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  • Author: Alessandro D. Genazzani x
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Vincenzo Guardabasso, Alessandro D. Genazzani, Johannes D. Veldhuis and David Rodbard

Abstract.

A new objective method is presented for investigating the presence of a temporal relationship between episodic release of two hormones. The two time series of hormone concentrations are first analysed by an objective method for peak detection. Both data series are then transformed into "quantized" or discretized series by recording the occurrence of a hormone pulse as an "event", characterized by the onset, the maximum, or another unique feature. The two quantized series are then matched, and the number of concordant events and discordant events are counted. Each point in series A is compared with a "time-window" of a selected number of points in series B, to accommodate small degree of mismatch between events in the two series. An index of concordance is computed, compensating for any spurious random coincidence: the "Specific Concordance", to evaluate the frequency of concordant events in excess of those expected on the basis of chance alone. This calculation is systematically repeated, interposing a range of time-lags between the two series. A graph of Specific Concordance versus time-lag indicates the time-lag corresponding to a maximal concordance. Simulations of random series of events are performed, and their degree of concordance is evaluated in a similar fashion, thus generating frequency distributions of Specific Concordance values under the null hypothesis of no temporal relationship. This permits the selection of criteria for statistical significance at any desired p-level, for one or many lag times, and for one or multiple subjects. Various degrees of concordance can also be simulated to evaluate the performance (sensitivity, statistical power) of this approach. These methods have been implemented as a collection of short microcomputer programmes, and applied to the study of the temporal relationship between β-endorphin and cortisol in normal subjects sampled every 10 min for 24 h. This analysis demonstrated concordance between events in the two series, with synchronous occurrence of β-endorphin and cortisol release events significantly more frequently than expected on the basis of random association (p<0.01).

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Alessandro D Genazzani, Fausta Massolo, Elena Ferrari, Andrea Gandolfi, Felice Petraglia and Andrea R Genazzani

Genazzani AD. Massolo F. Ferrari E, Gandolfi A, Petraglia F, Genazzani AR. Long -term GnRH-agonist administration revealed a GnRH-independent mechanism stimulating FSH discharge in humans. Eur J Endorcrinol 1996:134:77–83. ISSN 0804–4643

The present study evaluated the FSH and LH episodic discharge in different physiopathological conditions undergoing chronic GnRH-agonist administration. Four girls with true precocious puberty and five postmenopausal women were administered GnRH-agonist (3.73 leuprolide acetate every 4 weeks: Takeda Italia, Rome, Italy) for at least 4 months. Plasma LH and FSH secretory profiles were assessed before and under GnRH-agonist administration (after 21 and 120 days). Pulsatility studies were conducted for 4 h in the girls and for 6 h in postmenopausal women, with blood sampling intervals of 10 min. Pubertal and postmenopausal patients showed the distinct episodic co-secretion of LH and FSH before GnRH-agonist administration: this co-secretion disappeared in both groups after 21 and 120 days of treatment. Moreover, while LH concentrations decreased to almost undetectable levels and LH episodic release disappeared. FSH plasma levels were only partially reduced and FSH episodic secretion was detectable in both groups. In conclusion, this study demonstrated that long-term GnRH-agonist administration blocked LH but not FSH episodic release. These data enforce the hypothesis that FSH episodic discharge might be dependent not only on hypothalamic GnRH, but also on a GnRH-independent stimulatory pathway.

Alessandro D Genazzani, Department of Obstetrics and Gynecology, University of Modena, Via del Pozzo 71, 41100 Modena, Italy

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Alessandro D Genazzani, Felice Petraglia, Mario Gastaldi, Fausta Massolo, Monica Cellini, Gabriella Iori, Nicola Surico and Andrea R Genazzani

Genazzani AD, Petraglia F, Gastaldi M, Massolo F, Cellini M, Iori G, Surico N, Genazzani AR. Intrinsic secretory characteristics of luteinizing hormone and prolactin episodic release during pubertal development. Eur J Endocrinol 1994;131:80–5. ISSN 0804–4643

