Lower E2 Levels Research Articles

Is Letrozole needed for controlled ovarian stimulation in patients with estrogen receptor-positive breast cancer?

Objective: To assess the advantages and disadvantages of using Letrozole for controlled ovarian stimulation (COH) in young patients with estrogen receptor-positive (ER+) breast cancer, wishing to cryopreserve oocytes.Design: Retrospective cohort analysis.Setting: Sixteen Italian units for reproductive medicine and in vitro fertilization.Methods: Data of 50 ER+ breast cancer patients undergoing COH to cryopreserve oocytes before gonadotoxic chemotherapy with a Letrozole plus gonadotropins (Le+Gn) protocol were compared with those of 25 young women with ER– breast cancer, submitted to COH using a protocol with gonadotropins alone (Gn-only).Results: The Le+Gn protocol implied a significantly lower total Gn consumption and allowed to maintain significantly lower circulating E2 levels at all checkpoints throughout stimulation (peak E2 value 446 ± 357 versus 1553 ± 908 pg/ml, respectively; p = 0.001). On the other side, the Le+Gn protocol allowed a significantly lower yield of oocytes available for cryostorage (6.6 ± 3.5 versus 8 ± 5, respectively; p = 0.038).Conclusions: In breast cancer patients, the association of Letrozole to Gn significantly reduces the number of oocytes available for cryostorage in comparison with the use of Gn alone. On the other side, it is associated with significantly lower E2 levels during the whole stimulation cycle, a safety issue that has been traditionally considered advantageous in case of ER+ cancers.

Association of serum estradiol levels on the day of hCG administration with pregnancy rates and embryo scores in fresh ICSI/ET cycles down regulated with either GnRH agonists or GnRH antagonists

To investigate the interrelation between serum E2 level on hCG day, score of transferred embryos and pregnancy achievement. Records of 350 women aged 18-40years who underwent ovarian hyperstimulation in fresh cycles down regulated either with GnRH agonist (n=70) or GnRH antagonist (n=280) followed by oocyte pick-up, ICSI and embryo transfer are retrospectively analyzed. Median E2 levels on hCG day of cycles ending with and without pregnancy were similar (p=0.308). ROC curve for AUC of E2 on hCG day with dependent variable pregnancy rate also demonstrated that the E2 level on hCG day cannot be used to predict pregnancy in IVF/ICSI cycles (AUC 0.532, 95% confidence interval: 0.471-0.593). Grouping cycles according to their E2 levels on hCG day also did not demonstrate any detrimental effect of either low or high E2 levels on hCG day both in agonist and antagonist cycles. Pregnancy rates are strongly correlated with mean and total score of transferred embryos. Interrelation of E2 on hCG day and pregnancy rate is independent from score of transferred embryos. E2 on hCG day is not correlated with pregnancy rates and cannot be used to predict pregnancy in neither agonist nor antagonist cycles, no matter its level or percentile is used.

Do estrogen receptor alpha polymorphisms have any impact on the outcome in an ART program?

To investigate two of the most studied estrogen receptor alpha polymorphisms (PvuII and XbaI) in combination, in order to evaluate their impact on an ART program outcome. 203 normally ovulating women who underwent IVF or ICSI treatment were genotyped for PvuII and XbaI polymorphisms in ESR1 intron 1 using Real-Time PCR. The relationship between the presence of polymorphic alleles and the ovulation induction parameters and outcome was examined. Women were grouped according to the number of polymorphic alleles they carried in two groups (0-2 versus 3-4 polymorphic alleles). The presence of 3 or more polymorphic alleles was associated with significantly lower E2 levels on the day of hCG administration and a significantly lower rate of good quality embryos. There is an association between ESR1 polymorphisms and some ART parameters such as the level of E2 on the day of hCG administration and the quality of the embryos. These results underline the importance of ESR1 as a candidate gene for the prediction of ovarian response to IVF/ICSI protocols. Future research work concerning several more genes is necessary for a better evaluation of patients before entering an IVF/ICSI program.

