Biomedical subjects

M L Kottler

Publications and source records attributed to M L Kottler.

At least 19 recordsLinked to original sources

PubMed1995

Subregional mapping of the human gonadotropin-releasing hormone receptor (GnRH-R) gene to 4q between the markers D4S392 and D4S409.

We have isolated nine yeast artificial chromosomes (YACs) containing the gene that encodes the human gonadotropin-releasing hormone receptor (GnRH-R) gene by screening the YAC library of the Centre d'Etude du Polymorphisme Humain (Hôpital Saint-Louis, Paris, France) by the use of the polymerase chain reaction. We defined the location of the GnRH-R gene relative to 4q microsatellite markers D4S392 and D4S409. The genetic positions of these markers on chromosome 4 are 76 and 77 cM, respectively. This location was further established by chromosomal in situ hybridization.

Base Sequence↗

PubMed1995

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)

Animals↗

PubMed1994

Nucleotide sequence analysis of mRNAs predicts that rat pituitary and gonadal gonadotropin-releasing hormone receptor proteins have identical primary structure.

In order to examine whether the paradoxical, extrapituitary ovarian and testicular gonadotropin-releasing hormone binding activity in rat was related to conventional pituitary GnRH receptor, the presence and nature of GnRH receptor gene transcripts were analysed by a reverse transcription-coupled polymerase chain reaction method. Different primer pairs designed to amplify regions of mRNA encompassing the complete open reading frame plus a large part of the 3'-untranslated region revealed the presence of GnRH receptor transcripts of strictly identical nucleotide sequence in both pituitary and gonads, predicting a unique primary structure for the receptor protein. In addition, restriction analysis of rat genomic DNA suggested that a single gene encodes the mRNA subspecies identified to date and demonstrated the presence of introns included within the highly conserved coding region. Although post-translational modifications of the GnRH-receptor may differ in the various tissues examined, these data at least clarify the nature and identity of gonadal GnRH receptors.

Amino Acid Sequence↗

PubMed1994

Gonadal and adrenal catheterization during adrenal suppression and gonadal stimulation in a patient with bilateral testicular tumors and congenital adrenal hyperplasia.

We report the case of a patient with bilateral testicular tumors and congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Catheterization of the left testicular and adrenal veins was performed. The presence of 11 beta-hydroxylated steroids in the spermatic veins confirmed the presence of testicular tumor secondary to adrenal rest cells. After adrenal suppression by dexamethasone combined with gonadal stimulation with hCG, a dramatic decrease in androgens and adrenal steroids was observed in the peripheral blood. Compared to the periphery, 21-deoxycortisol and 11 beta-hydroxy-delta 4-androstenedione levels remained higher than that of 21-deoxycorticosterone in the gonadal vein, but not in the adrenal vein, which seems to indicate that the nature of this ectopic tissue is unusual and that its sensitivity to dexamethasone depends on the adrenocortical zones. No rise in estradiol or testosterone was obtained after hCG stimulation, suggesting that all of the testicular tissue was inactive or destroyed. This finding was confirmed by histological examination.

Adrenal Glands↗

PubMed1993

[Recent data on the gonadoliberin receptor and the neuropeptide control mechanisms for gene expression of gonadotropin hormones].

GNRH plays a pivotal role in the neurohormonal control of reproduction by promoting hte secretion of pituitary gonadotrophins, LH and FSH. GnRH also stimulates the synthesis of constitutive gonadotrophin subunits alpha and beta and its own receptor number. Gonadotrophin synthesis appears to be regulated by GnRH through various molecular mechanisms that include, in a complementary and in some cases differential manner, enhanced transcriptional activity of subunit genes and polyadenylation of transcripts. The latter is known to result in increased stability and/or translational activity of mRNAs. These effects of GnRH are mimicked by the direct activation of protein kinases A and C, two different but possibly interconnected signalling pathways that may account for the pleiotropic and concerted alterations of both synthesis and release of gonadotrophins. GnRH operates on the gonadotropic cell level via a transmembrane, G-protein coupled receptor, the structure of which has recently been determined by molecular cloning. This receptor differs from the other members of hte super-family essentially by a rather short length (only 327-328 amino acids) and a truncated carboxyterminus. Recent experiments suggest a genomic control of the GnRH receptor synthesis, especially by GnRH itself, the importance, and role of which remains to be established for the pituitary gonadotropic function.

