Ultrasonographic soft markers for detection of rectosigmoid deep endometriosis.

OBJECTIVES: The aim of this study was to evaluate the use of ultrasound (US) soft markers as a first-line imaging tool to raise suspicion of rectosigmoid (RS) involvement in women suspected of having deep endometriosis. METHODS: We included in this prospective observational study all patients with clinical suspicion of deep endometriosis who underwent diagnostic transvaginal US evaluation at our unit from January 2016 to February 2017. Several US soft markers were evaluated for prediction of RS involvement (presence of US signs of uterine adenomyosis, presence of an endometrioma, adhesion of the ovary to the uterus (reduced ovarian mobility), presence of 'kissing ovaries' (KO) and absence of the 'sliding sign'), using as the gold standard expert US examination for the presence of RS endometriosis. RESULTS: Included were 333 patients with clinical suspicion of deep endometriosis. Of these, 106 had an US diagnosis of RS endometriosis by an expert. The only significant variables found in the prediction model were absence of the sliding sign (odds ratio (OR), 13.95; 95% CI, 7.7-25.3), presence of KO (OR, 22.5; 95% CI, 4.1-124.0) and the interaction between these two variables (OR, 0.03; 95% CI, 0.004-0.28). Regarding their interaction, RS endometriosis was present when KO was absent and the sliding sign was present in 10% (19/190) of cases, when both KO and the sliding sign were present in 71.4% (5/7) of cases, when both KO and the sliding sign were absent in 60.8% (76/125) of cases and when KO was present and the sliding sign was absent in 54.5% (6/11) of cases. Thus, when the sliding sign was absent and/or KO was present, transvaginal US showed a specificity of 75% (95% CI, 69-80%) and a sensitivity of 82% (95% CI, 73-88%). CONCLUSIONS: US findings of absence of the sliding sign and/or presence of KO in patients with clinical suspicion of endometriosis should raise suspicion of RS involvement and indicate referral for expert US examination, with a low rate of false-negative diagnosis. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Validation of ultrasound strategies to assess tumor extension and to predict high-risk endometrial cancer in women from the prospective IETA (International Endometrial Tumor Analysis)-4 cohort.

OBJECTIVES: To compare the performance of ultrasound measurements and subjective ultrasound assessment (SA) in detecting deep myometrial invasion (MI) and cervical stromal invasion (CSI) in women with endometrial cancer, overall and according to whether they had low- or high-grade disease separately, and to validate published measurement cut-offs and prediction models to identify MI, CSI and high-risk disease (Grade-3 endometrioid or non-endometrioid cancer and/or deep MI and/or CSI). METHODS: The study comprised 1538 patients with endometrial cancer from the International Endometrial Tumor Analysis (IETA)-4 prospective multicenter study, who underwent standardized expert transvaginal ultrasound examination. SA and ultrasound measurements were used to predict deep MI and CSI. We assessed the diagnostic accuracy of the tumor/uterine anteroposterior (AP) diameter ratio for detecting deep MI and that of the distance from the lower margin of the tumor to the outer cervical os (Dist-OCO) for detecting CSI. We also validated two two-step strategies for the prediction of high-risk cancer; in the first step, biopsy-confirmed Grade-3 endometrioid or mucinous or non-endometrioid cancers were classified as high-risk cancer, while the second step encompassed the application of a mathematical model to classify the remaining tumors. The 'subjective prediction model' included biopsy grade (Grade 1 vs Grade 2) and subjective assessment of deep MI or CSI (presence or absence) as variables, while the 'objective prediction model' included biopsy grade (Grade 1 vs Grade 2) and minimal tumor-free margin. The predictive performance of the two two-step strategies was compared with that of simply classifying patients as high risk if either deep MI or CSI was suspected based on SA or if biopsy showed Grade-3 endometrioid or mucinous or non-endometrioid histotype (i.e. combining SA with biopsy grade). Histological assessment from hysterectomy was considered the reference standard. RESULTS: In 1275 patients with measurable lesions, the sensitivity and specificity of SA for detecting deep MI was 70% and 80%, respectively, in patients with a Grade-1 or -2 endometrioid or mucinous tumor vs 76% and 64% in patients with a Grade-3 endometrioid or mucinous or a non-endometrioid tumor. The corresponding values for the detection of CSI were 51% and 94% vs 50% and 91%. Tumor AP diameter and tumor/uterine AP diameter ratio showed the best performance for predicting deep MI (area under the receiver-operating characteristics curve (AUC) of 0.76 and 0.77, respectively), and Dist-OCO had the best performance for predicting CSI (AUC, 0.72). The proportion of patients classified correctly as having high-risk cancer was 80% when simply combining SA with biopsy grade vs 80% and 74% when using the subjective and objective two-step strategies, respectively. The subjective and objective models had an AUC of 0.76 and 0.75, respectively, when applied to Grade-1 and -2 endometrioid tumors. CONCLUSIONS: In the hands of experienced ultrasound examiners, SA was superior to ultrasound measurements for the prediction of deep MI and CSI of endometrial cancer, especially in patients with a Grade-1 or -2 tumor. The mathematical models for the prediction of high-risk cancer performed as expected. The best strategies for predicting high-risk endometrial cancer were combining SA with biopsy grade and the subjective two-step strategy, both having an accuracy of 80%. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Learning curve for ultrasonographic diagnosis of deep infiltrating endometriosis using structured offline training program.

