ACTA ENDOCRINOLOGICA (BUC)

The blood-CSF barrier (BCB), as a component of the blood-brain barrier, is protective for the maternal brain. This study assesses estradiol, prolactin, glycoproteic hormones (hCG, FSH, LH, TSH) and thyroxine across the BCB in pregnancy after 38 weeks. Method. 35 pregnant women were simultaneously sampled in serum and CSF during caesarian section and compared to 27 non-pregnant fertile women undergoing surgery for benign gynecological disorders. The study was approved by the local Ethics Committee. Results were analysed as nonparametric variables. Compared to non-pregnant controls, we found high serum estradiol levels at term, also reflected in the CSF, while the CSF/serum ratio was non-significantly modified (median ratio 0.1 versus 0.1, p=NS). Prolactin showed a similar proportional increase in serum and CSF levels at term, with unmodified CSF/serum ratio (median ratio 0.14 versus 0.18, p=NS). hCG showed a similar profile across the BCB. FSH was significantly lower at term, but still conserved the CSF/ serum ratio. LH was undetectable in pregnancy. In peripartum TSH showed a unique profile across the BCB as it was the only one showing an increased CSF/serum ratio compared to non-pregnant controls (median ratio 0.11 versus 0.04, p<0.0001). Thyroxine was significantly increased in both serum and CSF, and showed a CSF/serum ratio unmodified from non-pregnant women (median ratio 0.02 versus 0.02, p=NS). Conclusion. There is an increase of BCB permeablity for TSH in term pregnancy. The peripartum increase in estradiol and decrease in HCG could be involved. We suggest that the unique TSH profile maintains the necessary thyroxine levels in pregnancy at term.

Introduction: Pseudo-primary hyperaldosteronism of pregnancy was previously reported by our group during correction in twin-to-twin transfusion syndrome (TTTS). Aim: Focus on plasma volume changes and renin-angiotensin (RAS) and aldosterone response in 45 TTTS patients requiring amnioreductions above 1000 ml for severe hydramnios. Methods: 45 patients necessitating placental surgery and amnioreduction >1000ml for severe TTTS, under local anesthesia, as previously described. Assesment of plasma volume variations (%ΔPV) and simultaneous assays of aldosterone, renin, angiotensin II and ANP performed by standard kits prior to, 6 hours after and 12-24 hours after procedure. Statistical results expressed as median and interquartile ranges for non-parametric data, after correction of post-op levels with %ΔPV. Results: Depletion of 1600 ml (1000-3700) amniotic fluid (extravascular depletion) unexpectedly increased the intravascular plasma volume by 20,38% and dramatically changed the hormonal picture of primary hyperaldosteronism. Aldosterone decreased from a median of 730 pg/ml (T0) to 553 pg/ml (T6) to 515,9 pg/ml (T24). ANP increased from 8,95 pg/ml (T0) to 14,51pg/ml (T6) to 19,9 pg/ml (T24) pg/ml (ANOVA p=0,0036), while renin and angiotenin II stayed unchanged (ANOVA p=0,91). Conclusion: Depletion of extracelular fluid (amnioreduction) is indicated for the correction of hyperaldosteronism in pregnancies with severe hydramnios, to reduce to normal the aldosteron levels without the interference of the renin-angiotensin system, while natriuretic activity increases through ANP and, possibly, other less known natriuretic factors .