Deficiencies in immunoassay methods used to monitor serum Estradiol levels during aromatase inhibitor treatment in postmenopausal breast cancer patients

Optimal care for breast cancer patients undergoing aromatase inhibitor (AI) treatment is ensured when estradiol (E2) levels are adequately suppressed. To assess treatment efficacy accurately, it is important to measure the serum E2 levels using a well validated assay method with high sensitivity and specificity. This translates into the urgent need to evaluate various E2 immunoassay kits, which are frequently used in hospital settings to measure E2 serum levels in patients undergoing AI treatment, so clinicians obtain accurate and reliable measurements allowing appropriate clinical decision making. Our objective was to evaluate the performance of different commercially available and commonly used E2 immunoassay kits regarding measurement of E2 levels in the serum of postmenopausal breast cancer patients treated with AIs, in comparison to a highly accurate and reliable mass spectrometry assay. Clinical and demographic data were obtained from 77 postmenopausal breast cancer patients who were treated with an AI. Serum E2 levels were measured by 6 immunoassay methods and by liquid chromatography-tandem mass spectrometry (LC-MS/MS), which served as the standard for comparison. Analysis of E2 by LC-MS/MS showed that 70% of the samples had levels that were <5 pg/ml. Three of the assays carried out with commercial E2 immunoassay kits had poor sensitivities and were not able to detect E2 levels <10 or <20 pg/ml. Although two of the E2 assays using commercial kits demonstrated a better sensitivity (5 pg/ml), the measured E2 values were substantially higher than those obtained by LC-MS/MS. The assay with the sixth commercial E2 kit grossly underestimated the true E2 values. E2 assays carried out with commercial E2 immunoassay kits lack the accuracy to measure the very low serum E2 levels found in patients being treated with AIs. Serum samples from such patients should be sent to laboratories that use a mass spectrometry assay.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-2-5) contains supplementary material, which is available to authorized users.

Increased Neurokinin B (Tac2) Expression in the Mouse Arcuate Nucleus Is an Early Marker of Pubertal Onset with Differential Sensitivity to Sex Steroid-Negative Feedback than Kiss1

At puberty, neurokinin B (NKB) and kisspeptin (Kiss1) may help to amplify GnRH secretion, but their precise roles remain ambiguous. We tested the hypothesis that NKB and Kiss1 are induced as a function of pubertal development, independently of the prevailing sex steroid milieu. We found that levels of Kiss1 mRNA in the arcuate nucleus (ARC) are increased prior to the age of puberty in GnRH/sex steroid-deficient hpg mice, yet levels of Kiss1 mRNA in wild-type mice remained constant, suggesting that sex steroids exert a negative feedback effect on Kiss1 expression early in development and across puberty. In contrast, levels of Tac2 mRNA, encoding NKB, and its receptor (NK3R; encoded by Tacr3) increased as a function of puberty in both wild-type and hpg mice, suggesting that during development Tac2 is less sensitive to sex steroid-dependent negative feedback than Kiss1. To compare the relative responsiveness of Tac2 and Kiss1 to the negative feedback effects of gonadal steroids, we examined the effect of estradiol (E(2)) on Tac2 and Kiss1 mRNA and found that Kiss1 gene expression was more sensitive than Tac2 to E(2)-induced inhibition at both juvenile and adult ages. This differential estrogen sensitivity was tested in vivo by the administration of E(2). Low levels of E(2) significantly suppressed Kiss1 expression in the ARC, whereas Tac2 suppression required higher E(2) levels, supporting differential sensitivity to E(2). Finally, to determine whether inhibition of NKB/NK3R signaling would block the onset of puberty, we administered an NK3R antagonist to prepubertal (before postnatal d 30) females and found no effect on markers of pubertal onset in either WT or hpg mice. These results indicate that the expression of Tac2 and Tacr3 in the ARC are markers of pubertal activation but that increased NKB/NK3R signaling alone is insufficient to trigger the onset of puberty in the mouse.

Changes in calcitropic hormones, bone markers and insulin-like growth factor I (IGF-I) during pregnancy and postpartum: a controlled cohort study