OBJECTIVE: To assess the learning curves of trainees during a structured offline/hands-on training program for the ultrasonographic diagnosis of deep infiltrating endometriosis (DIE). METHODS: Four trainees (all Ob/Gyn postgraduates with at least 5 years' experience in ultrasonography in obstetrics and gynecology, but with no experience of sonographic examination of DIE) participated in the study. They underwent a 2-week training program with a single trainer. Day 1 was devoted to theoretical issues and guided offline analysis of 10 three-dimensional ultrasound volumes. During the following days, four sessions of real-time sonographic examinations were performed in a DIE referral center ultrasound unit. In between these sessions, the trainees analyzed four datasets offline, each containing 25 volumes. At the end of each set, misinterpreted volumes were reassessed with the trainer. Presence or absence of DIE at surgery was considered the gold standard. The trainees' learning process was evaluated by learning-curve cumulative summation (LC-CUSUM) and the deviations of the trainees' level of performance at the control stage was assessed by CUSUM (standard CUSUM), for different locations of DIE. RESULTS: The trainees reached competence after an average of 17 (range, 14-21) evaluations for bladder, 40 (range, 30-60) for rectosigmoid, 25 (range, 14-34) for forniceal, 44 (range, 25-66) for uterosacral ligament (USL) and 21 (range, 14-43) for rectovaginal septum (RVS) locations of DIE, and then kept the process under control, with error levels of less than 4.5% until the end of the test. The overall accuracy for each trainee in diagnosis of DIE at the different locations ranged from 0.91 to 0.98 for bladder DIE, from 0.80 to 0.94 for rectosigmoid DIE, from 0.90 to 0.94 for forniceal DIE, from 0.79 to 0.82 for USL DIE and from 0.89 to 0.98 for RVS DIE. CONCLUSIONS: The suggested 2-week training program, based on a mixture of offline and live scanning sessions, is feasible and apparently provides effective training for the ultrasonographic diagnosis of DIE. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Transvaginal ultrasound vs magnetic resonance imaging for diagnosing deep infiltrating endometriosis: systematic review and meta-analysis.

