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F. Petraglia, V. Locatelli, F. Facchinetti, M. Bergamaschi, A. R. Genazzani, and D. Cocchi


Endogenous opioid peptides have a tonic inhibitory control on LH secretion, participating in the functional changes of the hypothalamic-pituitary-ovarian axis. To evaluate the activity of the endogenous opioid systems during the oestrous cycle, we measured plasma LH levels after naloxone administration (5 mg/kg, s.c.) at 09.00 and 16.00 h on all days of the cycle (two further measurements were taken at 14.00 and 18.00 h on the day of pro-oestrus) and after one dose or one week's treatment with oestradiol benzoate (OB; 0·2 μg/rat). Concentrations of LH were measured in the same experimental models after injection of LH-releasing hormone (LHRH; 1 μg/kg, i.p.) or saline. Naloxone induced a significant rise in LH levels on the day of oestrus, dioestrus day-1 and dioestrus day-2; this response was blunted on the morning of pro-oestrus and absent in the afternoon and after acute and chronic OB treatment. Conversely LHRH was most effective in increasing LH levels on the day of pro-oestrus and in OB-treated rats.

These results indicate that opioid mechanisms, independently of the time of day and the pituitary responsiveness, exhibit a reduced activity when preovulatory changes occur, probably as a result of increased oestrogen levels.

J. Endocr. (1986) 108, 89–94

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F. Petraglia, M. Baraldi, G. Giarrè, F. Facchinetti, M. Santi, A. Volpe, and A. R. Genazzani


Immunoreactive (Ir) β-endorphin concentrations were determined in plasma, anterior pituitary (AP), neurointermediate pituitary lobe (NIL) and mediobasal hypothalamus (MBH) of pregnant (12–14 and 18–20 days) and fertile control rats, during labour and lactation. Immunoreactive Met-enkephalin concentrations were also evaluated in the MBH.

Concentrations of Ir β-endorphin in plasma, AP and NIL of rats during early and late pregnancy were significantly higher than in controls, the plasma and AP contents showing an increasing pattern in the second half of gestation. During labour, Ir β-endorphin concentrations in plasma and AP reached the highest values, whereas those in NIL remained unchanged. Lactating rats showed Ir β-endorphin concentrations in NIL and plasma in a range similar to that found in pregnant rats, resulting in concentrations in the AP not significantly different from those of non-pregnant controls.

Immunoreactive β-endorphin and Ir Metenkephalin concentrations in MBH of pregnant rats were almost twice as high as in controls, rising markedly during labour; during lactation levels were in the same range as in non-pregnant controls.

These results indicate that pregnancy and labour are characterized by high plasma, pituitary and hypothalamic concentrations of Ir β-endorphin as well as by high hypothalamic Ir Met-enkephalin levels, and that Ir β-endorphin concentrations vary differently during pregnancy, lactation and labour in the two pituitary lobes, supporting the existence of different control mechanisms in the AP and NIL.

J. Endocr. (1985) 105, 239–245

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F. Petraglia, V. Locatelli, A. Pen̄alva, D. Cocchi, A. R. Genazzani, and E. E. Müller


The effect of acute administration of the opioid receptor antagonist naloxone hydrochloride (5 mg/kg, s.c.) on plasma LH levels was evaluated in female and male rats 24, 36 and 48 h and 1,3 and 5 weeks after gonadectomy and in 5-week gonadectomized rats after acute or chronic (2 weeks) administration of oestradiol benzoate (OB, 10 μg/rat per day, s.c.), testosterone propionate (TP, 150 μg/rat, s.c.) or dihydrotestosterone propionate (DHT, 150 μg/rat, s.c.) respectively. Concurrent evaluation of plasma LH after administration of LH releasing hormone (LHRH, 1 μg/kg, i.p.) was performed in the same experimental groups.