Pregnancy and lactation cause major changes in calcium homeostasis and bone metabolism. This population-based cohort study presents the physiological changes in biochemical indices of calcium homeostasis and bone metabolism during pregnancy and lactation We describe physiological changes in calcium homeostasis, calcitropic hormones and bone metabolism during pregnancy and lactation. We studied 153 women planning pregnancy (n=92 conceived) and 52 non-pregnant, age-matched female controls. Samples were collected prior to pregnancy, once each trimester and 2, 16 and 36 weeks postpartum. The controls were followed in parallel. P-estradiol (E2), prolactin and 1,25-dihydroxyvitamin D (1,25(OH)2D) increased (p<0.001) during pregnancy, whereas plasma levels of parathyroid hormone (P-PTH) and calcitonin decreased (p<0.01). Insulin-like growth factor I (IGF-I) was suppressed (p<0.05) in early pregnancy but peaked in the third trimester. Postpartum, E2 was low (p<0.05); prolactin decreased according to lactation status (p<0.05). 1,25(OH)2D was normal and IGF-I was again reduced (p<0.05). P-PTH and calcitonin increased postpartum. From early pregnancy, markers of bone resorption and formation rose and fall, respectively (p<0.001). From the third trimester, bone formation markers increased in association with IGF-I changes (p<0.01). Postpartum increases in bone turnover markers were associated with lactation status (p<0.001). During lactation, plasma phosphate was increased, whereas calcium levels tended to be decreased which may stimulate PTH levels during and after prolonged lactation. The increased calcium requirements in early pregnancy are not completely offset by increased intestinal calcium absorption caused by high 1,25(OH)2D since changes in bone markers indicated a negative bone balance. The rise in bone formation in late pregnancy may be initiated by a spike in IGF-I levels. The high bone turnover in lactating women may be related to high prolactin and PTH levels, low E2 levels and perhaps increased parathyroid hormone-related protein levels.

Higher Levels of Endogenous Estradiol are Associated with Frailty in Postmenopausal Women from the Toledo Study for Healthy Aging

Adverse effects of higher endogenous estradiol (E2) levels on various clinical outcomes and on determinants of the frailty syndrome have recently been reported. However, there are no data about the potential relationship between E2 and frailty. We aimed to study the association between E2 levels and frailty among older postmenopausal women not taking hormonal therapy. We used data from the Toledo Study for Healthy Aging, a Spanish population-based cohort study. Frailty was defined according to Fried's approach. Multivariate odds ratios (OR) and 95% confidence intervals (CI) associated with E2 levels were estimated using polytomous logistic regression. E2 levels decreased significantly with age and educational level, whereas they increased with body mass index, high-sensitivity C-reactive protein (hs-CRP), and impairment in Katz activities of daily living. Higher E2 levels were associated with the prevalence of frailty among women younger than 79 yr, but not in the oldest group (p interaction = 0.047). After adjustment, OR of frailty associated with a 1 sd increase of E2 was 1.51 (95% CI, 1.04-2.20; P = 0.03). We identified an interaction between E2 and hs-CRP on the prevalence of frailty (P value = 0.042). Women with both higher E2 and hs-CRP (defined as values into the upper tertile) had an age-adjusted OR of 4.2 (95% CI, 1.7-10.5; P = 0.002), compared with women with low levels of both E2 and hs-CRP. Higher E2 levels were associated with frailty in postmenopausal women. The synergism between higher E2 and hs-CRP levels suggests the existence of physiopathological mechanisms connecting inflammation and estrogen to frailty.

Recurrence of empty follicle syndrome with stimulated IVF cycles

Aim: To determine the incidence of recurrent empty follicle syndrome (EFS) and to analyse the factors associated with this phenomenon. Methods: Retrospective analysis comparing all EFS cycles with cycles in which oocytes were retrieved in our in vitro fertilization (IVF) unit between 1998 and 2006. Results: Of 8292 IVF cycles, 163 (2.0%) resulted in empty follicles. Risk factors for EFS included advanced age (37.7 ± 6.0 years vs. 34.2 ± 6.0 years, p < 0.001), longer infertility (8.8 ± 10.6 years vs. 6.3 ± 8.4 years, p < 0.05), higher baseline follicle-stimulating hormone levels (8.7 ± 4.7 IU/L vs. 6.7 ± 2.9 IU/L, p < 0.001) and lower E2 levels before the human chorionic gonadotropin injection (499.9 ± 480.9 pg/mL vs. 1516.3 ± 887.5 pg/mL, p < 0.001) compared with cases in which ova were retrieved. Among patients with EFS, recurrent EFSs occurred in 15.8% of subsequent cycles. Conclusion: The EFS is a sporadic event in the majority of patients. However, in about 16% of the patients, EFS may recur. These cases may be a variant form of poor response and patients with repetitive EFS syndrome should be counseled concerning their chances to conceive.