OBJECTIVE: To perform a systematic review of studies comparing the accuracy of transvaginal ultrasound (TVS) and magnetic resonance imaging (MRI) in diagnosing deep infiltrating endometriosis (DIE) including only studies in which patients underwent both techniques. METHODS: An extensive search was carried out in PubMed/MEDLINE and Web of Science for papers from January 1989 to October 2016 comparing TVS and MRI in DIE. Studies were considered eligible for inclusion if they reported on the use of TVS and MRI in the same set of patients for the preoperative detection of endometriosis in pelvic locations in women with clinical suspicion of DIE and using surgical data as a reference standard. Quality was assessed using the QUADAS-2 tool. A random-effects model was used to determine pooled sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-) and diagnostic odds ratio (DOR). RESULTS: Of 375 citations identified, six studies (n = 424) were considered eligible. For MRI in the detection of DIE in the rectosigmoid, pooled sensitivity was 0.85 (95% CI, 0.78-0.90), specificity was 0.95 (95% CI, 0.83-0.99), LR+ was 18.4 (95% CI, 4.7-72.4), LR- was 0.16 (95% CI, 0.11-0.24) and DOR was 116 (95% CI, 23-585). For TVS in the detection of DIE in the rectosigmoid, pooled sensitivity was 0.85 (95% CI, 0.68-0.94), specificity was 0.96 (95% CI, 0.85-0.99), LR+ was 20.4 (95% CI, 4.7-88.5), LR- was 0.16 (95% CI, 0.07-0.38) and DOR was 127 (95% CI, 14-1126). For MRI in the detection of DIE in the rectovaginal septum, pooled sensitivity was 0.66 (95% CI, 0.51-0.79), specificity was 0.97 (95% CI, 0.89-0.99), LR+ was 22.5 (95% CI, 6.7-76.2), LR- was 0.38 (95% CI, 0.23-0.52) and DOR was 65 (95% CI, 21-204). For TVS in the detection of DIE in the rectovaginal septum, pooled sensitivity was 0.59 (95% CI, 0.26-0.86), specificity was 0.97 (95% CI, 0.94-0.99), LR+ was 23.5 (95% CI, 9.1-60.5), LR- was 0.42 (95% CI, 0.18-0.97) and DOR was 56 (95% CI, 11-275). For MRI in the detection of DIE in the uterosacral ligaments, pooled sensitivity was 0.70 (95% CI, 0.55-0.82), specificity was 0.93 (95% CI, 0.87-0.97), LR+ was 10.4 (95% CI, 5.1-21.2), LR- was 0.32 (95% CI, 0.20-0.51) and DOR was 32 (95% CI, 12-85). For TVS in the detection of DIE in the uterosacral ligaments, pooled sensitivity was 0.67 (95% CI, 0.55-0.77), specificity was 0.86 (95% CI, 0.73-0.93), LR+ was 4.8 (95% CI, 2.6-9.0), LR- was 0.38 (95% CI, 0.29-0.50) and DOR was 12 (95% CI, 7-24). Confidence intervals of pooled sensitivities, specificities and DOR were wide for both techniques in all the locations considered. Heterogeneity was moderate or high for sensitivity and specificity for both TVS and MRI in most locations assessed. According to QUADAS-2, the quality of the included studies was considered good for most domains. CONCLUSION: The diagnostic performance of TVS and MRI is similar for detecting DIE involving rectosigmoid, uterosacral ligaments and rectovaginal septum. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Accuracy of transvaginal ultrasound for diagnosis of deep endometriosis in uterosacral ligaments, rectovaginal septum, vagina and bladder: systematic review and meta-analysis.

OBJECTIVE: To review the diagnostic accuracy of transvaginal ultrasound (TVS) in the preoperative detection of endometriosis in the uterosacral ligaments (USL), rectovaginal septum (RVS), vagina and bladder in patients with clinical suspicion of deep infiltrating endometriosis (DIE). METHODS: An extensive search was performed in MEDLINE (PubMed) and EMBASE for studies published between January 1989 and December 2014. Studies were considered eligible if they reported on the use of TVS for the preoperative detection of endometriosis in the USL, RVS, vagina and bladder in women with clinical suspicion of DIE using the surgical data as a reference standard. Study quality was assessed using the PRISMA guidelines and QUADAS-2 tool. RESULTS: Of the 801 citations identified, 11 studies (n = 1583) were considered eligible and were included in the meta-analysis. For detection of endometriosis in the USL, the overall pooled sensitivity and specificity of TVS were 53% (95%CI, 35-70%) and 93% (95%CI, 83-97%), respectively. The pretest probability of USL endometriosis was 54%, which increased to 90% when suspicion of endometriosis was present after TVS examination. For detection of endometriosis in the RVS, the overall pooled sensitivity and specificity were 49% (95%CI, 36-62%) and 98% (95%CI, 95-99%), respectively. The pretest probability of RVS endometriosis was 24%, which increased to 89% when suspicion of endometriosis was present after TVS examination. For detection of vaginal endometriosis, the overall pooled sensitivity and specificity were 58% (95%CI, 40-74%) and 96% (95%CI, 87-99%), respectively. The pretest probability of vaginal endometriosis was 17%, which increased to 76% when suspicion of endometriosis was present after TVS assessment. Substantial heterogeneity was found for sensitivity and specificity for all these locations. For detection of bladder endometriosis, the overall pooled sensitivity and specificity were 62% (95%CI, 40-80%) and 100% (95%CI, 97-100%), respectively. Moderate heterogeneity was found for sensitivity and specificity for bladder endometriosis. The pretest probability of bladder endometriosis was 5%, which increased to 92% when suspicion of endometriosis was present after TVS assessment. CONCLUSION: Overall diagnostic performance of TVS for detecting DIE in uterosacral ligaments, rectovaginal septum, vagina and bladder is fair with high specificity.

