A first-trimester serum TSH in the 4-10 mIU/L range is associated with obstetric complications in thyroid peroxidase antibody-negative women.

PURPOSE: The impact of mild subclinical hypothyroidism on pregnancy outcomes in TPOAb-negative women is poorly explored. The aim of the present study was the evaluation in a wide cohort of TPOAb-negative pregnant women the role of subclinical hypothyroidism (SCH) on several pregnancy outcomes. METHODS: The study included women aged ≥ 18 years with a singleton pregnancy without known thyroid disease with serum TSH concentration between 0.4 and 10 mIU/L and TPOAb negative. Data about clinical and demographic features were collected. A blood sample was drown to test TSH, TPOAb, ANA and ENA concentration. The mean uterine artery pulsatility index was measured. Risk of adverse obstetric and fetal outcomes was collected. RESULTS: The cohort included 2135 pregnant women. Pregnant women with TSH 4-10 mUI/L had a significantly higher frequency of family history of thyroid diseases, and personal history of celiac disease diseases, type 1 diabetes mellitus, rheumatic disease, antinuclear antibody (ANA) and anti-extractable nuclear antigen (ENA) positive tests. The risk for pre-eclampsia and small for gestational age (SGA) was significantly higher in pregnant women with first-trimester TSH 4-10 mIU/L. A first-trimester TSH serum level greater than 4 mIU/L was associated with a significant increase in the occurrence of abnormal uterine artery pulsatility index, with a more than threefold increase in the risk of developing pre-eclampsia and with the risk of SGA. CONCLUSIONS: In TPOAb-negative pregnant women, a first-trimester serum TSH level ranging from 4 to 10 mIU/L is significantly and independently linked to an increased uterine artery pulsatility index as well as to negative pregnancy outcomes such as pre-eclampsia, SGA and gestational diabetes.

Gonadal and uterine function in female survivors treated by chemotherapy, radiotherapy, and/or bone marrow transplantation for childhood malignant and non-malignant diseases.

OBJECTIVE: To evaluate gonadal function and uterine volume in a cohort of female survivors treated by chemotherapy, radiotherapy, and/or stem cell transplantation (SCT) for childhood malignant and non-malignant diseases. DESIGN: An observational study. SETTING: S. Matteo Hospital, Pavia, Italy. POPULATION: A cohort of 135 female survivors. METHODS: A clinical, hormonal, and ultrasonographic evaluation. Thirty-three patients (24%) had non-malignant haematologic diseases (thalassaemia or sickle cell anaemia), 68 (50%) had leukaemia, 23 (17%) had lymphomas, and 11 (8%) had solid tumours. In total, 106 patients had received SCT, preceded by a conditioning regimen. MAIN OUTCOME MEASURES: Anti-Müllerian hormone (AMH) and Inhibin-B, and uterine volume. RESULTS: The median concentrations of AMH and Inhibin-B in the entire cohort were 0.12 ng/ml (interquartile range, IQR, 0.1-0.5 ng/ml) and 3.5 pg/ml (IQR 0.1-13.2 pg/ml), respectively. In a stepwise ordered logistic regression analysis, conventional chemotherapy for the treatment of malignancies, as opposed to total body irradiation (TBI), was the only oncologically significant predictor of increased AMH levels (OR 4.8, 95% CI 1.9-12, P < 0.001). Conditioning treatment before or after menarche did not influence AMH concentrations (P = 0.24). The best predictor of reduced uterine volume was TBI during the preparation for the allograft (OR 3.5, 95% CI 1.4-8.4, P = 0.006). Increasing age at treatment (OR 0.86, 95% CI 0.77-0.95, P = 0.04), chemotherapy, as opposed to other treatments (OR 0.09, 95% CI 0.03-0.28, P < 0.001), and solid tumours as opposed to either leukaemia/lymphomas or non-malignant diseases (OR 0.2, 95% CI 0.07-0.56, P = 0.002) were associated with larger uterine volumes. CONCLUSIONS: Conditioning therapies for SCT, including TBI, had the worst effects on uterine volume and gonadal reserve. Increasing age at treatment and conventional chemotherapy were associated with less detrimental effects on uterine volume.

