids and therefore to the development of secondary sexual characteristics. The aim of medical treatment is to suppress the secretion of sex hormones. A dramatic improvement has been achieved with the development of gonadotropin releasing hormone agonists which induce a reversible suppression of gonadotropin secretion. Since 1986, triptorelin (Decapeptyl) (D-Trp6-LHRH) has been available for this indication as a sustained-release formulation allowing an intramuscular injection of 3.75 mg every 4 weeks. Results published up to now concern 352 children (325 girls and 27 boys). The pituitary-gonadal suppressive effect has been confirmed. The complete suppression of gonadal secretions induced a rapid regression of secondary sexual characteristics as early as the 3rd month of therapy, and decreased the growth rate acceleration which normalizes during the 3rd year of therapy. The progression of bone maturation clearly slowed down at the end of the first year of treatment so the final height prognosis significantly improved. Whatever length of the treatment period, the reversibility of the suppressive effect of triptorelin has been demonstrated. Puberty resumed 3 to 9 months after stopping the treatment. Tolerance of the medication was excellent. The rare side effects were minor and never led to treatment discontinuation: headaches (8% of the cases), hot flushes (12% of the cases). The percentage of drop out was very low.

[Innocuousness of the limited reuse of injection materials by insulin-dependent diabetics]. / Innocuité de la réutilisation limitée du matériel d'injection chez les diabétiques insulino-traités.

A survey was conducted in 120 insulin-dependent diabetics to determine their routine daily procedure for insulin injection and the possible reuse of the material employed. Aseptic precautions were usually sufficient, half of the diabetic patients (51.6%) conforming with the overall rules for hygiene generally recommended. Spontaneous reuse of injection material was rare (10/120), and local incidents as a result of reuse infrequent: pain from the 3rd injection in 2 patients and an abdominal abscess in a third case due to total lack of asepsis rules. Insulin injections in 37 insulin-dependent diabetics admitted to hospital care were administered throughout their stay by means of plastic syringes and needles used 3 times consecutively. The mean number of needles-syringes used per diabetic was 7.3, representing a total of 813 injections. Infectious sequelae were not observed and minor local incidents (pain, pruritus) were rare and unrelated to the reuse of equipment. Limited reuse, under satisfactory conditions of asepsis, of material termed for "once only use" appears to be free from risk particularly with respect to infection. Generalization of this practice will provide substantial economy in the treatment of diabetes.

[Treatment of acromegaly with a new slow release somatostatin analog, lanreotide]. / Traitement de l'acromégalie par un nouvel analogue de la somatostatine, le lanréotide à action prolongée.

Treatment of Acromegaly has been improved by the development of the somatostatin analogs characterized by an increased specificity and longer duration of action. One of these analogs-Lanreotide- (Somatuline) is supplied under a slow release formulation and does not require several daily injections like other analogs presently available. The clinical pharmacodynamic studies that have been conducted in healthy and acromegalic patients show that the i.m. injection of a single dose of this slow-release formulation leads to a significant decrease of the plasma GH and IGF-1 levels. This effect lasts at least 14 days. The Lanreotide slow-release formulation has been used to treat 123 acromegalic patients who presented with a still evolutive disease after conventional therapy. The product was given at a 30 mg-dose every 10 or 14 days during a 3-to 24-month period. This treatment led to a reduction of the symptoms and to a decrease of GH hypersecretion. GH and IGF-1 levels have been normalized respectively in 46% and 32% of the patients. The observed results allow to conclude to an immediate efficacy of the treatment (without escape sign). The adverse drug events are minor and transitory. The antitumor effects are modest and inconstant. The slow release formulation seems to provide the patients with a better quality of life, as compared to the several daily injections.

[Diabetic thoracoabdominal neuropathy. Clinical and electrophysiological study with evaluation of the autonomic nervous system]. / Neuropathie diabétique thoraco-abdominale. Etude clinique et électrophysiologique avec évaluation du système nerveux autonome.

We report on eight patients with diabetic thoracoabdominal neuropathy in whom careful evaluation of peripheral and autonomic nervous system function was performed. All patients had non insulin-dependent diabetes mellitus of 10.5 +/- 6.7 years mean (+/- SD) known duration with poor glycemic control. Thoracic (n = 7) or abdominal (n = 1) pain of sudden onset involved several adjacent dermatomal segments and was bilateral and asymmetrical in 7/8 patients. Four patients had hypoesthesia in the painful zone and six presented with significant weight loss (6.2 +/- 4.3 kg) which reversed after the relief of pain. Truncal electromyogram was abnormal in 7/7 patients. Nerve damage was not limited to thoracic nerves since electrophysiological studies evidenced distal polyneuropathy in all patients. The autonomic nervous system was also involved. Sympathetic skin response was abnormal in 7/7 patients and autonomic cardiovascular function tests demonstrated cardiac denervation in 5/5 patients. In 4/4 patients a marked relief of pain was noted within one week with amitriptyline treatment. This report confirms the characteristic clinical presentation of diabetic thoracoabdominal neuropathy. Moreover, it suggests that this neuropathy is part of a diffuse damage that also involves peripheral nerves of the limbs and autonomic nervous system.