Severe ovarian hyperstimulation syndrome after letrozole-gonadotropin stimulation: a case report

Ovarian hyperstimulation syndrome (OHSS) results from an exaggerated response to ovulation induction, characterized by a fluid shift from the intravascular space to third space compartments. The incidence of moderate OHSS is approximately 3–6% and severe OHSS occurs in 0.1–3% of treatment cycles [1, 2]. A number of causal mechanisms have been investigated, involving estradiol (E2), human chorionic gonadotropin (hCG), and vascular endothelial growth factor (VEGF). A strong association between E2 concentrations and risk for developing OHSS has been observed consistently [3]. A growing awareness and interest in treatments aimed at fertility preservation (FP) has led many women to pursue urgent oocyte or embryo cryopreservation. Those with estrogen-sensitive cancers often receive adjunctive treatment with letrozole, in efforts to limit exposure to elevated estrogen concentrations that typically result from exogenous gonadotropin stimulation; letrozole inhibits estrogen production by binding competitively to the cytochrome P450 component of the aromatase enzyme. Combination stimulation regimens yield results comparable to those achieved with standard gonadotropin stimulation protocols, but are associated with significantly lower E2 levels [4]. The risk of OHSS for women receiving adjunctive treatment with letrozole generally is considered low, because E2 levels are markedly lower than in cycles stimulated with gonadotropins alone. In fact, no cases of severe OHSS have been reported in a patient receiving combined treatment with letrozole and gonadotropins. Here, we report a case of severe OHSS arising in a woman with breast cancer after stimulation with exogenous gonadotropins, despite treatment with letrozole and having only moderately elevated E2 concentrations.

Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study

To verify whether hypogonadism represents a risk factor for cardiovascular (CV) morbidity and mortality and to verify whether testosterone replacement therapy (TRT) improves CV parameters in subjects with known CV diseases (CVDs). Meta-analysis. An extensive Medline search was performed using the following words 'testosterone, CVD, and males'. The search was restricted to data from January 1, 1969, up to January 1, 2011. Of the 1178 retrieved articles, 70 were included in the study. Among cross-sectional studies, patients with CVD have significantly lower testosterone and higher 17-β estradiol (E(2)) levels. Conversely, no difference was observed for DHEAS. The association between low testosterone and high E(2) levels with CVD was confirmed in a logistic regression model, after adjusting for age and body mass index (hazard ratio (HR)=0.763 (0.744-0.783) and HR=1.015 (1.014-1.017), respectively, for each increment of total testosterone and E(2) levels; both P<0.0001). Longitudinal studies showed that baseline testosterone level was significantly lower among patients with incident overall- and CV-related mortality, in comparison with controls. Conversely, we did not observe any difference in the baseline testosterone and E(2) levels between case and controls for incident CVD. Finally, TRT was positively associated with a significant increase in treadmill test duration and time to 1 mm ST segment depression. Lower testosterone and higher E(2) levels correlate with increased risk of CVD and CV mortality. TRT in hypogonadism moderates metabolic components associated with CV risk. Whether low testosterone is just an association with CV risk, or an actual cause-effect relationship, awaits further studies.

Preliminary study of letrozole use for improving spermatogenesis in non-obstructive azoospermia patients with normal serum FSH

We investigated whether letrozole (2.5 mg day(-1)) improves sperm count in non-obstructive azoospermia (NOA) patients. Four men were included in this study, and they had folliculo-stimulating hormone and other hormone levels within the normal range and no varicoceles or chromosomal aberrations. These four patients were administered letrozole for 3 months. Sperm count, testicular volume, gonadotropin, testosterone (T) and estradiol (E2) blood levels were assessed before, during and 1 week after the suspension of treatment. All patients showed spermatozoa in their ejaculate, increased gonadotropin and T levels and lower E2 levels (P<0.05 in all cases), when letrozole was administered. This suggests that letrozole treatment might improve sperm count in an NOA sub-population; however, more studies, including the proper controls, are needed to confirm its efficacy.