Amino Acid Sequence↗

PubMed1992

Relationships between androgen and estrogen sulfates in breast cyst fluid.

In 28 breast cyst fluids obtained from 20 patients (age 29-65 years) sodium, potassium and the sulfates (S) of estrone (E1), estradiol (E2), dehydroepiandrosterone (DHEA) and androsterone (A) were determined. The radioimmunoassays (RIA) used were validated for this particular biological fluid. According to electrolyte ratio (Na+/K+) the cyst fluids were subdivided into two groups: the first with low (less than 3) (n = 16) and the other with high (greater than 3) (n = 12) values. Markedly higher steroid sulfate levels were observed in the first group, the mean levels being: 147.7 nmol/l, 54.6 nmol/l, 108.1 mumol/l and 158.0 mumol/l for E1S, E2S, DHEAS and AS respectively. The mean levels in the second group were: 13.6 nmol/l, 6.7 nmol/l, 68.8 mumol/l and 33.6 mumol/l for E1S, E2S, DHEAS and AS, respectively. In the first group only E1S and E2S levels were significantly correlated (r = 0.51; P less than 0.05). Conversely, the steroid sulfate levels were significantly correlated with each other in the group with high electrolyte ratio. These data have confirmed preceding results and have clearly shown that breast cyst fluids with low electrolyte ratio contain more E2S than the other group. This finding might be correlated with the fact that patients with these breast cysts lined by with apocrine epithelium may be at a greater risk of breast cancer than those with the other type.

Adult↗

PubMed1992

Effects of short-term GnRH agonist--human menopausal gonadotrophin stimulation in patients pre-treated with progestogen.

The recent use of gonadotrophin-releasing hormone agonist in a short-term regimen has allowed the effectiveness of human menopausal gonadotrophin (HMG) stimulation to be markedly improved. It seems to be related to the flare-up effect of the agonist in the early follicular phase of the cycle. However, individual hormonal responses to the agonist are quite variable and four patterns of oestradiol secretion have been described. The present study indicates that in women pre-treated with progestogen, only two patterns of serum oestradiol are observed in the flare-up period, with a significant increase in 57% of patients. Significant correlations are observed between oestradiol values and the endogenous gonadotrophin surge (positively with luteinizing hormone, r = 0.38; P less than 0.05 and negatively with follicle stimulating hormone, r = 0.48; P less than 0.005). Furthermore, there was a significant relationship between the hormonal flare-up and the ovarian parameters following HMG stimulation. In conclusion, in progestogen-pre-treated women, the serum oestradiol level during the flare-up period is a reliable index to predict subsequent effectiveness of ovarian stimulation with HMG.

Adult↗

PubMed1991

[Breast cysts].

The mammary cyst is part of the fibro-cystic disease. Only cysts with a diameter of more than 3 mm would have a pathological significance. Its clinical symptomatology is well known. The clearing puncture is the essential diagnostic and therapeutic act. Mammography, sustained by cystography, furnishes highly worthy information. Thermography and ultra-sonography may also be useful. Its pathogeny is still being very much discussed. Hormonal factors are incriminated: hyperestrogenemia, luteal deficiency, dysprolactinemia are inconstant. They are neither necessary nor sufficient to induce the cystic disease. The titration of TeBG may perhaps open an interesting path for research. The study of intracystic steroids (among which DHEAS) furnishes instructive results. Intracystic glycoproteins, proteins and electrolytes are also the objects of promising research. Recently, the interest lying in the study of EGF, its possible relation to DHEAS and the intracystic Na/K ratio were emphasized. It is also important to notice the presence of cysts with a flat wall or with a hyperplastic wall, of the apocrine type. The psychogenic factors seem to be determining in the cystic flare-ups. The relations with breast cancer remain the fundamental problem. Although the cyst itself only exceptionally degenerates into cancer (cyst-epithelioma), the very presence of a macrocytic disease multiplies by 3 or 4 the risk of cancer. The treatment is composed of psychotherapy, tranquillizers and a clearing puncture of the strained cysts. The administration of phlebotonics, anti-prostaglandins, colostrum extracts, can give substantial results. The author gives details about the part of hormonal treatment as a function of the titrations and the severity of the case. If it appears necessary to block the gonadotropic function, Danazol is a very effective agent. Surgery has but a small place. Indication of subcutaneous mastectomy will rest upon a very severe case-selection.

