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Biomedical subjects

J C Thalabard

Publications and source records attributed to J C Thalabard.

At least 19 recordsLinked to original sources

Identification of pulses in hormone time series using outlier detection methods.

The identification of discrete hormonal secretory pulses is of critical importance in clinical endocrinology. Pulses are defined as sudden increases in hormone concentration followed by exponential decay. We propose a model-based iterative procedure for pulse detection in pulsatile hormone time series. Our model is seen to be analogous to the model for innovation outliers in autoregressive series, and outlier detection techniques for pulse identification are adapted to the endocrine context. An original feature of the procedure is that it distinguishes between true pulses and gross observation outliers in the series. Simulation experiments are used to investigate the behaviour of the method under physiologically or clinically relevant circumstances. Five experimental endocrine series from rhesus monkeys, where the times of the pulses are known from the concomitant recording of the electrical activity of the hypothalamus, are analysed.

Animals

Cyclical mastalgia as a marker of breast cancer susceptibility: results of a case-control study among French women.

A matched case-control study in a population of urban, non-menopaused women living in Paris was performed between 1983 and 1985 to investigate the risk of breast cancer (BC) in relation to various factors with a particular interest in the effect of the use of oral contraceptive (OC) and the existence of cyclical mastalgia (CM). Two hundred and ten non-menopaused women, less than 45 years old, with newly diagnosed BC were compared to 210 controls from the same geographic area matched on year of birth, age, education level and age at first full term pregnancy (FFTP), when justified. The adjusted Relative Risk of BC (RRa) was significantly increased for a total duration of OC use longer than 72 months (RRa 2.80; 95% CI 1.56-5.01), as well as the RRa for OC use above 48 months before FFTP (3.26 95% CI 1.37-7.76) and, to a lesser extent, the RRa for OC use above 48 months after FFTP (2.02 95% CI 1.07-3.84) respectively. Adjustment was performed on familial history of BC, personal history of Benign Breast Disease (BBD), age at menarche. A previous history of cyclical mastalgia was found to be associated with an increased risk of BC. The significant increase remained after adjustment on the previously mentioned confounding factors and OC use: RRa 2.12; 95% CI (1.31-3.43). Under a precise definition related to the hormonal environment, mastalgia appear to be an interesting marker of breast cell susceptibility, the importance of which can only be validated by prospective studies.

Age Factors

Fertility in women with late-onset adrenal hyperplasia due to 21-hydroxylase deficiency.

Fertility was evaluated in 53 female patients with late-onset adrenal hyperplasia (LAH) due to 21-hydroxylase deficiency. The majority of patients (n = 33) were seen for isolated postpubertal hirsutism, 9 patients consulted for sterility, and 11 for irregular menstrual cycles. At the time of diagnosis, the ages of patients ranged from 15-40 yr (mean +/- SD, 24.6 +/- 5.2). No patient had major signs of virilization. The plasma 17-hydroxyprogesterone level was higher than normal in all patients (26.8 +/- 18.9 nmol/L; range, 3.4-139.4) and dramatically increased to 140.1 +/- 80.6 nmol/L (range, 35.2-324.2) after ACTH treatment. Plasma androgen levels were high (testosterone, 3.25 +/- 2.03 nmol/L; delta 4-androstenedione, 13.65 +/- 5.60 nmol/L). Plasma basal and LHRH-stimulated values were normal for FSH and high for LH. Basal and TRH-stimulated plasma PRL levels were normal. Among these 53 LAH patients, only 20 desired a pregnancy. These had a total of 38 pregnancies. Ten patients became pregnant before the diagnosis of LAH and without any treatment; they had a total of 18 pregnancies, 12 of which were successful. Moreover, 19 normal pregnancies without any spontaneous abortion were carried to term by 14 of 16 hydrocortisone-treated patients. One patient needed the association of one cure of clomiphene citrate. Hypofertility in LAH patients seems, therefore, to be relative. Its mechanism is hormonal, with anovulation or dysovulation, due to the continuous steroid feedback of adrenal origin on the hypothalamo-pituitary axis. Hydrocortisone is the appropriate treatment in most cases, reducing adrenal androgen overproduction and relieving hypothalamic-pituitary gonadotropin function, thereby making possible cyclic ovarian activity and ovulations.

17-alpha-Hydroxyprogesterone

Effects of gonadotrophin releasing hormone antagonist and agonist on the pulsatile release of gonadotrophins and alpha-subunit in postmenopausal women.