In rats of both sexes, a significant rise in plasma LH after naloxone was observed in sham-operated and recently gonadectomized rats (24–48 h); in female rats 36 and 48 h after gonadectomy the rise was higher than in controls. One, 3 and 5 weeks after gonadectomy, naloxone failed to stimulate LH release in both female and male rats. In gonadectomized rats undergoing steroid replacement therapy, OB administered 72 h before testing, TP (16 and 72 h) and DHT (16 h) were the most effective in reinstituting the LH response to naloxone. Chronic administration of gonadal steroids did not restore normal LH responsiveness to naloxone. In most experimental groups, LH responses after naloxone were clearly unrelated to pituitary LH responsiveness to LHRH, which indicates that the opioid antagonist was acting via the central nervous system. In conclusion, these results demonstrate that: (1) gonadal steroids are critically important for the inhibitory effect of endogenous opioids on LH secretion to be manifested; (2) inhibition by the opiatergic system on LH secretion is more dependent on a modulatory action of gonadal steroids than on their simple presence or absence.

J. Endocr. (1984) 101, 33–39

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P Florio, F Arcuri, P Ciarmela, Y Runci, R Romagnoli, M Cintorino, AM Di Blasio, and F Petraglia

Urocortin is a 40-amino acid peptide belonging to the corticotropin-releasing factor (CRF) family. In human reproductive tissues, urocortin expression has been previously demonstrated in the ovary, in the placenta and fetal membranes and in pregnant uterine tissues, while no data are available on the expression of the peptide in the nonpregnant uterus. In this study, urocortin expression was evaluated by both immunohistochemistry and reverse transcription-polymerase chain reaction, in human uterine tissues and cells at different phases of the menstrual cycle. Urocortin was immunolocalized in endometrial epithelial and stromal cells, as well as in the myometrium, and in vascular smooth muscle cells. No differences between proliferative and secretory phase were observed. These results were confirmed by reverse transcription-polymerase chain reaction analysis of isolated endometrial epithelial and stromal cells, and myometrial specimens. These findings open new questions on the roles played by urocortin in the human uterus.

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D D'Antona, FM Reis, C Benedetto, LW Evans, NP Groome, DM de Kretser, EM Wallace, and F Petraglia

Activin A levels are elevated in maternal serum of pregnant women with hypertensive disturbances. Because follistatin is a circulating binding protein for activin A, the present study was designed to evaluate whether serum follistatin and activin A levels also change in patients with hypertensive disorders in the last gestational trimester. The study design was a controlled survey performed in the setting of an academic prenatal care unit. Healthy pregnant women (controls, n=38) were compared with patients suffering from pregnancy-induced hypertension (PIH, n=18) or pre-eclampsia (n=16). In addition, the study included a subset of patients with pre-eclampsia associated with intrauterine growth restriction (IUGR, n=5). Maternal blood samples were withdrawn at the time of diagnosis (patients) or in a random prenatal visit (controls), and serum was assayed for follistatin and activin A levels using specific enzyme immunoassays. Hormone concentrations were corrected for gestational age by conversion to multiples of median (MoM) of the healthy controls of the same gestational age. Follistatin levels were not different between controls and patients, while activin A levels were significantly increased in patients with PIH (1.8 MoM), pre-eclampsia (4.6 MoM), and pre-eclampsia+IUGR (3.2 MoM, P<0.01, ANOVA). The ratio between activin A and follistatin was significantly increased in patients with PIH (1.5 MoM) and was further increased in patients with pre-eclampsia (4.5 MoM) and in the group with pre-eclampsia+IUGR (2.6 MoM). Follistatin levels were positively correlated with gestational age in control subjects (r=0. 36, P<0.05) and in patients with PIH (r=0.46, P<0.05) or pre-eclampsia (r=0.61, P<0.01), while activin A correlated with gestational age only in the healthy control group (r=0.69, P<0.0001). The finding of apparently normal follistatin and high activin A levels in patients with PIH and pre-eclampsia suggests that unbound, biologically active, activin A is increased in women with these gestational diseases.