Adolescent↗

PubMed1991

[Contraception and breast cancer].

The role of oral contraceptives in the development of breast cancer has given rise and still gives rise to many debates, accentuated by the economic and social impact of contraception. Several problems can the brought forward: can oral contraceptives (OC) play a role in the development of breast cancer? Can they aggravate it? Can they prevent it? We have various means at our disposal to help us in answering those difficult questions: fundamental studies, mechanisms of action of steroid hormones in the development of the mammary gland, comprehension of the mechanisms of carcinogenesis, epidemiological studies which enable us to define the notion of relative risk. At present, there is no emergence of the notion of an aggravation of the risk of breast cancer linked with the intake of oral contraceptives. However, it must be reminded that the use of oral contraceptives is still recent if we take into account the existence of a latency period before an eventual harmful effect appears and the fact that the oestro-progestative compositions have been greatly modified in those last few years. However, the present studies are centred on the populations said to be "at risk". The results of studies on women who have taken an OC before their first pregnancy or before the age of 25 still remain contradictory. Those of women with a family history of breast cancer or hyperplastic lesions are reassuring but need to be confirmed. Finally, a protective effect of a contraceptive composition is yet to be demonstrated.

Breast Neoplasms↗

PubMed1991

[What is mastopathy at risk? Epidemiologic and clinical basis].

One out of 11 women is destined to develop breast cancer. All women should be "under observation". Does a "normal" breast really exist? A discharge from a single orifice could suggest a papillomatosis, a real borderline lesion, the adenofibroma practically never degenerates, the essential problem is that of the fibrocystic disease, (or mastosis) which was the object of a recent detailed analysis (W. Dupont and D. Page), pre-menstrual mastodynia does not seem to be a risk factor. On the other hand, certain dystrophic lesions constitute a high risk, such as atypical epithelial hyperplasia, especially if it is associated with a direct family history of breast cancer. Recent studies on mammary cysts insist on their hormone and electrolyte content, the presence of EGF, as well as that of certain proteins (GCDFP 15). They also insist on the local tissue enzymatic activities, the importance of myoepithelial cells and of fibroblasts. On a practical level, the attention is drawn on: cysts whose diameter exceeds 5 mm, certain histological lesions found during the biopsies. The value of mammography and thermography in the assessment of the high risk is discussed. Finally, the present well-established notions are recalled: the family history, late pregnancies, the diet, the weight, certain pathological associations, the endogenous hormonal balance bearing on E2/P and the blood prolactin level, the exogenous hormone intake.

Breast Neoplasms↗

PubMed1990

Regulation of plasma corticosteroid-binding globulin in adult cynomolgus monkey (Macaca fascicularis) during different reproductive states.

The plasma concentration of the corticosteroid-binding globulin (mCBG) has been measured in Macaca fascicularis, during different stages of reproduction and under hormonal treatments. The mCBG level was determined by a specific electroimmunoassay. There was no difference between females in the follicular phase and intact males; mCBG concentrations were respectively (mean +/- SEM) 469 +/- 53 and 443 +/- 25.6 nmol/l. The mCBG levels levels were similar during both the luteal (469 +/- 33.5 nmol/l) and the follicular phase (469 +/- 53 nmol/l). Compared to intact males, the mCBG levels were higher (P less than 0.05) in castrated males (527 +/- 6.6 nmol/l). During gestation, no systematic variations were found and the mCBG levels were not statistically different from the values found during the follicular phase. When estradiol benzoate was administered to castrated animals, the mCBG concentrations increased rapidly. In contrast, the values were reduced slightly by testosterone treatment. The sex-steroid action on the mCBG levels was discussed and compared with the mSBP levels. We question also, the mechanisms involved in the regulation of the mCBG levels during pregnancy.