OBJECTIVE: The present study was designed to further assess the mechanism of action of GnRH and GnRH analogues. DESIGN AND PATIENTS: Both the Nal-Glu GnRH antagonist and the D-Trp6 GnRH agonist were administered sequentially to nine normal, post-menopausal women. MEASUREMENTS: A baseline study of pulsatile LH, FSH and free alpha-subunit secretion was performed, with sampling every 10 min for 8 h, and then repeated 8 h after a single subcutaneous injection of Nal-Glu GnRH antagonist (5 mg). Sampling was repeated 21 days after the intramuscular injection of a depot preparation of D-Trp6 GnRH (3.75 mg) in the same women. RESULTS: The baseline sampling period showed synchronous pulses of LH and free alpha-subunit. The antagonist Nal-Glu decreased plasma LH (71%) and free alpha-subunit (43%). However, with the single dose of 5 mg, pulsatile LH and free alpha-subunit release were not completely suppressed and remained temporally correlated. The GnRH agonist had a potent inhibitory action on plasma immunoreactive LH (IRMA) (93%). In contrast, it increased the mean plasma levels of free alpha-subunit from 1.66 +/- 0.01 to 5.06 +/- 0.02 micrograms/l (205%). The pulsatile secretory patterns of both LH and free alpha-subunit were abolished by the agonist. Immunoreactive FSH levels were decreased by the antagonist (24%) and suppressed by the agonist (93%). CONCLUSIONS: The pulsatile study confirms the different mechanism of action of GnRH analogues. Following antagonist administration, low amplitude free alpha-subunit pulses persist and are synchronous with residual LH pulses. In contrast, LH and free alpha-subunit are not maintained under agonist treatment. These data provide evidence for the differential regulation of LH and free alpha-subunit by GnRH.

Female

Radiotelemetric monitoring of hypothalamic gonadotropin-releasing hormone pulse generator activity throughout the menstrual cycle of the rhesus monkey.

Continuous monitoring of the electrophysiological manifestations of GnRH pulse generator activity was achieved by radiotelemetry throughout the menstrual cycles of unrestrained rhesus monkeys. The characteristic increases in hypothalamic multiunit activity (MUA volleys) associated with each LH pulse measured in the peripheral circulation were of lower frequency during the luteal phase than in the follicular phase of the cycle. Multiunit activity volley frequency increased as functional luteolysis progressed and achieved maxima of approximately one volley per hour within the first few days of the follicular phase. Unexpectedly, a dramatic decline in pulse generator frequency was observed coincidentally with the initiation of the preovulatory LH surge. Evidence is presented to support the conclusion that this deceleration of pulse generator activity is the consequence of the preovulatory rise in plasma estrogen concentration. As reported in women, a significant reduction in GnRH pulse generator frequency was observed at night during the follicular phase, but not during the luteal phase, of the menstrual cycle.

Animals

The use of the antiprogestin RU486 (mifepristone) as an abortifacient in early pregnancy--clinical and pathological findings; predictive factors for efficacy.

RU486, a potent antiprogesterone steroid was administered to 124 women requesting therapeutic abortion. All were less than 49 days from their last menstrual period. Ten of these subjects (Group I) received high doses of RU486 in a decremental dose regimen (400, 300, 200 and 100 mg/day) over 4 successive days and 14 received 50 mg/day for 7 days (Group II). A further 50 subjects (Group III) received 100 mg/day for seven days and the remaining 50 subjects (Group IV) received 450 mg in a single dose. In the first three groups, half the daily dose was given in the morning and the remainder in the evening. Blood was collected before, and on Days 4 and 7 and then once a week after commencing therapy until disappearance of circulating beta HCG. In addition to beta HCG, estradiol-17 beta (E2), progesterone (P), cortisol, and various metabolic and hematological parameters were measured. Plasma RU486 concentrations were also assayed in Group II, III and IV subjects on Day 7 of therapy and in some cases on Days 14 and 21. Ultrasonography was performed in all cases on Day 1 and on Day 14. All the patients bled within five days following RU486 administration, for 1 to 21 days. A complete abortion occurred in 60% in Group I, 50% in Group II, 86% in Group III, and 80% in Group IV. The difference between the last two groups and the first two was significant at p less than 0.01. The non-responders were submitted to a uterine vacuum aspiration. A stepwise discriminant analysis was performed and indicated that the best predictors of the outcome of therapy were beta HCG values and the gestational sac diameter. With these criteria, the prediction was accurate in 86.4% of the cases. The best results were obtained in the cases where the ultrasonic measurement of gestational sac was under 10 mm in diameter and the initial beta HCG values under 15,000 mIU/ml. Among the observed side effects were moderate pelvic cramps (20.9%), nausea (27%), fainting (4.8%); 61.3% of the women complained of fatigue. Heavy bleeding occurred in 15.3% of the women but only one of them required blood transfusion. In the patients with complete abortion, beta HCG values decreased to below 500 mIU/ml by Day 14 (but in 11 cases values fell below 2,000 mIU/ml only by Day 21). Plasma estradiol and progesterone also fell. Cortisol levels increased during therapy especially in subjects of Group I, but returned to basal values after termination of treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Abortifacient Agents