Estradiol levels in men with congenital hypogonadotropic hypogonadism and the effects of different modalities of hormonal treatment

To evaluate the degree of E2 deficiency in male congenital hypogonadotropic hypogonadism (CHH), and its response to different hormonal treatments. Retrospective and prospective studies. Academic institution. Untreated or treated CHH, healthy men, untreated men with Klinefelter syndrome (KS). Serum sex hormone-binding globulin (SHBG) and total E2 (TE2) as well as bioavailable (BE2) and free (FE2) levels were measured and determined. Total, bioavailable, and free testosterone, TE2, BE2, FE2 were compared in normal men, untreated and treated CHH and in untreated KS. TE2, BE2, and FE2 levels were very significantly lower in untreated patients with CHH (n=91) than in controls (n=63) and in patients with KS (n=45). The TE2 correlated positively with serum total T in patients with CHH. The TE2 also correlated very positively with serum LH in the combined population of patients with CHH and healthy men, suggesting that low E2 levels in CHH are due to severe LH-driven T deficiency. All fractions of circulating E2 were very significantly higher in patients with CHH receiving T enanthate (n=101) or the FSH-hCG combination (n=88) than in untreated patients with CHH. Contrary to dihydrotestosterone (DHT), both T enanthate and combined FSH-hCG therapy significantly and prospectively increased TE2 levels in patients with CHH. Contrary to KS, the male hypogonadism observed in CHH is associated with profound E2 deficiency, which can be overcome by aromatizable androgen or combined gonadotropin therapy.

Effects of salpingectomy on ovarian response in controlled ovarian hyperstimulation for in vitro fertilization: a reappraisal

To evaluate the effects of salpingectomy on ovarian response in controlled ovarian hyperstimulation (COH), 36 women who underwent controlled ovarian stimulation cycles for IVF before and after salpingectomy were studied. The overall number of dominant follicles and the number of oocytes aspirated before and after salpingectomy were comparable (7.2 ± 3.8 vs. 7.3 ± 3.7 and 10.2 ± 6.6 vs. 10.3 ± 7.4, respectively) as well as maximal E(2) levels, daily doses of gonadotropins, and the number of dominant follicles before and after surgery on the operated side, demonstrating that salpingectomy does not influence ovarian response in COH.

Estrogen signaling in microvascular arteries: Parturition reduces vasodilation by reducing 17β-estradiol and nNOS

Few studies have examined the potential effects of childbirth on the responses of the female vasculature – especially the resistance microvasculature of non-reproductive tissues. In the present study we have investigated the response of mesenteric microvascular resistance vessels to estrogen (E2), an important vasoactive hormone. Vessels were obtained from either nulliparous or postpartum female Sprague–Dawley rats, and isometric tension studies were performed. We found that E2 induced a concentration-dependent, endothelium-independent relaxation of microvessels precontracted with 10 −5 M phenylephrine; however, E2-induced relaxation was reduced by nearly half in vessels from postpartum animals compared to nulliparous controls. Inhibiting nitric oxide synthase activity with 10 −4 M l-NMMA or l-NPA (which exhibits selectivity for type 1 or nNOS) attenuated the relaxation effect of E2 on arteries from nulliparous animals. In contrast, l-NPA had little effect on arteries from postpartum animals, suggesting a reduced influence of nNOS after parturition. Moreover, expression of nNOS protein in microvessels was decreased 39% in the postpartum state compared to arteries from nulliparous animals. We propose that the impaired E2-induced relaxation response of microvessels from postpartum animals reflects a downregulation of NO production due to lower nNOS expressed in vascular smooth muscle cells. We measured a 73% decrease in serum E2 levels in the postpartum state compared to nulliparous animals. Because E2 has been shown to increase nNOS protein expression, we propose that lower E2 levels after parturition decrease expression of nNOS, leading to a reduced vasodilatory capacity of resistance microvessels.

Relationship between Lymphocytes, IL2 and the Hormones E2, LH, PRG and FSH in Menopausal and Postmenopausal Women

PROBLEM In this baseline study, our aim is to show the relationship of parameters and gonad hormones in menopausal and postmenopausal women. METHOD Blood samples were taken from menopausal and postmenopausal women (12-14 months and ≥10 years, respectfully, since their last menstruation). Adolescents aged 13.7 ± 0.7 were used as controls. Hormones were measured by ELISA and percentages of CD45, CD4, CD8, CD3, CD19, IL-2, CD25 and HLA-DR were measured by flow cytometry. RESULTS Both groups showed an increase in the percentage of CD3, CD4 and CD8. Levels of CD19 were significantly lower in the postmenopausal group. However, changes in immunologic parameters during menopause were less marked than the hormonal changes observed in these groups. Most of the correlations LH × CD3 (-ve), LH × IL2R (-ve) and E2 × CD19 (+ve) suggesting how menopausal women with particularly high LH or low E2 levels may be affected. Only CD3 and HLA-DR correlated with the hormonal changes in the postmenopausal group. IL-2 levels were high in the menopausal group and low in the postmenopausal group; however, no correlation was observed. DISCUSSION Menopause is characterized by increased levels of IL-2, which has critical immune-modulatory effects. These changes may be related to the overall hormonal change process observed during menopause.