Vertebrate nonapeptide neurohormones constitute an evolutionarily conserved family, involved in vital functions, such as hydro-osmotic balance regulation, reproduction and social behaviour. Two human members of this family are known, vasopressin (AVP) and oxytocin (OXT), with their highly homologous genes closely located on Chr 20p13. Presence of vasotocin (AVT) in man has been suggested, but remains controversial, and genetic evidence is lacking. AVT activity could be explained by the presence of a third distinct gene for AVT or an RNA-processing mechanism involving products of AVP and/or OXT genes. To test the first hypothesis, we developed bioinformatics and experimental approaches using genomic DNA and fetal tissues mRNAs. Family-specific primers for AVT and neurophysin were designed based on CODEHOP strategy and used in our experiments. Results of bioinformatics and genomic DNA experiments (family-specific and Alu step-out PCR) suggest there is no evidence for an AVT gene in the genome. RNA-based techniques 3?-RACE and Family-Specific Domain Restriction Fragment RTPCR provided evidence for new transcript species that could code for AVT. Further experiments will be needed to characterize them. We discuss potential mechanisms of AVT mRNA generation based on AVP and OXT mRNAs, by alternative splicing, heterologous transsplicing or RNA-editing. While all methods we developed proved feasible, current results suggest there is no AVT gene in the genome, but specific mRNAs could be present in fetal tissues. Their full characterization may potentially allow identification of vasotocin mRNA and shed light on a subject of fundamental scientific interest.

Introduction. Estrogens are known to have a neuroprotective role and to influence the permeability of the blood brain barrier (BBB). An ongoing debate exists on the changing effects of estrogens on target tissues with advancing age and at menopause and on the potential disruptive role of increasing gonadotropin levels.\r\nThe aim of the present study was to assess the permeability of the BBB for estradiol, FSH and LH in three physiological states: early follicular phase, preovulatory phase and at menopause.\r\nMethod. Hormonal levels were assessed simultaneously in the serum and cerebrospinal fluid (CSF) of 15 women at menopause (mean age 60?8 years), 16 of reproductive age in early follicular phase and 11 in preovulatory phase (mean age 31?7 years), all undergoing surgery for benign gynecologic disorders. FSH, LH and estradiol levels were assessed using chemo luminescence and are expressed as median and 10-90 percentile interval. Statistical analysis assessed the serum-CSF correlation and the CSF/serum ratio for each hormone between groups.\r\nResults. Estradiol serum levels were 26.2 pg/ml (6.4-43.5) at menopause (n=15), 58.5 pg/ml (25.7-75.9) in early follicular phase (EFP, n=16) and 221.2 pg/ml (113.7-405.5) in preovulatory phase (PREOV, n=11). CSF estradiol is 18.5 pg/ml (0.4-30.5) at menopause, 5.4 pg/ml (2.2-10.2) in EFP (p<0.001) and 17.3 pg/ml (10.3-34.6) in PREOV patients. Estradiol serum and CSF levels correlate positively in the fertile cycle (r=0.72, p<0.0001) and negatively at menopause (r=-0.88, p<0.05). The CSF/serum ratio for estradiol is 0.8 (0.01-4.4) at menopause, 0.1 (0.04-0.13) in EFP and 0.1 (0.03-0.13) in PREOV patients. FSH serum levels were 75.8 mUI/ml (35.9-129.8) at menopause, 7.7 mUI/ml (3.5-11.4) in EFP and 7.3 mUI/ml (3.1-10.7) in PREOV patients. CSF FSH is 2.7 mUI/ml (0.4- 5.9) at menopause, significantly higher than 0.7 mUI/ml (0.3-1) in EFP (p<0.001) and 0.5 mUI/ml (0.2-1) in PREOV patients (p<0.05). FSH serum and CSF levels correlate positively in the fertile cycle (r=0.8, p<0.0001) and do not correlate at menopause (p=NS). The CSF/serum ratio for FSH is 0.03 (0.01-0.1) at menopause, significantly lower than 0.09 (0.06-0.16) in EFP (p<0.001) and is 0.06 (0.03-0.13) in PREOV phase. LH serum levels were 57.4 mUI/ml (27.5-84.8) at menopause, 4.7 mUI/ml (1.7-7.1) in EFP and 5.5 mUI/ml (4.9-8.02) in PREOV phase. CSF LH is 1.6 mUI/ml (0.7-2.6) at menopause, significantly higher than 0.4 mUI/ml (0.1-1) in EFP (p<0.001) and 0.5 mUI/ml (0.2-0.9) in preovulatory phase (p<0.05). The CSF/serum ratio for LH is 0.03 (0.01-0.07) at menopause, it is significantly lower than 0.09 (0.03-0.27) in EFP (p<0.001) and is 0.07 (0.03-0.14) in preovulatory phase.\r\nConclusions. This study shows the negative correlation of serum and CSF estradiol levels at menopause reflecting the need of constant estrogen levels within the CSF despite low chronic serum levels. Simultaneously, the CSF/serum ratio for gonadotrophins is\r\nreduced significantly at menopause and the positive correlation of serum and CSF levels is lost, reflecting a protective mechanism against rising levels of FSH and LH.

