Low E2 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.

GnRH agonist (GnRHa) priming increases the number of in vitro matured (IVM) oocytes available for cryopreservation in cancer patients seeking urgent fertility preservation (FP)

E2 and follicular size and may complicate clinical decision making. This study seeks to determine whether continuous AI use throughout stimulation impacts oocyte maturity and function. DESIGN: Retrospective. MATERIALS AND METHODS: FP patients with breast cancer treated with an AI (letrozole) were compared to FP patients with other malignancies not using AIs. The AI group had oocyte maturation induced when leading follicles reached 20mm as suggested by Oktay et al, compared with the standard of 18mm. Endocrine levels, oocyte maturity (MII/retrieved oocytes), MII yield (MII/follicles R14mm) and fertilization rates were compared. RESULTS: 24 AI patients were compared with 22 controls. The age, AMH, and antral follicle counts were equivalent. In contrast to prior reports, total gonadotropin usage was similar. The AI group had lower peak E2 levels (536 vs 1972 pg/mL; P 400 pg/mL). The AI group had higher peak P levels (1.1 vs 0.7 ng/mL; P<0.01) and a trend toward a higher risk of premature P rise R1.5 ng/mL (29% vs 5%; P1⁄40.06). Despite larger follicles, the AI group had a lower maturity rate (68% vs 80%; P<0.001). The MII yield was lower in the AI group (P1⁄40.04). Among those who underwent ICSI (15 AI, 14 noAI), the fertilization rate was lower in the AI group (76% vs 84%; P1⁄40.03). CONCLUSION: Despite efforts to prevent supraphysiologicE2 inbreast cancer FP cycles, most AI stimulations result in elevated E2 levels. Although the impact of elevated P on oocyte quality in FP cycles is not established, it may reflect an altered intrafollicular endocrine milieu and post-maturity. Caution shouldbe exercisedwhenchangingdecisionmaking inFPpatients receivingAIs.

Bidirectional modulatory effect of 17β-estradiol on NMDA receptors via ERα and ERβ in the dentate gyrus of juvenile male rats

The neurosteroid 17β-estradiol (E2) is synthesized by aromatase in both male and female hippocampi and is known to modulate hippocampal synaptic functions. However, as some contradictory findings regarding the modulatory effects of E2 have been reported in the literature, its physiological role and mechanism of action in the hippocampus remain controversial. Our recent study showed that a low E2 dose (1 nM) increased the amplitude of NMDA receptor-mediated EPSCs (NMDAR-EPSCs) and lowered the threshold for the induction of NMDA receptor-dependent long-term potentiation (NMDAR-LTP), while a high E2 dose (7 nM) exerted opposite effects in the dentate gyrus of juvenile male rat hippocampal slices. The present study is a follow-up that explores the underlying mechanism of this bidirectional effect of E2. We found that the ERα agonist PPT reproduced the actions of the low E2 dose on NMDAR-EPSCs and NMDAR-LTP, while the ERβ agonist DPN reproduced the actions of the high E2 dose. Moreover, PPT, but not DPN, restored the decrease in NMDAR-EPSCs induced by the aromatase inhibitor letrozole, suggesting that E2 synthesized constitutively in the hippocampus enhances NMDA receptor function via ERα. The PPT-induced enhancement in NMDAR-EPSCs was mediated by Src family kinase, but was not caused by NR2B modulation. These findings demonstrate that E2 exerts condition-dependent bidirectional effects on NMDA receptor-mediated transmission and, thus, synaptic plasticity via ERα and ERβ in the dentate gyrus of juvenile male rats.

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.

Influences on endometrial development during intrauterine insemination: clinical experience of 2,929 patients with unexplained infertility

To characterize relationships associated with adverse endometrial development in patients undergoing IUI for unexplained infertility. A retrospective review of 2,929 patients from 2004-2011. Large metropolitan infertility practice. Patients with unexplained infertility undergoing first IUI cycle at age less than 43 years, with a total motile sperm count ≥ 8 million. Clomiphene citrate (CC) with FSH stimulation followed by IUI. Endometrial thickness, serum E2 (in picograms per milliliter) levels on the day of hCG trigger administration, body mass index (BMI) (in kilograms per meter squared), total motile sperm, follicle number, and clinical pregnancy. Of the 2,929 patients who met the inclusion criteria, 466 (15.9 %) achieved a clinical pregnancy. Pregnancy rates (PRs) increased significantly with increasing endometrial thickness on the day of hCG administration and with increasing serum E2 level, but were not significantly related to age, BMI, or follicle numbers according to multiple logistic regression modeling. Peak endometrial thickness declined with age and increasing E2 levels. The BMI was associated with thicker endometrium, but it was also associated with lower peak E2 levels. The impact of "endometrial factor" infertility may be underappreciated in IUI therapy. Targeted therapies to optimize the endometrium represent an important new area to improve in current fertility success rates.