Chronic estradiol-17β exposure increases superoxide production in the rostral ventrolateral medulla and causes hypertension: reversal by resveratrol

Women are exposed to estrogen in several forms, such as oral contraceptive pills and hormone replacement therapy. Although estrogen was believed to be cardioprotective, lately, its beneficial effects are being questioned. Recent studies indicate that oxidative stress in the rostral ventrolateral medulla (RVLM) may play a role in the development of hypertension. Therefore, we hypothesized that chronic exposure to low levels of estradiol-17β (E(2)) leads to hypertension in adult-cycling female Sprague Dawley (SD) rats potentially through generation of superoxide in the RVLM. To test this hypothesis, young adult (3 or 4 mo old) female SD rats were either sham-implanted or implanted (subcutaneously) with slow-release E(2) pellets (20 ng/day) for 90 days. A group of control and E(2)-treated animals were fed lab chow or chow containing resveratrol (0.84 g/kg of chow), an antioxidant. Rats were implanted with telemeters to continuously monitor blood pressure (BP) and heart rate (HR). At the end of treatment, the RVLM was isolated for measurements of superoxide. E(2) treatment significantly increased mean arterial pressure (mmHg) and HR (beats/min) compared with sham rats (119.6 ± 0.8 vs. 105.1 ± 0.7 mmHg and 371.7 ± 1.5 vs. 354.4 ± 1.3 beats/min, respectively; P < 0.0001). Diastolic and systolic BP were significantly increased in E(2)-treated rats compared with control animals. Superoxide levels in the RVLM increased significantly in the E(2)-treated group (0.833 ± 0.11 nmol/min·mg) compared with control (0.532 ± 0.04 nmol/min·mg; P < 0.05). Treatment with resveratrol reversed the E(2)-induced increases in BP and superoxide levels in the RVLM. In conclusion, these findings support the hypothesis that chronic exposure to low levels of E(2) induces hypertension and increases superoxide levels in the RVLM and that this effect can be reversed by resveratrol treatment.

Modification of estrogen's association with Alzheimer's disease risk by genetic polymorphisms

Contrasting effects of estrogen treatment on cognitive function and Alzheimer's disease (AD) risk have been reported. It may be that genetic factors modify these relations. In the present study, 696 participants from the Oxford Project to Investigate Memory and Ageing were included (355 AD cases, 341 controls). Those individuals with other types of dementia and those using hormone treatment had been excluded. Analyses controlled for body mass index, age at blood sampling, and education. Analyses of variance revealed main effects, but not an interaction, for apolipoprotein E (APOE) and Catechol-O-methyl transferase (COMT) genotypes on estradiol (E2) levels in men ( p = 0.003 and p = 0.10, respectively), but not in women ( p = 0.82 and p = 0.49, respectively). Men carrying the APOE ε4 allele had lower E2 levels, while those carrying the COMT Val/Val alleles had higher E2 levels compared to Met/Val ( p < 0.05) allele carriers. Higher estrone (E1) levels and carrying the APOE ε4 allele (but not COMT alone, or in combination with the APOE genotype) were independent risk factors for AD. Similar to earlier studies, the heterozygous COMT genotype (Met/Val) showed a synergistic effect with the APOE ε4 allele being non-significantly associated with lower cognitive function. In conclusion, the present study suggests that elevated E1 levels significantly increase AD risk in both men and women. However, interactions between APOE ε4 and genetic polymorphisms related to sex steroid metabolism and AD risk need to be further investigated.

Management of Infertile Women with Endometriosis. What's the Result of Leaving Ovarian Endometrioma during IVF-ET Cycles?