Introduction. The gold standard for surgery of fibroids is vaginal surgery and a preoperative treatment that facilitates this approach through reduction of the uterine\r\nvolume is of utmost importance. GnRH agonists and selective progesterone receptor modulators (SPRM) have both been tested to this effect.\r\nObjective. To evaluate whether uterine shrinkage induced by preoperative GnRH agonists in women with uteruses > 280g may\r\nfacilitate vaginal hysterectomy (VH).\r\nMaterial and methods. 23 women scheduled to have an abdominal hysterectomy based on the uterine size over 280 g were allocated to receive the GnRH agonist triptorelin 3.75 mg monthly for three months. Uterine weight (estimated by ultrasound), serum levels of estradiol and Hb were assessed before treatment and monthly afterwards three times.\r\nResults. Estradiol levels decreased from 235.9?15 to 38?3.7pg/mL at three months (p<0.0001), after an initial flare up. Hb increased from 11.85?1.8 to 12.7?0.74 g/dL.\r\nThe uterine weight decreased from 443.5?39 to 294.8?31 g (by 33.5%), all patients benefitting from a VH.\r\nConclusion. In women with a large uterus impending an abdominal hysterectomy, a 3-month preoperative course of GnRH agonists facilitates VH by decreasing uterine size by 30%.

Introduction: Prolactinomas may grow during pregnancy. Dopamine agonists (DA) prevent tumor growth, but usually suppress prolactin (PRL) both in mother and fetus. Possible long-term consequences on fetal development remain unknown.\r\nAim: to assess whether DA treatment throughout pregnancy in a dosage able to maintain physiological gestational serum levels of prolactin (PRL) still prevents prolactinoma growth.\r\nPatients and methods: We evaluated 68 pregnancies in 49 women with prolactinoma (PRM) and 46 pregnancies in healthy women as controls. Thirty-three pregnancies were recorded in 27 women treated throughout pregnancy with bromocriptine (BRC) (n = 25) or cabergoline (CAB) (n = 2) divided in 2 groups: group A (22 pregnancies in 18 patients) had suppressed serum PRL (below the 5th percentile of the control group Z during the last trimester); group B (11 pregnancies in 10 patients) had physiological serum PRL levels. Other 26 pregnancies in 21 patients were incompletely evaluated and included only in the pregnancy outcome and cure rate analysis. Treated patients were compared with the control group Y 8 women with PRM who discontinued DA after pregnancy induction (9 pregnancies) and a control group Z of 46 healthy pregnant women, randomly selected from two departments of Obstetrics. Patients with multiple pregnancies were recorded in each corresponding study group.\r\nResults: In the control group Y, tumor size showed an increase in 2 (intrasellar macroPRM) out of 8 cases (25%). DA treatment throughout gestation in 27 women with PRM prevented the growth in all cases and induced a shrinkage of more than 30% of tumor mass in 8/14 macroPRM (57.1%), i.e., in 4/7 (57.1%) of macroPRM with physiological serum PRL levels during pregnancy, and in 5/8 (62.5%) of macroPRM with suppressed PRL levels (p = NS) (1 patient had pregnancies in both groups). Low dose DA (BRC 2.5 ? 5 mg/day or CAB 0.5 mg/week) maintains physiological PRL levels in 6/12 (50%) macroPRM, but suppressed PRL in 80% of microPRM. Cure was recorded in 6/49 (12.2%) of patients. Two patients with PRM-induced neuroophthalmic syndrome were successfully treated with DA throughout 1 and respectively 3 pregnancies.\r\nConclusions: Some women with prolactinomas showed a tumour size increase if they were not treated with dopamine agonists throughout pregnancy. Maintaining physiological serum PRL levels during pregnancy (frequently with low doses of DA) prevented tumor growth, avoiding a PRL suppression that may have subtle influence on long-term foetal development.