Tissue characterization using mean gray value analysis in deep infiltrating endometriosis.

OBJECTIVES: To investigate differences in tissue characterization using three-dimensional sonographic mean gray value (MGV) between retrocervical and rectosigmoid deeply infiltrating endometriosis, and to assess intra- and interobserver concordance in MGV quantification. METHODS: In this retrospective study, stored ultrasound volumes from 50 premenopausal women (mean age, 32 years) with 57 histologically confirmed nodules of deep endometriosis were retrieved from our database for analysis. A single experienced operator had acquired all volumes. For each nodule, the MGV was evaluated using virtual organ computer-aided analysis (VOCAL) software with semiautomated sphere-sampling (1 cm3) from the central part of the nodule. In these patients the MGV was also quantified from the myometrium of the fundal part of the uterus. In addition, two observers calculated the MGV in a subset of 24 volumes in order to quantify inter- and intraobserver agreement using intraclass correlation coefficients (ICC). RESULTS: Mean MGV was significantly higher in rectosigmoid nodules (n = 34) than in nodules with a retrocervical location (n = 23) (23.863 vs. 17.705; P < 0.001). MGV of the myometrium was significantly higher in comparison with that of nodules in both locations (P < 0.001 for both). Intra- and interobserver measurement reproducibility was excellent (ICC > 0.95). CONCLUSIONS: Retrocervical and rectosigmoid endometriotic nodules display significantly different MGVs. Measurement of MGV is highly reproducible and its clinical value in the diagnosis and assessment of distribution of deep endometriosis should be assessed in future studies.

Association between different morphological types and abnormal karyotypes in early pregnancy loss.

OBJECTIVES: To identify the abnormal transvaginal ultrasound (TVS) findings typical of aneuploidic pregnancies that end with early pregnancy loss (EPL). METHODS: This was a prospective clinical trial over a 2½-year period from January 2004 to June 2006 at the University Hospital of Cagliari, Italy. One hundred and fifty-six singleton pregnancies with EPL were evaluated by TVS, both before and at the moment of EPL diagnosis. Fetal karyotyping was performed on products of conception using microsatellite analysis to exclude maternal contamination in 46,XX cases. The proportions of abnormal karyotypes were compared among different groups of EPLs characterized by different morphological features. RESULTS: Six morphological types were identified in EPLs, one normal and five abnormal (small gestational sac, small embryo/fetus, early symmetrical arrested growth, enlarged yolk sac and empty sac). The highest rate of chromosomal abnormalities was observed in the early symmetrical arrested growth group (100%), followed by small embryo/fetus (94.1%), enlarged yolk sac (93.3%) and empty sac (72.2%) groups. The majority of cases of trisomy 22 (92.3%) were in the enlarged yolk sac group and the majority of cases with a 45,X karyotype were in the small embryo/fetus group (77.8%). CONCLUSIONS: There is an association in EPLs between some abnormal karyotypes and some morphological types. The demonstration by TVS of abnormalities in the development of early pregnancy structures could be helpful for predicting aneuploidy in EPLs.

[Prevention of postoperative abdominal adhesions in gynecological surgery. Consensus paper of an Italian gynecologists' task force on adhesions]. / Aderenze addominali postoperatorie e loro prevenzione in chirurgia ginecologica. Documento di consenso si una "task force" di ginecologi italiani sulle aderenze.