The intrinsic characteristics of LH and prolactin (PRL) episodic secretion were evaluated in a group of 18 children (8M and 10F). The children were divided into two groups according to the Tanner stage: Group A (Tanner ≤ 1, N = 7, 3M and 4F, 6–10 years of age) and group B (Tanner 2–3, N = 11, 5M and 6F, 9–11 years of age). A pulsatility study of 4 h, sampling every 10 min, was carried out in all children. LH and PRL plasma levels were assayed by IFMA and RIA respectively. LH and PRL secretory episodes were then identified on plasma determinations using the program detect. Instantaneous secretory rates (ISR) were then computed for both LH and PRL using the specific algorithm within the detect program. Plasma LH levels were different between the two groups of children. Group A children showed undetectable LH plasma levels (below the minimal detectable dose of 0.1 mIU/ml), while group B demonstrated LH plasma levels in the normal range of values for age and sexual development (1.5±0.3 mIU/ml, mean ± sem), LH pulse frequency for group B was 3.2 ±0.4 peaks/4 h. No significant differences in mean plasma PRL levels, pulse frequency and pulse amplitude were observed between the two groups of children. Computation of ISR for LH (group B only) and PRL (both groups) identified the intrinsic episodic characteristics of the two hormones. No significant differences in LH and PRL pulse frequencies were observed when comparing the results estimated on ISR with those estimated on plasma concentrations. No significant changes in PRL pulse amplitude were observed between the two groups. Conversely, a shorter duration of LH and PRL secretory episodes was found. In conclusion, in children PRL secretory bursts from lactotropes lasted the same number of minutes independently of the Tanner stages. Moreover, the LH secretory events were clearly detectable during the daytime only when puberty had already started. The duration of PRL and LH secretory events was similar to adult fertile subjects. These data indicate that the gonadal maturation does not modify LH and PRL secretory events from the pituitary.

Alessandro D Genazzani, Department of Obstetrics and Gynecology, University of Modena, Via del Pozzo 71, 41100 Modena, Italy

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Vincenzo Rochira, Lucia Zirilli, Alessandro D Genazzani, Antonio Balestrieri, Claudio Aranda, Bibiana Fabre, Paula Antunez, Chiara Diazzi, Cesare Carani and Laura Maffei

Background: In men, the feedback of gonadotropins is regulated by estrogens that come from the aromatization of testosterone, but the relative contribution to the inhibition of LH and FSH secretion by the amount of locally produced estrogens within the hypothalamus and/or the pituitary, and the amount of circulating estrogens still remains unknown.

Objective: In order to evaluate the effect of regulation induced by estradiol on the hypothalamic–pituitary–gonadal (HPG) axis, we studied the pulsatility of LH and FSH in two aromatase-deficient men (called subject 1 and subject 2), in which the production rate of estrogen (both local and circulating) is completely, or at least severely, impaired.

Design: FSH and LH were evaluated in terms of their pulsated secretion and as GnRH-stimulated secretion in two phases: phase 1, before estrogen treatment; and phase 2, during estrogen treatment with 25 μg transdermal estradiol twice weekly.

Methods: Blood samples were taken during phase 1 and phase 2 at 0800 h for basal measurements of LH, FSH, inhibin B, testosterone, and estradiol. The analysis of the pulsatility of LH and FSH was performed by sampling every 10 min for 8 h in the two phases. Gonadotropin response to GnRH-stimulation test was studied by serial standard sampling after 100 μg GnRH i.v. bolus in phases 1 and 2.

Results: Estrogen treatment led to a significant reduction in both LH-pulsated frequency (7.5 ± 0.7 in phase 1, 4.5 ± 0.7 in phase 2) and amplitudes (3.5 ± 0.006 in phase 1, 1.9 ± 0.4 in phase 2) of peaks, whereas FSH showed only a conspicuous reduction in serum levels and a trend towards the reduction of the amplitudes of its peaks without modification of the frequency of the pulses. Both testosterone and gonadotropins decreased during phase 2, whereas estradiol reached the normal range in both subjects. Transdermal estradiol treatment significantly lowered the peaks of both serum LH and FSH after GnRH as well as the incremental area under the curve after GnRH administration in both subjects. Basal serum inhibin B levels were slightly higher before transdermal estradiol treatment (phase 1) than during estrogen treatment (phase 2) in both subjects.

Conclusions: The administration of estrogen to aromatase-deficient men discloses the effects of circulating estrogens on LH secretion, exerted both at pituitary level, as shown by the decrease of basal and GnRH-stimulated secretion of LH and the LH pulsed amplitude, and at hypothalamic level as shown by the reduction of the frequency of LH pulses. The present study, coupling the outcomes of basal, GnRH-stimulated and the pulsatile evaluation of LH and FSH secretion in two aromatase-deficient men, demonstrates that circulating estrogens play an inhibitory role in LH secretion by acting on the hypothalamus and the pituitary gland of men. The discrepancy among testosterone levels, the arrest of spermatogenesis and a slightly inappropriate respective increase of serum FSH (lower than expected) suggests a possible role of estrogens in the priming and the maturation of HPG axis in men, an event that has never occurred in these two subjects as a consequence of chronic estrogen deprivation.