Background. Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening complication of the luteal\r\nphase or early pregnancy after ovulation induction or ovarian stimulation. The late OHSS form presents an onset more than 10 days after ovulation triggering and is\r\ninfluenced by pregnancy-related HCG secretion.\r\nReport. This paper presents three cases of pregnancy-related OHSS after IVF/ICSI cycles discussing risk factors and management according to European Guidelines.\r\nResults. Individual risk factors are identified such as low BMI, high antral follicle count at the beginning of the ovarian stimulation, high estradiol over 3000 pg/ml.\r\nPatients had moderate OHSS (case 2) and severe OHSS (case 1 and 3). In-patient treatment was 3-14 days. OHSS resolved in\r\nall cases, without manifestations of the critical form.\r\nConclusion. The duration of OHSS is longer in the late form, is pregnancy-related and should be monitored for adverse\r\npregnancy outcomes. However the incidence of fatal risks is low and the treatment is successful.

Background. Hirsutism is part of current criteria of polycystic ovary syndrome (PCOS), as a clinical expression\r\nof hyperandrogenism.\r\nObjective. To evaluate the significant factors for hirsutism severity in PCOS.\r\nPatients. A total of 235 PCOS patients, consecutively coming for medical advice, aged 18-35 yrs, all of Romanian origin, were diagnosed according to Rotterdam criteria.\r\nMethods. Hirsutism, quantified using the modified Ferriman-Gallwey (mFG) procedure, was defined by values equal or\r\nmore than 6. Other parameters evaluated were: body mass index (BMI), fasting insulinemia, insulin resistance quantified by QUICKI, total testosterone (TT), free androgen index (FAI), dehydroepiandrosterone sulfate (DHEAs), 17OH progesterone, fasting glycemia. In a subset of 106 patients, androgen receptor (AR) was explored by CAG repeat\r\ngenotyping and X-chromosome inactivation analysis.\r\nResults. The total PCOS population (235) was divided in group A (n=139, 59.14%) with hirsutism and group B (n=96, 40.85%) without hirsutism. In univariate correlations, serum\r\ninsulin levels (p<0.05) and insulin resistance quantified by QUICKI (p<0.05), but not FAI, TT, DHEAs, 17OH progesterone or BMI were associated significantly with mFG score, in group A of hirsute PCOS patients and also in group B\r\nof nonhirsute PCOS. In a stepwise regression mFG model,\r\nincluding TT, insulin and BMI, only insulin remained independently associated with mFG score (p<0.05) in the group A of hirsute PCOS patients, whereas in group B\r\nof the nonhirsute PCOS, there were not significant associations. Androgen receptor parameters explored in 106 cases, i.e. by the biallelic means and X-weighted biallelic means of CAGn, did not show significant associations with mFG score in univariate correlations. Only insulin was significantly associated (p<0.05) in another stepwise\r\nregression model of mFG including as parameters insulin, TT, biallelic means of CAGn and BMI.\r\nConclusions. Our results support that insulin is significantly associated with the\r\nseverity of mFG score in PCOS patients, independent of serum androgens or androgen receptor sensitivity expressed by\r\nCAGn polymorphism. This suggests a possible pathogenic role of high insulin level for the development and progression\r\nof hirsutism, at least in PCOS.