Adhesions are the most frequent complication of abdominopelvic surgery, causing important short- and long-term problems, including infertility, chronic pelvic pain and a lifetime risk of small bowel obstruction. They also complicate future surgery with considerable morbidity and expense, and an important mortality risk. They pose serious quality of life issues for many patients with associated social and healthcare costs. Despite advances in surgical techniques, the healthcare burden of adhesion-related complications has not changed in recent years. Adhesiolysis remains the main treatment although adhesions reform in most patients. There is rising evidence, however, that surgeons can take important steps to reduce the impact of adhesions. A task force of Italian gynecologists with a specialist interest in adhesions having reviewed the current evidence on adhesions and considered the opportunities to reduce adhesions in Italy, have approved a collective consensus position. This consensus paper provides a comprehensive overview of adhesions and their consequences and practical proposals for actions that gynecological surgeons in Italy should take. As well as improvements in surgical technique, developments in adhesion-reduction strategies and new agents offer a realistic possibility of reducing adhesion formation and improving outcomes for patients. They should be adopted particularly in high risk surgery and in patients with adhesiogenic conditions. Patients also need to be better informed of the risks of adhesions.

Prolactin-releasing action of gonadotropin-releasing hormone in hypogonadal women.

To gain insight into the PRL-releasing effect of GnRH, serum PRL and gonadotropin responses to a 10-microgram iv bolus dose of exogenous GnRH were studied in hypergonadotropic hypogonadal women (HHW) and patients with functional hypothalamic amenorrhea (FHA). The results were compared with those obtained in normal cycling women during the early follicular phase of the cycle. GnRH induced a significant increase in PRL levels (P less than 0.001) in HHW compared to early follicular phase women, in whom no significant response occurred. In HHW, the maximal PRL percent increment was positively correlated with the ratio of the maximal percent increments of FSH and LH (r = 0.93). GnRH induced a significant increase in PRL levels in every FHA patient, but in four of them (high PRL responders), the PRL response was at least 5-fold greater than in the other six (low PRL responders). The clinical profiles, basal hormone concentrations, and LH responses to GnRH were similar in these two groups of FHA patients, but the FSH response to GnRH was greater (P less than 0.05) in the high PRL responders. The maximal percent increment of PRL was also positively correlated with the maximal percent increment of FSH (r = 0.76; P = 0.01). These data demonstrate that in these two hypogonadal models, the PRL response to exogenous GnRH corresponds to the FSH response and suggests that GnRH-stimulated PRL release may be mediated by a paracrine effect between FSH-enriched gonadotrophs and lactotrophs.

Dose-related prolactin inhibitory effect of the new long-acting dopamine receptor agonist cabergoline in normal cycling, puerperal, and hyperprolactinemic women.

Two different single doses (400 and 600 micrograms) of the new long-acting dopamine agonist cabergoline (CBG) were given to 12 normal cycling women, 17 puerperal women, and 24 hyperprolactinemic women (12 with idiopathic hyperprolactinemia and 12 with pituitary adenoma). Plasma PRL was determined in blood samples collected before and at frequent intervals for 5 days after CBG administration. Both CBG doses induced marked inhibition of PRL secretion in all women. A decrease in plasma PRL levels was evident 1-2 h after CBG administration and persisted for up to 5 days. The 600-micrograms CBG dose had a more potent (P less than 0.05) PRL inhibitory effect than the 400-micrograms dose in normal, puerperal, and hyperprolactinemic women. Moreover, while 400 micrograms CBG prevented lactation in 3 of 7 puerperal women, 600 micrograms CBG prevented lactation in 5 of 5 puerperal women. A moderate blood pressure decrease occurred 3-6 h after CBG treatment, but no other side-effects occurred. These results demonstrate that CBG induces a dose-related inhibition of PRL secretion in normal women as well as in puerperal and hyperprolactinemic women. The potent long-lasting PRL inhibitory effect of CBG in conjunction with the absence of side-effects typical of dopaminergic compounds suggest that this drug is an advance in the medical treatment of hyperprolactinemia.

Dexamethasone reduces the postcastration gonadotropin rise in women.

To investigate the influence of glucocorticoids on gonadotropin release in humans, we studied the effects of dexamethasone (DXM) administration on basal and GnRH-stimulated gonadotropin secretion in normal women after bilateral ovariectomy (OVR). From the 7th to the 14th day after OVR, 9 women received DXM (2.25 mg/day) and 13 women received placebo (control women). Plasma FSH and LH concentrations were measured before OVR and daily from the 7th to the 14th day after surgery. In addition, the FSH and LH responses to exogenous GnRH (10 micrograms, iv bolus dose) were determined in all DXM-treated women and in 5 control women on the 7th and 14th days after surgery. Plasma gonadotropin levels increased similarly in all women on the 7th day after OVR. DXM administration significantly limited (P less than 0.001) the progressive rise of basal LH and FSH levels from days 7 to 14. DXM treatment also blunted (P less than 0.005) the OVR-induced increase in the responsiveness of both LH and FSH to exogenous GnRH. These findings suggest that glucocorticoids inhibit the secretion of both gonadotropins at the pituitary level in ovariectomized women.