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AE Calogero, MA Palumbo, AM Bosboom, N Burrello, E Ferrara, G Palumbo, F Petraglia, and R D'Agata

The central nervous system (CNS) is able to synthesize and/or metabolize steroid hormones. These neuroactive steroids are capable of modulating several brain functions and, among these, they seem to regulate the hypothalamic-pituitary-gonadal (HPG) axis. Indeed, recent observations have shown that 5 alpha-pregnane-3 alpha-ol-20-one (allopregnanolone), one of the most abundant naturally occurring neuroactive steroids, suppresses ovulation and sexual behaviour when administered within the CNS. The present study was undertaken to evaluate the effects of allopregnanolone and its inactive stereoisomer, 5 alpha-pregnane-3 beta-ol-20-one, upon the release of gonadotropin-releasing hormone (GnRH) from individually-incubated hemihypothalami. Allopregnanolone suppressed GnRH release in a concentration-dependent manner with maximal activity in the nanomolar range, a range at which this neurosteroid is capable of playing a biological action. The specificity of allopregnanolone suppression of GnRH release was provided by the lack of effect of its known inactive stereoisomer. To evaluate the involvement of gamma-aminobutyric acidA (GABAA) receptor, we examined the effects of two neurosteroids with GABA-antagonistic properties, pregnanolone sulfate (PREG-S) and dehydroepiandrosterone sulfate (DHEAS), and of bicuculline, a selective antagonist of the GABA binding site on the GABAA receptor, on allopregnanolone (10 nM)-suppressed GnRH release. Both PREG-S and bicuculline overcame the inhibitory effects of allopregnanolone on GnRH release, whereas DHEAS did not. To substantiate the involvement of the GABAA receptor further, we tested the effects of muscimol, a selective agonist for this receptor, which suppressed GnRH release. In conclusion, allopregnanolone suppressed hypothalamic GnRH release in vitro and this effect appeared to be mediated by an interaction with the GABAA receptor. We speculate that the inhibitory effect of allopregnanolone on the HPG axis may also be caused by its ability to suppress hypothalamic GnRH release.

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F Petraglia, A M Di Blasio, P Florio, R Gallo, A R Genazzani, T K Woodruff, and W Vale


The aim of the present study was to evaluate whether spontaneous labor at term and pathological preterm labor are associated with changes in the expression of activin A and activin receptor mRNAs in fetal membranes. In addition, amniotic fluid activin A concentration in women delivering at term or undergoing preterm labor was also measured.

The expression of activin βA subunit and activin receptor type II and type IIB mRNAs was assessed by reverse transcriptase-PCR on specimens of amnion and chorion collected from patients delivering at term or undergoing preterm labor. Control specimens were collected from women delivered by elective cesarean section who had not experienced labor.

A specific two-site ELISA was used to measure activin A concentrations in the amniotic fluid. A cross-sectional study of amniotic fluid retrieved by amniocentesis from 109 pregnant women was carried out. Patients were classified into the following groups: (1) healthy controls at term but not in labor (n=25); (2) healthy controls at term in spontaneous labor (n=40); (3) healthy controls between 23 and 36 weeks of gestation (n=12); (4) patients in preterm labor responding to tocolytic treatment (n=19); (5) patients in preterm labor with subsequent delivery (n=13).

Activin βA subunit and activin receptor type IIB mRNA levels in both the chorion and amnion in women delivering at term or after preterm labor were significantly higher than in women delivering without undergoing labor (P<0·01). Expression of activin receptor type II mRNA in membranes did not differ among the three groups of women. Amniotic fluid activin A concentration in patients in labor was significantly higher than in those at term but not in labor (P<0·01). Patients in preterm labor had significantly higher amniotic fluid activin A concentrations than women at the same stage of gestation (P<0·01). The highest values were found in women undergoing preterm labor and subsequent delivery.

In conclusion, spontaneous labor and preterm labor are characterized by increased synthesis and release of activin A from amniotic and chorionic cells and by an augmented expression of activin type IIB receptor.

Journal of Endocrinology (1997) 154, 95–101