Effect of triptorelin (Decapeptyl) combined with heparin on estradiol levels in MCF-7 mammary cancer cells after incubation with estrone sulfate.

The effects of triptorelin (Decapeptyl) and heparin, alone or in combination, on the intracellular concentration of estradiol (E2) after incubation of estrone sulfate (E1S) with the MCF-7 mammary cancer cells was investigated. Although heparin (10 mg/l culture medium) or Decapeptyl (5 x 10(-7) or 5 x 10(-5) mol/l) did not affect the levels of radioactive E2 after incubation with [3H]E1S, the combination of Decapeptyl and heparin significantly decreased the radioactive uptake and the intracellular concentrations of [3H]E2. In the absence of Decapeptyl and heparin incubations with E1S, the resulting E2 concentration (in nmol/kg DNA +/- SD) was 558 +/- 44; after heparin (10 mg/l) plus Decapeptyl (5 x 10(-7) or 5 x 10(-5) mol/l) the values were 389 +/- 55 and 165 +/- 18, respectively. It is concluded that Decapeptyl with heparin can decrease very significantly the conversion of E1S to E2 in MCF-7 cells, an observation that suggests new possibilities for the control of E2 in hormone-dependent breast cancer.

Non-responsiveness of serum gonadotropins and testosterone to pulsatile GnRH in hemochromatosis suggesting a pituitary defect.

We investigated the potential pituitary origin of gonadal insufficiency in hemochromatosis. Gonadotropin secretion was studied in seven patients with hemochromatosis and hypogonadism, before and after chronic pulsatile GnRH therapy. Pulsatile LH secretion was studied before (sampling every 10 min for 6 h) and after 15-30 days of chronic pulsatile GnRH therapy (10-12 micrograms per pulse). Prior to GnRH therapy, all the patients had low serum testosterone, FSH and LH levels. LH secretion was non-pulsatile in four patients, while a single pulse was detected in the remaining three. Chronic pulsatile GnRH administration did not increase serum testosterone levels; similarly, serum LH levels remained low: neither pulse frequency nor pulse amplitude was modified. We conclude that hypogonadism in hemochromatosis is due to pituitary lesions.

Receptors and neurohormones in human pituitary adenomas.

In order to go further into the pathogenesis of human pituitary adenomas, we studied receptors for neurohormones (thyroliberin, TRH; dopamine, DA; somatostatin, SRIH), for estradiol and epidermal growth factor (EGF) thought to influence hormone secretion and/or cell growth. The following results were obtained: (1) the receptors listed above, with the exception of EGF receptors in the adenomas, are present in normal pituitary tissue and in prolactin (PRL)- and growth hormone (GH)-secreting adenomas; (2) they are functional and their affinities are not different in normal or tumoral tissues; (3) their density is variable and depends on the type of secreting adenoma (GH or PRL), the size of the tumor and the plasma level of the hormone which is secreted, and (4) in nonsecreting adenomas, only TRH receptors are found with characteristics identical to those observed in secreting adenomas. We also showed that TRH is contained in normal and tumoral pituitary tissues. TRH and SRIH are released in vitro from adenomatous cells in large amounts, suggesting their possible synthesis by the pituitary. In both cases a local regulation is observed. TRH release is stimulated in the presence of DA while SRIH is inhibited in the presence of TRH. This neuropeptide release may be implicated in the pituitary hormone regulation through a paracrine or an autocrine mechanism. Thus, the neurohormone receptors found in pituitary adenomas should be dependent on a more complex regulation than it has been envisaged till now.

[Release of thyrotropin releasing hormone (TRH) from human prolactin-secreting pituitary adenoma cells. Modulation by dopamine]. / Libération de thyrolibérine (TRH) par les cellules adénomateuses hypophysaires humaines à prolactine. Modulation par la dopamine.

We found, by radioimmunoassay, that thyrotropin-releasing-hormone (TRH) was present in human prolactin (PRL)-secreting adenomas (mean: 89 +/- 45 (SEM) fmol/mg proteins) and was released by perifused adenomatous cells at levels varying from 5 to 60 fmol/10(6) cell/2 min. TRH release was increased in the presence of dopamine (DA) 10(-6) M but was not modified by the presence of somatostatin (SRIH) 10(-6) M.