Animals↗

PubMed1990

Y chromosome and aggression in strains of laboratory mice.

Intermale attack behavior differences in laboratory strains of inbred mice have Y chromosome correlates in a small number of strain comparisons. Moreover, the Y correlates interact with autosomal or pseudoautosomal genes. Recent data on the genetics of the Y do not contradict these conclusions. The discovery of several polymorphic loci of the Y could pave the way for a direct confirmation of Y correlates of attack behavior by linkage detection. The involvement of the Y in this behavior has been put forward. Plasmatic testosterone concentration reactivity of some target organs to exogeneous testosterone appears to be correlated with two independent loci of the Y acting in an additive or interactive manner with autosomal or pseudoautosomal loci. However, the association between testosterone action and attack behavior in males needs further evidence, and in any case this association does not underline linear mechanisms.

Aggression↗

PubMed1990

Opponent strain effect on eliciting attacks in NZB mice: physiological correlates.

In agonistic encounters between male mice, the characteristics of the opponent may influence the attacking behavior of its partner. The present study shows that the opponent's ability to elicit attacking behavior in NZB males is strain dependent. BALB/c opponents elicit attacks more frequently, earlier and more intensively than C57BL/6 males. Plasma testosterone concentration was found to be higher in BALB/c than in C57BL/6 intact males. The weight of seminal vesicles in castrated males of both strains increased with injections of either 10- or 250-micrograms testosterone propionate (TP). This response was greater in BALB/c with the higher TP dose. The submandibular glands reacted to TP only in castrated BALB/c males with the higher dose. Furthermore, BALB/c males produced more marking secretions than C57BL/6 males. These results suggest that for these two strains, a higher testosterone sensitivity and a greater production of secretions are associated with a higher probability of opponents to elicit attacks. Genetic hypotheses on the underlying mechanisms are discussed.

Aggression↗

PubMed1990

Effect of testosterone on regulation of the level of sex steroid-binding protein mRNA in monkey (Macaca fascicularis) liver.

Two specific oligonucleotide probes complementary to different regions of human sex steroid-binding protein (SBP) cDNA were used to study the levels of hepatic monkey SBP mRNA during different hormonal states. In females the SBP mRNA level was higher than in males and paralleled the serum SBP level. After castration, the SBP concentration increased in the serum but was reduced after testosterone treatment. In contrast, the hepatic SBP mRNA level decreased after castration and was restored by testosterone treatment. These results suggest a high homology of the nucleotide sequence between human and monkey SBP mRNAs. The changes in liver SBP mRNA levels may explain the sex difference in plasma SBP concentrations, but mechanisms other than the regulation of transcription may regulate the plasma concentration in monkeys.

Animals↗

PubMed1989

Sex steroid-binding protein: identification and comparison of the primary product following cell-free translation of human and monkey (Macaca fascicularis) liver RNA.

A very close similarity in molecular, steroid-binding and immunological properties have been demonstrated for the sex steroid-binding proteins of plasma from human (hSBP) and monkey (mSBP): both are glycoproteins composed of two similar subunits able to bind one steroid molecule and to cross-react with the same antibodies. After translation of human and monkey (Macaca fascicularis) liver mRNAs by a wheat-germ embryo extract, in the presence of labelled amino-acids, we have characterized in both cases a single radioactive polypeptide immunologically related to SBP, migrating in SDS-PAGE as a single band and having a molecular weight of about 42,000. This protein could be displaced from the antibody by pure unlabelled SBP in excess. The difference in molecular weight between the in vitro translation product and the native SBP sub-unit is probably due to the absence of glycosylation in the neo-synthesized protein. The radioactivity incorporated into mSBP was 4 times higher than the radioactivity incorporated into hSBP, suggesting that the amount of mRNA for SBP is higher in monkey than in human liver. Our results show that the two sub-units of hSBP and mSBP derive from a common precursor, representing respectively 0.0050% and 0.0013% of the total neosynthesized proteins in monkey and in human liver.

Animals↗

PubMed1989

Ultradian, circadian and seasonal variations of plasma progesterone and LH concentrations during the luteal phase.