The dependency of folliculogenesis and corpus luteum function on pulsatile gonadotropin secretion in cycling women using a gonadotropin-releasing hormone antagonist as a probe.

A potent GnRH antagonist, [Ac-delta 3-Pro1,p-F-D-Phe2,D-Trp3,6]GnRH (4F-Antag), was used as a probe to determine the relative dependency of ovarian cyclicity on pulsatile gonadotropin secretion. 4F-Antag was administered in a dose of 80 micrograms/kg sc twice a day for 3 consecutive days during different phases of the menstrual cycle. This treatment resulted in a prompt attenuation of pulsatile gonadotropin secretion in all women studied. Maximal suppression of gonadotropin levels, expressed as percent change from baseline, averaged 48% for LH and 22% for FSH. The reduced pulsatile gonadotropin release induced by 4F-Antag administration during the early follicular phase resulted in a significant decrease in serum estradiol levels during the period of treatment and was followed by a prolongation of follicular phase (2.4 days) and cycle length (3.5 days), but no alteration of subsequent cyclic ovarian steroid profiles compared to control cycles. Treatment initiated during the midfollicular phase 4-6 days before the expected LH surge resulted in a more dramatic decline in serum estradiol levels and prolongation of follicular phase length by 5-6 days compared to control cycles. Normal luteal function was preserved. These alterations were compatible with induction of the demise of the dominant follicle followed by the reinitiation of follicular recruitment. Administration of 4F-Antag during the midluteal phase resulted in rapid falls in serum estradiol and progesterone levels and the onset of menstrual bleeding in all women. The luteolytic effect of 4F-Antag was completely negated by the administration of hCG. These data indicate that 4F-Antag interferes with ongoing cyclic ovarian function by reducing pulsatile gonadotropin stimulation, which disrupts folliculogenic processes and induces the demise of the corpus luteum. From these findings we infer that the functional integrity of ovarian cyclicity is remarkably sensitive to brief (3 days) and partial reduction in pulsatile gonadotropin secretion.

Pharmacological activation of gamma-aminobutyric acid-system blunts prolactin response to mechanical breast stimulation in puerperal women.

To evaluate whether the gamma-aminobutyric acid (GABA)ergic system participates in the control of PRL secretion during the puerperium, different doses of sodium valproate (DPA), a drug that increases endogenous GABA activity, were administered orally to puerperal women who did not wish to breast feed their infants. Two groups of five women were each given DPA in doses of 400 and 800 mg, respectively. PRL levels were measured in plasma samples collected before and after drug administration. Another group of five puerperal women was treated with 800 mg DPA 60 min before mechanical breast stimulation using an electric breast pump for 15 min. Circulating PRL levels were measured in samples obtained before, during, and after breast stimulation. No drug-associated side effects were observed. After placebo administration, no significant variations in plasma PRL levels occurred in any subject. The lower dose of DPA (400 mg) induced a slight decrease in plasma PRL levels, but 800 mg of the drug induced a significant fall (P less than 0.05 vs. baseline values) in PRL, with a maximum percent decrease (68.2 +/- 4%) 180 min after DPA treatment. Mechanical breast stimulation performed after placebo treatment induced a significant increase (P less than 0.01) in plasma PRL levels, with peak values (37 +/- 10% above baseline values) 10 min after the onset of stimulation. When DPA was administered to the same women, a significant decrease (23 +/- 3%) in plasma PRL occurred during breast stimulation. Thereafter, PRL values continued to fall in spite of breast stimulation. PRL levels were significantly decreased after DPA treatment compared to both basal values (P less than 0.01) and the levels found in the same patients during control tests (P less than 0.05). These results demonstrate that enhancement of endogenous GABAergic tone induced by DPA significantly decreases basal PRL levels and blunts PRL release after mechanical breast stimulation. In agreement with animal data, a possible physiological role of GABA in the control of PRL release during puerperium may be suggested.