Effects of uncomplicated vaginal delivery and epidural analgesia on fetal arterial acid-base parameters at birth in gestational diabetes.

AIM: To investigate the effects of uncomplicated vaginal delivery and epidural analgesia on fetal acid-base parameters in women with gestational diabetes (GDM) compared with controls. METHODS: A retrospective case-control study of 142 women with gestational diabetes and 284 controls. To evaluate the effect of diabetes and analgesia on acid-base status correcting for potential confounders we used ordered logistic equations including quartiles of fetal arterial acid-base parameters collected at birth as outcomes and categories of diabetes and epidural analgesia as explanatory variables. RESULTS: In the GDM group cord base deficit (-2.63 mmol/l, interquartile range [IQR]=4.2 to -0.65 mmol/l vs. -1.9 mmol/l, IQR=-3.3 to -0.2 mmol/l, p=0.009, odds ratio (OR)=1.51, 95% confidence interval (CI)=1.04-2.18) was lower and concentration of calcium higher (1.49 mmol/l, IQR=1.42-1.56 mmol/l vs. 1.47 mmol/l, IQR=1.41-1.51 mmol/l, p=0.009, OR=1.69, 95% CI=1.12-2.56) compared with controls. Epidural analgesia in the GDM group was associated with reduced cord concentration of glucose (84.0mg/dl [4.7 mmol/l], IQR=70-103.3mg/dl vs. 92.5mg/dl [5.1 mmol/l], IQR=76.5-121.8 mg/dl, p=0.004), lactate (2.65 mmol/l (IQR=1.80-4.20) vs. 3.70 mmol/l (IQR=2.90-5.55 mmol/l), p=0.002) and less pronounced base deficit (-2.05 mmol/l, IQR=-3.90 to -0.17 mmol/l vs. -2.8, IQR=-5.57 to -1.05 mmol/l, p=0.01, OR=0.7, 95% CI=0.49-0.99). CONCLUSIONS: In uncomplicated pregnancies and deliveries, well-controlled gestational diabetes mellitus has potentially significant detrimental effects on fetal acid-base status at birth. Epidural analgesia reduces cord arterial glucose and lactates.

Utility of breast ultrasonography in the diagnostic work-up of precocious puberty and proposal of a prognostic index for identifying girls with rapidly progressive central precocious puberty.

OBJECTIVE: To determine the utility of breast ultrasono- graphy in the diagnostic work-up of precocious puberty and to create a prognostic index for early differentiation between non/slowly progressive or transient forms of precocious puberty and rapidly progressive central precocious puberty. METHODS: We recruited consecutively 60 girls with precocious pubertal development. In all the girls we evaluated Tanner stage, basal and gonadotropin-releasing hormone (GnRH)-stimulated follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels, estradiol (E2) levels, and bone age, and performed pelvis and breast ultrasound examinations. Logistic regression models were fitted to identify possible diagnostic factors for rapidly progressive central precocious puberty and non/slowly progressive or transient forms. RESULTS: Ultrasound breast volume>or=0.85 cm3 was associated with rapidly progressive central precocious puberty (P=0.01). Uterine volume>or=5 cm3, LH peak>or=7 IU/L, presence of an endometrial echo, E2 levels>or=50 pmol/L and bone age>2 SD above expected were significantly associated with rapidly progressive central precocious puberty. A multivariate model including uterine volume, E2 level, bone age, presence of an endometrial echo and ultrasound breast volume revealed a strong ability to classify rapidly progressive forms. From this multivariate analysis a prognostic index for rapidly progressive central precocious puberty was defined. CONCLUSIONS: Ultrasound imaging allows better definition of the breast and the maturation stage than does use of Tanner's stages. Ultrasound breast volume>or=0.85 cm3 is an independent predicting factor of rapidly progressive central precocious puberty. A prognostic index that was created from a multivariate model including uterine volume, E2 level, presence of an endometrial echo, bone age and ultrasonographically determined breast volume, may help in the early differentiation between rapidly progressive central precocious puberty and non/slowly progressive or transient forms.