The circadian variations in plasma progesterone (P) and LH concentrations were investigated in six women, aged 23-40 years. All were studied in the mid-luteal phase (7 +/- 2 days after LH mid-cycle surge). Experiments were conducted in autumn and in spring. Blood samples were obtained every 15 min for 24 hr. Plasma P and LH concentrations were measured by RIA. Each subject's time-series was analysed using three methods; visual inspection (chronogram), spectral analysis to estimate component periods of rhythms (tau) and cosinor analysis to quantify the rhythms parameters. Marked temporal variations in plasma P concentration were observed in each subject. The maximal variations over a 24-hr period, ranged between 13-58.5 mmol/l. Differences related to sampling time were statistically validated by ANOVA (p less than 0.00001). Significant harmonic periods were detected by spectral analysis but differed among subjects. In all subjects but one, a circadian rhythm was detected. The acrophase location was similar (about 0700 hr) in the four subjects studied in autumn, but ranged from 1940 to 0320 hr in those studied in spring. An ultradian rhythm with tau = 8 hr was also validated in six time-series with similar acrophases (about 0200, 1000, and 1800 hr). Cosinor analysis of pooled data revealed that the 24-hr, 12-hr, and 8-hr rhythms were statistically significant (p = 0.001) in autumn. algebraic sum of these three cosine functions yielded a circadian waveform with peak-times occurring near 0300 and 1130 hr and a trough-time about 2200 hr. In spring, the circadian pattern appeared quite different, and peak-times were found near 0700 and 2000 hr, and trough-times near 0300 and 1500 hr. Furthermore, the 24-hr mean of P was higher in autumn (28.9 +/- 0.4 nmol/l) than in spring (17.2 +/- 0.4 nmol/l), p from ANOVA less than 0.00001. The evidence for a similar circadian LH pattern is not as strong. Seasonal, circadian and ultradian rhythms characterize the physiologic time structure of plasma P concentration in mid-luteal phase.

Activity Cycles↗

PubMed1988

Identification of the primary translation product of the sex steroid-binding protein from monkey liver mRNA in a cell-free system.

The synthesis of monkey (Macaca fascicularis) Sex steroid-Binding Protein (mSBP) in a wheat germ cell-free system in response to liver RNA was demonstrated by use of a specific antiserum raised against purified native human SBP. Antibodies precipitate a single translation product behaving as a 42 kDa protein in sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Western blots of monkey sera subjected to SDS-PAGE and immunorevelation show that the native mSBP migrates as 2 molecular species (50 and 53 kDa) present in the approximate ratio of 1:10, respectively. The difference in apparent molecular weights of the primary translation product and the reduced mature mSBP may represent glycosylation that occurs post translationally. We describe for the first time the biosynthesis of mSBP at the molecular level and suggest that both components of mSBP derive from a common differentially processed precursor. Its mRNA is poorly represented, since the neosynthesized mSBP represents about 0.005% of the total proteins encoded by liver mRNA.

Animals↗

PubMed1988

Regulation of plasma sex-steroid-binding protein in adult cynomolgus monkeys (Macaca fascicularis) during different reproductive states.

Levels of the sex-steroid binding protein (mSBP) have been characterized in Cynomolgus monkeys, during different stages of reproduction and under hormonal treatments, by an immunoassay allowing a specific and accurate measurement of the protein itself. Using an antiserum specific for native human SBP, we have determined the mSBP level by electroimmunodiffusion. This method correlates closely with the binding capacity measured by a steady-state polyacrylamide electrophoresis. The levels are lower in males (M = 88 +/- 8.6 nmoles/1, n = 6) than in females in the follicular phase (M = 123 +/- 4.4 nmoles/1, n = 5, p less than 0.001) and in castrated males (M = 172 +/- 13.3 nmoles/1, n = 3, p less than 0.001). During gestation, the SBP level decreases (M = 69 +/- 16.3 nmoles/1, n = 7, in the latter part of pregnancy), but during lactation, it is similar to follicular values. Estrogen treatment fails to increase SBP levels in castrated animals, but the values are reduced by testosterone treatment. Since these results are different from those observed in women, we question the validity of using monkeys as models for understanding the mechanisms controlling the concentration of SBP in human blood.

Animals↗