Inhibitory effect of the dopamine agonist bromocriptine on the postcastration gonadotrophin rise in women.

Basal or stimulated gonadotrophin plasma levels were measured after bilateral ovariectomy in untreated and bromocriptine (BCT)-treated normal women. BCT was orally administered from the 7th to the 14th day after ovariectomy at a dose of 3.75 mg/day. BCT significantly (P less than 0.05) inhibited LH release, both basally and after LRF stimulation. Plasma FSH levels were also reduced in treated subjects, but this decrease did not reach statistical significance relative to controls. The blunted postcastration gonadotrophin rise found with BCT administration suggests that pituitary gonadotropin secretion is, in part, under dopaminergic inhibitory control.

High testosterone levels of ovarian origin affect adrenal steroidogenesis?

Androgens of ovarian origin have been suggested to affect adrenal enzymatic activity. To investigate this possibility, the 17-hydroxyprogesterone (17-OH P) and cortisol (F) responses to an ACTH stimulation test (0.25 mg iv, bolus) were evaluated in 10 normal women and in 39 hyperandrogenic women with normal (14 subjects) or high (25 subjects) testosterone (T) levels. The 17-OH P release and the ratio between 17-OH P and F release in response to the ACTH stimulation test were significantly higher (P less than 0.05) in hyperandrogenic women with high T levels than in normal subjects. Eight hyperandrogenic women with high T received intranasal GnRH agonist (Buserelin, 1200 micrograms/day) for 4 weeks, and the 17-OH P and F release in response to the ACTH stimulation was reassessed after agonist treatment. At the end of GnRH agonist administration the mean circulating levels of T were significantly reduced (P less than 0.05). The F response to the ACTH test was not modified by pretreatment with the GnRH agonist. The 17-OH P response to the ACTH stimulation test after the GnRH agonist was unchanged in comparison with control tests, as well as the ratio between 17-OH P and F responses to the ACTH test. These data do not seem to confirm, as previously suggested, that high T levels of ovarian origin affect adrenal steroidogenesis.

Pulsatile luteinizing hormone release in postmenopausal women: effect of chronic bromocriptine administration.

Pulsatile LH release was studied in 28 healthy postmenopausal women by obtaining blood samples every 5 min for 4 h either basally or after 30 days of bromocriptine (BCT; 3.75 mg/day; n = 14) or placebo (n = 14) administration. Basally, mean plasma LH levels were 46.3 +/- 3.5 (+/- SE) and 53.4 +/- 4.6 mIU/mL in the BCT and placebo groups, respectively. Mean LH pulse frequencies were 4.2 +/- 0.3 and 4.0 +/- 0.4 pulses/4 h, mean pulse amplitudes were 19.2 +/- 1.9 and 20.1 +/- 1.5 mIU/mL, and mean interpulse intervals were 54.3 +/- 3.1 and 54.6 +/- 3.2 min in the two groups, respectively. BCT administration induced no significant changes in mean plasma LH levels, but it significantly (P less than 0.01) decreased LH pulse frequency (1.7 +/- 0.3 pulses/4 h) and amplitude (12.7 +/- 0.8 mIU/mL) and significantly (P less than 0.01) increased mean interpulse interval (126.1 +/- 17.5 min). Placebo administration did not induce any significant changes in pulsatile LH release. These results demonstrate that in postmenopausal women LH secretion is circhoral, and BCT administration can blunt LH pulsatility, suggesting dopaminergic regulation of the GnRH-LH pulse generator.

Hormonal dynamics during luteal-follicular transition.

To gain insights into the neuroendocrine basis for the initiation of folliculogenesis, the hormonal dynamics during the period from the late luteal to the early follicular phase of the menstrual cycle (the luteal-follicular transition) were examined. Blood samples were obtained at 2-h intervals for 5 consecutive days in seven women and at 15-min intervals for 8 h on each of 4 consecutive days in five women. The results indicate that the luteolytic process, as reflected by an exponential decline of both serum estradiol and progesterone levels, began at least 64 h before the onset of menses. During estradiol and progesterone withdrawal, there was a selective increase in mean serum FSH levels (P less than 0.001) beginning 24 h before and reaching a peak 24 h after the onset of menses. The frequency of LH pulses increased slightly but not significantly during this period, with a significant rise in mean serum LH levels on the day of menses. Thus, an acute rise in FSH concentrations the day before and in LH concentrations the day after the onset of menses occurs during luteal-follicular transition. The dissociation of FSH and LH secretion observed suggests that additional neuroendocrine events other than changes in pulsatile GnRH secretion may be operative during this period. These findings indicate that the initiation of folliculogenesis for the ensuing cycle occurs during the late luteal phase by a process of selective augmentation in FSH secretion independent of hypothalamic GnRH secretion. This event may ultimately prove to be a manifestation of the action of recently characterized ovarian peptides on FSH secretion.