Duration of phasic electrical activity of the hypothalamic gonadotropin-releasing hormone pulse generator and dynamics of luteinizing hormone pulses in the rhesus monkey.

The secretion of luteinizing hormone (LH) by the pituitary gland is a pulsatile phenomenon. In the rhesus monkey, each pulse of LH in the peripheral circulation is associated with a characteristic increase in multiunit electrical activity (MUA) recorded from the medial basal hypothalamus. These "volleys" of electrical activity initiate the release of gonadotropin-releasing hormone (GnRH) into the pituitary portal circulation from the terminals of neurosecretory cells. Their duration varies from 1-3 min in normal, adult intact females to 10-25 min in long-term ovariectomized monkeys. A variety of pharmacological interventions also modify volley duration. The purpose of this investigation was to determine the physiological significance of alterations in volley duration. The dynamics of LH pulses in ovariectomized animals were observed in a number of experimental circumstances in which MUA volley duration was reduced from a maximum of 23 min to a minimum of 4 min without significantly altering their frequency. The magnitude of each LH pulse was assessed by calculating the area under the curve delineated by the time course of LH above baseline. In eight experiments, a linear regression of these values on volley duration failed to reveal a significant correlation between MUA volley duration and the magnitude of LH pulses. These results suggest that all of the GnRH secreted per pulse is released at the onset of each MUA volley, the remainder of the increase in electrical activity having no further action on GnRH secretion, although effects on other systems cannot be excluded.

Activity Cycles

Corticotropin-releasing factor and gonadotropin-releasing hormone pulse generator activity in the rhesus monkey. Electrophysiological studies.

The effect of corticotropin-releasing factor (CRF) on the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator, the central neuronal system governing pulsatile pituitary luteinizing hormone (LH) secretion, was studied electro-physiologically in 6 ovariectomized rhesus monkeys bearing bilateral arrays of recording electrodes implanted in the mediobasal hypothalamus. 'Volleys' of increased multiunit activity (MUA) were recorded for 6-10 h in animals placed in primate chairs. The circulating concentrations of LH and cortisol were determined by radioimmunoassay in blood samples taken every 10 min for 3-4 h prior to the administration of CRF (200 micrograms, i.v.) and for 3-6 h thereafter. CRF resulted in a significant decrease in the frequency of pulse generator activity in 4 of 6 animals, a significant decrease in the duration of MUA volleys and a rise in circulating cortisol levels in all 6 monkeys. Treatment with metyrapone (30 mg/kg, i.m.), an inhibitor of adrenal steroidogenesis that prevented the CRF-induced rise in serum cortisol levels, did not reverse the inhibitory effects of CRF on the frequency or duration of MUA volleys. The opiate antagonist naloxone (0.8 mg/kg, i.v., 10 min prior to CRF followed by 0.8 mg/kg/h infusion) blocked the effects of CRF on MUA volley frequency in 2 of 3 animals, but failed to block the effect of CRF on MUA volley duration, suggesting that endogenous opioids may mediate the action of CRF on pulse generator frequency but not on duration.

Animals

Duration and frequency of multiunit electrical activity associated with the hypothalamic gonadotropin releasing hormone pulse generator in the rhesus monkey: differential effects of morphine.

The effects of morphine on the frequency and duration of the characteristic bursts or 'volleys' of multiunit electrical activity (MUA) associated with pulsatile pituitary luteinizing hormone (LH) secretion were studied in unanesthetized ovariectomized rhesus monkeys bearing bilateral arrays of electrodes implanted in the mediobasal hypothalamus. Morphine administration resulted in a dose-dependent decrease in MUA volley duration and frequency. When morphine was infused at 10 micrograms/kg/h, the inhibiting effect on volley duration was observed without a change in volley frequency. It is concluded that the frequency and duration of hypothalamic MUA volleys associated with pulsatile LH secretion may be independently regulated.