Prevalence of undiagnosed autoimmune rheumatic diseases in the first trimester of pregnancy. Results of a two-steps strategy using a self-administered questionnaire and autoantibody testing.

OBJECTIVE: To evaluate the prevalence of undiagnosed rheumatic diseases in the first trimester of pregnancy. DESIGN: We screened for rheumatic diseases in 1210 consecutive pregnant women during the first trimester of pregnancy using a 10-item questionnaire. SETTING: A university hospital in northern Italy. POPULATION: One hundred and thirty-seven (11.3%) women who answered positively to at least one question constituted the cases and were compared with 107 negative controls. METHODS: Cases and controls were tested for rheumatic autoantibodies (antinuclear antibody, anti-double-stranded DNA, anti-extractable nuclear antigen, anticardiolipin antibody, anti-beta2-glycoprotein I antibodies and lupus anticoagulant) and were evaluated by a rheumatologist for a definite diagnosis of rheumatic disease. MAIN OUTCOME MEASURES: Prevalence of undiagnosed rheumatic disease in the first trimester of pregnancy. RESULTS: The overall rate of positivity to the antibodies tested was 43.1% (59/137) among cases and 9.3% (10/107) in the controls (P < 0.001). A definitive diagnosis of rheumatic disease was made in 35 cases (25.5%) and in none of the controls (P <0.001). In stepwise logistic regression analysis, photosensitivity (adjusted OR 5.72; 95% CI 2.38-13.8), erythema or malar rash (adjusted OR 3.91; 95% CI 1.53-10) and history of two or more miscarriages (adjusted OR 5.6; 95% CI 1.55-20.6) were independent predictors of a definitive diagnosis of rheumatic disease (area under receiving operator curve = 0.814; 95% CI 0.76-0.86). Birthweight was lower (3180 g +/- 475 compared with 3340 g +/- 452, P= 0.008), and overall serious pregnancy complications (miscarriage, fetal growth restriction, delivery before 34 weeks of pregnancy and severe pre-eclampsia) were higher among cases (12/137) than controls (2/107) (adjusted OR 5.60; 95% CI 1.29-24.3; P= 0.021). CONCLUSIONS: A two-step screening process with a self-administered questionnaire proved to be a useful method to screen for undiagnosed rheumatic diseases during the first trimester of pregnancy.

Ultrasonography endometrial patterns in different hormonal treatments to induce ovulation.

As several studies report that transvaginal ultrasound of endometrial thickness may help distinguish fertile from infertile cycles, we assessed endometrial growth and morphology in 124 infertile women. The patients underwent different ovulation induction treatments: clomiphene citrate (CC), human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG), analogous Gn-RH and hMG (aGn-RH+hMG). CC administration is followed by a slackening of endometrial maturation. The US pattern H (typical of the ovulatory phase) appears on day 13 (76.9% of the cases) in spontaneous cycles and on day 16 (75% of the cases) in CC-induced cycles. The H pattern on day 20 in CC-induced cycles persisted in the patients who did not conceive. In aGn-RH-stimulated cycles the endometrial pattern H appears on days 13 (41.66%) and 16 (83.33%), not preceded by a Hi image. The endometrial pattern Hi was always observed in the patients who did not conceive. Our retrospective study of endometrial US morphology shows that the different ovulation induction treatments may affect the day of appearance of the various endometrial patterns. These results, which need further confirmation, can allow the changes of conceiving to be investigated during the stimulation protocol of every single stimulated cycle.

[Combined use of goserelin acetate and human menopausal gonadotropin in the induction of follicular growth in a program of fertilization in vitro and embryo transfer]. / Uso combinato del Goserelin acetato e della gonadotropina umana menopausale nell'induzione della crescita follicolare in un programma di fertilizzazione in vitro e embrio-transfer.