The effects of the gabaergic drug, sodium valproate, on prolactin secretion in normal and hyperprolactinemic subjects.

To find out whether the gamma-aminobutyric acid (GABA)ergic system affects PRL secretion in humans, sodium valproate (DPA or Na-dipropyl-acetate), a drug inducing increase of endogenous GABA, was administered to 20 normal and 15 hyperprolactinemic subjects. PRL circulating levels were measured by RIA in the samples obtained after acute oral treatment with 400 mg DPA. A significant decrease (P less than 0.01) in comparison with basal levels was observed in normal women from 30-180 min after drug administration. DPA treatment also lowered blood PRL levels in hyperprolactinemic subjects (seven females) without evidence of pituitary tumor. A decrease very similar to the one found in normal subjects (P less than 0.05 vs. basal levels) was observed within 180 min from drug ingestion. Conversely, no significant changes were found after the same treatment in hyperprolactinemic patients with evidence of prolactinoma (seven females and one male). Taken together, these data seem to demonstrate that pharmacological enhancement of endogenous GABAergic tone is followed by inhibition of PRL secretion. They also suggest that GABA may exert an inhibitory control on PRL release in humans. In hyperprolactinemic subjects, this GABAergic control appears to be present only when a pituitary tumor cannot be demonstrated.

Effects of the dopamine antagonist veralipride on hot flushes and luteinizing hormone secretion in postmenopausal women.

The effects on hot flushes of the dopamine antagonist Veralipride versus placebo were investigated in a randomized double-blind study of postmenopausal healthy women (N = 20 in each group). Cutaneous temperature recording and plasma LH pulsatility were studied in eight patients from each group. Veralipride administration (100 mg/day for 30 days) induced a significant (P less than .01) reduction in vasomotor symptoms and was more effective (P less than .05) than placebo. Treatment was followed by the expected increase (P less than .001) in plasma prolactin levels and by a significant decrease (P less than .05) in mean plasma LH. A significant reduction (P less than .01) was observed in objectively recorded hot flushes after Veralipride treatment, whereas there was no significant change in the characteristics of LH pulsatility. Infusion of the opioid antagonist naloxone (N = 5) induced a significant (P less than .01) increase in LH secretion after Veralipride administration. These results suggest that the endogenous opioid system may mediate the endocrine and clinical effects of long-term Veralipride treatment.

Prevention of puerperal lactation by a single oral administration of the new prolactin-inhibiting drug, cabergoline.

To evaluate the efficacy of a single oral administration of the new ergot derivative Cabergoline in the prevention of post-partum lactation, we compared the effects of three different doses of the drug with those of placebo in 32 puerperal women. In a controlled, double-blind trial, the subjects were randomly allocated to four treatment groups receiving either placebo or 400, 600, or 800 micrograms Cabergoline (N = 8 in each group) within 24 hours after delivery. Treatment efficacy was assessed clinically by physical examination before (day 0) and at one, two, three, four, and 14 days after treatment. Plasma prolactin (PRL) concentrations were measured in blood samples collected before and at one, two, three, and four days after treatment. Lactation was prevented in four of the eight subjects (50%) who received 400 micrograms Cabergoline and in all subjects who received 600 or 800 micrograms Cabergoline. By contrast, only one of the eight subjects (12.5%) receiving placebo showed no signs of spontaneous lactation within the 14 days after delivery. No effects of placebo administration on plasma PRL levels were observed. Plasma PRL concentrations were significantly reduced starting from one day after Cabergoline administration, however, and the amount of inhibition of PRL secretion induced by different doses of the drug was not statistically different. These preliminary data demonstrate that Cabergoline has a dose-related effect in the prevention of postpartum lactation, and milk secretion can be prevented completely by a single oral administration of 600 or 800 micrograms of the drug.