Purpose The awareness of possible risk of damage to ovarian reserves after surgical treatment of ovarian endometriomas supports a more conservative approach in infertile women with ovarian endometrioma. A growing number of patients with ovarian endometrioma undergo In Vitro Fertilization and Embryo Transfer (IVF-ET) prior to surgery. The aim of this study was to assess the effect of ovarian endometrioma on IVF-ET cycles. Methods In a retrospective cohort pilot study, IVF-ET cycles performed by our group during the period 2000–2004 were assessed. One hundred and forty-four women with a history of surgery for endometriosis or endometriosis at the time of the cycle were included in the ‘study group'. Seventy infertile patients because of tubal factor constituted the ‘control group'. IVF-ET outcome was assessed. Results Patients with endometriosis required a higher total dosage of FSH/hMG and attained lower peak E2 levels, and fewer follicles and oocytes were obtained. Clinical pregnancy rate per patient was lower in the endometriosis group (24/144, 16.7%) when compared with tubal factor (20/70, 28.6%), clinical pregnancy rate per embryo transfer was similar (24/117, 20.5% and 20/61, 32.8% respectively). When stratifying results in the endometriosis group, patients with a history of prior surgery for ovarian endometrioma required a higher dosage of FSH/ hMG and attained a lower peak of estradiol. A trend with a consistent reduction in pregnancy rate in women with a history of prior surgery for ovarian endometrioma (5/37, 13% in patients with previous cystectomy and no recurrence; 2/17, 11.8% in patients with prior surgery and recurrence of endometrioma at pick-up; 2/10, 20% in women never operated with endometrioma at pick-up; 15/53, 28.3% in the minimal-mild endometriosis group; 20/61, 32.8% for tubal factor) was observed. Conclusions Both surgery for ovarian endometrioma and the existence of endometrioma during pickup appear to affect IVF-ET outcome. Patients with prior surgery and endometrioma recurrence at the time of pick-up revealed a further decrease in pregnancy rate.

Verbal Episodic Memory and Endogenous Estradiol: An Association in Patients with Mild Cognitive Impairment and Alzheimer's Disease

In the continuum of patients with Alzheimer's disease (AD), mild cognitive impairment (MCI), and normal controls, a possible association of verbal memory and endogenous estradiol (E2) levels was investigated. Verbal episodic memory was measured with a german version of the California verbal memory test (CVLT). Results were controlled for apolipoprotein E (ApoE) phenotype. We studied 37 controls, 32 MCIs and 117 ADs. Groups differed in all trials of the CVLT (P < 0.001) and in E2 levels (P < 0.001). E2 levels differed significantly between groups only among females (P < 0.001). In females correcting for age and ApoE, there was an overall correlation between CVLT delayed recall and level of E2 (P = 0.025). Stepwise regression analyses found E2 level to be a significant predictor for CVLT delayed recall (P < 0.001). It may be concluded that lower E2 levels occur more in the course of the disease than may be considered as a risk factor per se.

Chronic estradiol exposure induces oxidative stress in the hypothalamus to decrease hypothalamic dopamine and cause hyperprolactinemia

Estrogens are known to cause hyperprolactinemia, most probably by acting on the tuberoinfundibular dopaminergic (TIDA) system of the hypothalamus. Dopamine (DA) produced by TIDA neurons directly inhibits prolactin secretion and, therefore, to stimulate prolactin secretion, estrogens inhibit TIDA neurons to decrease DA production. However, the mechanism by which estrogen produces this effect is not clear. In the present study, we used a paradigm involving chronic exposure to low levels of estradiol-17β (E(2)) to mimic prolonged exposures to environmental and endogenous estrogens. We hypothesized that chronic exposure to low levels of E(2) induces oxidative stress in the arcuate nucleus (AN) of the hypothalamus that contains TIDA neurons and causes nitration of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of DA. This results in a significant decrease in DA and consequently, hyperprolactinemia. To investigate this, adult, intact female cycling rats were implanted with slow-release E(2) pellets (20 ng/day) for 30, 60, or 90 days and were compared with old (16-18 mo old) constant estrous (OCE) rats. Chronic E(2) exposure significantly increased the expression of glial fibrillary acidic protein and the concentrations of interleukin-1β (IL-1β) and nitrate in the AN that contains perikarya of TIDA neurons and increased nitration of TH in the median eminence (ME) that contains the terminals. These levels were comparable to those seen in OCE rats. We observed a significant decrease in DA concentrations in the ME and hyperprolactinemia in an exposure-dependent manner similar to that seen in OCE rats. It was concluded that chronic exposure to low levels of E(2) evokes oxidative stress in the AN to inhibit TIDA neuronal function, most probably leading to hyperprolactinemia.