Animals

Global breast attenuation:control group and benign breast diseases.

This paper deals with the estimation of the slope of attenuation in human breast tissue. The measurement is done in the reflection mode with a short time Fourier analysis. All important factors such as diffraction effect, tissue depth and specular reflectors are taken into account. A population of 49 normal women shows large inter-individual variations of the attenuation coefficient. A multiple linear regression allows correlation of this variation with the duration of the woman's genital life and pregnancies. A preliminary study is done on 10 benign diffuse breast diseases and shows a weak correlation with the type of the breast: normal or pathological. The utility of the quantification is discussed for one case of large fibrocystic disease.

Adult

Cyproterone acetate versus hydrocortisone treatment in late-onset adrenal hyperplasia.

Thirty late-onset adrenal hyperplasia patients consulting for isolated hirsutism were randomly divided into two groups; group 1 (n = 16) was treated with hydrocortisone in order to suppress androgen adrenal secretion, and group 2 (n = 14) received cyproterone acetate (CPA) antiandrogen therapy to inhibit peripheral androgen activity. The clinical and hormonal effects of each type of treatment were evaluated. Before treatment, the clinical and hormonal profiles of the two patient groups did not differ significantly. Excellent clinical evolution in terms of the regression of hirsutism was observed in the CPA-treated patients (54% decrease in the clinical score in 1 yr), in contrast with the slight decrease in hirsutism (26%) after hydrocortisone treatment. In hydrocortisone-treated patients, plasma androgen decreased to normal levels: testosterone from 3.05 +/- 1.45 to 1.46 +/- 0.42 nmol/L and delta 4-androstenedione from 13.6 +/- 4.1 to 6.33 +/- 1.47 nmol/L. Conversely, in CPA-treated patients, only a slight decrease in testosterone from 2.98 +/- 1.98 to 2.29 +/- 0.64 nmol/L and in delta 4-androstenedione from 12.9 +/- 5.9 to 9.86 +/- 2.23 nmol/L was observed. This slight decrease in plasma androgens contrasts with the rapid clinical improvement after CPA. These results emphasize the importance of peripheral receptivity to androgens in the clinical expression of hyperandrogenism. Moreover, they indicate that peripheral antiandrogen therapy may be more appropriate in late-onset adrenal hyperplasia patients than conventional adrenal inhibition using cortisone therapy.

Adolescent

Risk factors for breast fibroadenoma in young women.

In a case-control study, 178 women diagnosed with fibroadenoma (FA) between 1976 and 1982 were compared with 178 age-matched controls in order to assess the risk factors for FA. Women who had a previous diagnosis of breast disease were excluded. The odds ratios (OR) of FA were calculated for different risk factors of breast disease from bivariate analysis as well as multivariate regression analysis. The highest ORs were found for a previous premenstrual mastalgia before first childbirth and a familial history (FH) of breast cancer (BC). Oral contraceptive (OC) use before a first full-term pregnancy (FFTP) does not modify this risk. Also current use of standard oral contraceptives (SOC) containing 50 micrograms of ethinyl estradiol per pill appeared to be protective and the correlation with FA was negative. These findings underline: (a) the predictive value of premenstrual mastalgia for the subsequent development of breast disease; (b) only current high-dose OC use is protective.

Adenofibroma

A program running under MS-DOS for the analysis of epidemiologic stratified or matched data.

Breslow and Day's method for computing the conditional likelihood of the logistic model in case of stratified samples requires, at each iteration the generation, for each stratum, of all the permutations of nc elements drawn from a total of nc + nt elements, where nc and nt are respectively the numbers of the cases and of the controls. This procedure rapidly proves costly in time as nc and nt increase, and also when nc and nt differ from one stratum to the next. The use of this technique on microcomputers is therefore limited. Presented here is an algorithm written in FORTRAN, based on a binary representation of the possible permutations, which readily permits the implementation of Breslow and Day's model on a microcomputer.

Algorithms

Effects of a pure antiandrogen on gonadotropin secretion in normal women and in polycystic ovarian disease.