OBJECTIVE: to investigate the efficacy of a gonadotropin-releasing hormone analogue (GN-RH-a) in combination with human menopausal menotropin (hMG) for in-vitro fertilization. METHODS: 30 infertile women aged 32 to 37 years received a combined treatment with a long-acting slow-releasing Gn-RH-a and hMG to perform ovarian stimulation in a program of in-vitro fertilization. Serum levels of Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), 17-beta-estradiol (E2), Progesterone (P), were evaluated and transvaginal ultrasonographic examinations were performed during the treatment to assess the ovarian volume, the mean number and diameter of growing follicles and the endometrial morphology and thickness. Oocyte retrieval was performed by transvaginal-ultrasound-guided approach, 24-36 hours after the administration of human chorionic gonadotropin (hCG). RESULTS: our data suggest that the combined use of Gn-RH-a and exogenous gonadotropins is associated with a more uniform ovarian response and with the absence of premature LH discharge. Moreover, the Gn-RH-a as polymer implant provides a controlled delivery per day over a one-month period and avoids the inconvenience of a daily administration. CONCLUSIONS: this kind of Gn-RH-a formulation, in in-vitro fertilization programs, appears very effective in inducing a reversible hypogonadic state, easy to manage and well tolerated by the patient. Its association with exogenous gonadotropins appears to be effective in increasing the success rate of good quality oocyte retrieval.

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.

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.

Involvement of endogenous gabaergic system in the modulation of gonadotropin secretion in normal cycling women.

To investigate whether endogenous GABA participates in the control of gonadotropin secretion during the menstrual cycle, placebo or sodium valproate (DPA), an anticonvulsant drug which enhances endogenous GABA content by blocking GABA degradation, were administered to regularly cycling women both during early follicular and midluteal phase. In a first set of experiments, the effect of DPA administration (400 mg, orally) on basal gonadotropin secretion was evaluated in 13 subjects. During early follicular phase (n = 6), no significant changes in plasma gonadotropin levels were observed after DPA or placebo administration. Conversely, during midluteal phase (n = 7), DPA administration resulted in a significant fall (p less than 0.01) in plasma LH concentrations, with a maximal percent decrease of 41.8 +/- 6.7% after 120 min. No changes in plasma FSH levels were observed. In a second set of experiments, the effect of DPA pretreatment (400 mg, orally) on gonadotropin release stimulated by a pulse of exogenous GnRH (10 micrograms, iv bolus) was studied in 11 subjects. During both follicular (n = 4) and luteal phase (n = 7), DPA did not modify gonadotropin response to GnRH injected 1h after pretreatment. Finally, 8 subjects were submitted to iv injection with 10 micrograms GnRH 2h after pretreatment with DPA (400 mg, orally) or placebo. During both follicular (n = 4) and luteal phase (n = 4), no statistical differences in gonadotropin response to GnRH were found between DPA and placebo pretreatment. These findings demonstrated that during the estrogen-progesterone (midluteal) phase of menstrual cycle, endogenous GABA is involved in the inhibitory regulation of LH secretion at a central level.

Effects of the GABAergic drug, sodium valproate, on the prolactin release evoked by pharmacological stimuli in normal women.

Sodium valproate (DPA or Na-dipropylacetate), an anticonvulsant drug activating the endogenous GABAergic system, was administered orally at the dose of 400 mg to seventeen normal women 1 h before intravenous injections with three drugs which stimulate prolactin (PRL) release: TRH (200 micrograms bolus; six subjects); domperidone (5 mg bolus; six subjects); and sulpiride (5 mg bolus; five subjects). DPA pretreatment significantly blunted PRL response to both domperidone and sulpiride injections without affecting the PRL response to TRH. In particular, the quantitative PRL secretion (areas under curves) following domperidone and sulpiride tests appeared significantly reduced after DPA treatment in comparison to placebo (P less than 0.02 and P less than 0.01 for domperidone and sulpiride respectively). These results indicate that the pharmacological enhancement of the endogenous GABAergic system by DPA may blunt PRL response to both central and peripheral dopamine receptor blockade. These observations suggest that a GABAergic pathway inhibiting PRL secretion at the hypothalamic level competes, at least in part, with the dopaminergic system. Conversely, the lack of any effect of DPA on PRL response to TRH seems to suggest that pituitary TRH receptors are independent of any GABAergic control.