To assess the role of androgens in gonadotropin regulation in women, we studied the effects of a pure nonsteroidal antiandrogen, Anandron (Cassenne, Paris, France). Nine normally cycling women (group 1) with acne and/or seborrhoea and nine patients with polycystic ovarian disease (PCOD) (group 2) received Anandron (100 mg twice a day) and a placebo. Both treatments were administered orally, in a cross-over randomized design, for two consecutive cycles (group 1) or months (group 2) separated by one cycle or 1 month. Luteinizing hormone (LH) pulse frequency and amplitude (cluster analysis), basal and gonadotropin-releasing hormone (GnRH)-stimulated plasma LH/follicle-stimulating hormone (FSH) levels were determined on day 5 of each treatment or placebo cycle. On days 5, 10, 20, and 24 of each cycle or month, plasma estradiol (E2), estrone (E1), testosterone (T), dihydrotestosterone (DHT), androstenedione (A), dehydroepiandrosterone sulfate (DHAS), sex hormone-binding globulin (SHBG) levels, and urinary androstanediol glucuronide (3 alpha-diol G) were measured. Plasma progesterone (P) levels were determined on days 20 and 24 of each cycle (group 1) and on days 5, 10, 20, and 24 (group 2). In both groups, seborrhea and acne decreased markedly within the first month and practically disappeared after 2 months of Anandron treatment. No adverse side effects were reported. None of the normal patients had any disturbance of menstrual cycles as assessed by basal body temperature shift, ultrasonography, and plasma P levels. In PCOD patients, cycles remained anovulatory.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

Clobazam increases pulsatile luteinizing hormone secretion in normal men.

To investigate the effects of the 1,5-benzodiazepine, clobazam, on LH secretion in normal men, LH pulsatile secretion was defined after oral administration of 40 mg of clobazam or a placebo to 6 healthy male volunteers, according to a randomized cross-over design. LH pulse frequency increased significantly from a mean of 3.8 (range 3-5) pulses/8 h after placebo, to a mean of 5 (range 4-7) pulses/8 h (P less than 0.05), after clobazam. Mean LH concentrations and peak amplitudes did not change significantly. These results suggest that clobazam mediates its effects on LH secretion at the hypothalamic level by increasing the frequency of episodic GnRH release.

Adult

[Pulsatile administration of GnRH: from the future to the present].

Since the first clinical reports of the successful induction of ovulations and pregnancies using pulsatile administration of the neuropeptide GnRH by G. Leyendecker and L. Wildt's group in 1979, the role of the hypothalamic generator, as demonstrated in primates by E. Knobil, is widely accepted in human reproduction. During this time, an increasing number of group has experienced these therapies and there continues to be some controversies about the route of administration, the indications, the need for adjuvant therapies. A correct evaluation of these therapies needs multicentric studies and more accurate criteria: the MINITEL network provides a fast, inexpensive way to collect data from different groups and to perform studies with larger sample sizes. The Life table analysis method represents the more suitable method for evaluating and for comparing various therapy regimens. LH plasma pulsatility studies have been performed in humans in order to classify various "supra-pituitary" reproductive disorders. These studies are exposed to several methodological drawbacks and must be cautiously interpreted. Modelling is one of the new methodological issues which can give access to more physiological parameters.

Female

Biological effects of estradiol-17 beta in postmenopausal women: oral versus percutaneous administration.

To determine whether the route of administration or the type of estrogen used in estrogen replacement therapy (ERT) is more important in avoiding effects on hepatic function, 24 postmenopausal women were studied before and at the end of 2 months of oral or percutaneous administration of the same estrogen, estradiol-17 beta (E2). The treatments studied were oral micronized E2, 2 mg/day (9 women); oral E2 valerate, 2 mg/day (5 women), and percutaneous E2, 3 mg/day (10 women). Specific plasma biological and biochemical markers of estrogenic action were evaluated, namely, E2, estrone (E1), LH, FSH, sex steroid binding protein (SBP), renin substrate, antithrombin activity, and lipoproteins (high density lipoprotein cholesterol, low density lipoprotein cholesterol, very low density lipoprotein triglycerides). Both oral and percutaneous administration of E2 increased plasma E2 levels up to midfollicular values and decreased LH and FSH levels into the same range. Oral administration of E2 led to substantial increases in plasma E1, SBP, renin substrate, and VLDL levels, whereas AT decreased significantly. Percutaneous administration of E2 led to a physiological plasma E1/E2 ratio and did not induce any change in hepatic proteins. These data suggest that the route of administration of E2 determines the biochemical response to ERT in postmenopausal women. SBP is the most sensitive marker of the liver action of estrogen, and triglycerides also are simple and useful markers for this effect. Percutaneous E2 therapy is an effective method of ERT, and has no measurable effects on hepatic markers of estrogen action.

Administration, Oral