Short-term changes in serum sex steroid levels and cardiac function in healthy young men

Introduction: Male obesity is associated with an increase in estradiol (E2) and a decrease in testosterone (T). And, although sex steroids are associated with cardiovascular disease, direct effects on cardiac structure and function are hardly investigated in humans. Methodology: Twenty healthy men aged 20–40 years were randomized into two groups. One group was given an aromatase inhibitor (letrozole) only, thus obtaining a high testosterone and low E2 (group T). The other group received an aromatase inhibitor plus an E2 patch (dermestril), reaching a low testosterone and high E2 (group E). Serum levels of both testosterone and E2 remained within the normal reference range. The men underwent an echocardiography by a single cardiologist before the start of the intervention and after 7 days. Results: Total and free E2 serum levels were positively associated with ejection fraction (r=0.7, P=0.002 and r=0.6, P=0.007 respectively) at baseline in the whole group. In group E global circumferential strain decreased significantly from −25.3%±3.9 to −19.6%±2.5 after 1 week as compared to baseline (P=0.01). No significant changes in systolic function were observed in group T. Cardiac structure remained unaltered. Conclusion: In young healthy men, an increase in E2 and decrease in testosterone levels significantly decreased circumferential strain. The finding justifies larger studies of longer duration to discover the exact nature of the impact of changed sex steroids on cardiac function and remodelling in obesity.

Short‐term estrogen depletion does not promote hypertension in mice

Our lab has previously demonstrated that estrogen (E2) downregulates the expression and function of voltage‐gated, L‐type Ca2+ channels (CaL) in coronary arteries in vitro. In this study we hypothesized that the in vivo depletion of E2 would generate an increase in Ca2+‐dependent arterial tone. Mice (C57BL/6) underwent an ovariectomy (OVX) or sham surgery at 8‐wks of age. Biotelemetry measured a drop in heart rate (p=0.002) and blood pressure (p=0.09) in OVX mice within 2‐wks post‐surgery suggesting a baroreceptor reflex compensation. Mice were sacrificed 4‐wks post‐surgery and the mesenteric arteries isolated. The OVX mice demonstrated atrophied uteri and low E2 plasma levels. In the mesenteric arteries, Western blots demonstrated a slight (p=0.12) increase in CaL expression from OVX mice. Mesenteric arterial reactivity experiments indicated no difference between groups in their spontaneous tone and response to the CaL agonist, FPL64176 (3×10−7 to 1×10−6). This suggests that, while E2 depletion alone does not promote hypertension, other underlying pathologies in conjunction with E2 depletion may lead to hypertension and other cardiovascular diseases. Support: NIGMM of the NIH, Grant #P20 GM103429–11

Contributions of cyclooxygenase (COX) and NO synthase (NOS) pathways to endothelium‐dependent dilatation in the finger of women

We tested the roles of COX and NOS in finger vasodilatation evoked by iontophoresis of acetylcholine (ACh), using laser Doppler fluximetry. In 12 women in the low oestrogen (E2) phase of the menstrual cycle, aspirin (600mg p.o) decreased baseline finger red cell flux (RCF) from 55.0±7.8 to 30.6±5.5* perfusion units (pu; *: P&lt;0.05), and the ACh‐evoked response from +296.8±23.9 to +251.4±24.4* pu. In the high E2 phase, COX inhibition decreased baseline from 68.0 ± 13.8 to 38.4 ± 8.1*, but had no effect on the ACh response (259.5±27.4 vs 251.2±23.3 pu). On different days, NOS inhibition with L‐NAME had no effect on baseline RCF in the low, or high E2 phase. In the low E2 phase, the ACh response was unchanged (+228.26±25.8 vs 225.6±21.3pu), but aspirin then decreased the response further to 175.9±17.6*pu. In the high E2 phase, L‐NAME increased the ACh response from +198.1±23.7 to +229.2±27.4*pu; COX inhibition restored it to +202.8±27.8pu. We propose that in the finger, NOS generates both NO and O2− and thereby, ONOO− which inhibits PGI2 synthase. E2 facilitates NOS and PGI2 synthase such that when E2 is high, PGI2 contributes to endothelium‐dependent finger dilatation only after NOS inhibition.

PL.89 Functional Effects of Oestradiol on Cytokine Responses of Human Ectocervical Epithelial Cells to Toll-Like Receptor 2 and 4 Ligands

We have demonstrated that the pattern recognition toll-like receptors (TLR) 2&4 are upregulated during pregnancy in human cervical epithelium. We sought to determine whether oestradiol (E2) alters the immunological responses...

Association study between FSHR Ala307Thr and Ser680Asn variants and polycystic ovary syndrome (PCOS) in Northern Chinese Han women

Polycystic ovary syndrome (PCOS) is a common complex genetic endocrinopathy. It has high heritability, and twin studies indicate that it is a complex polygenic disorder. Searching for major genes of PCOS is crucial to clarify its molecular pathogenesis. A previous genome-wide association study in Chinese women with PCOS identified a region on chromosome 2p16.3 that encodes the follicle-stimulating hormone receptor (FSHR) genes as a reproducible PCOS susceptibility locus. In the present study, we performed a replication analysis of the association between two common variants of the FSHR gene and PCOS in Northern Chinese Han women. We recruited 384 unrelated PCOS patients and 768 healthy individuals from the Shaanxi province in the northern part of China. Two polymorphisms (Ala307Thr and Ser680Asn) of the FSHR gene and the clinical characteristics of the study subjects were analyzed in the case-control sample. The frequency of FSHR Ala307Thr and Ser680Asn variants along with the haplotype was not significantly different between the PCOS patients and the controls; however, the Ser680 variants may be associated with high levels of FSH and low E2 levels. The variant of Ser680 was not associated with PCOS but it may be related to high FSH levels. The present study suggests that the two variants of the FSHR gene are not a causative factor of PCOS in Northern Chinese Han women.

Estrogen status and psychophysical stress modify temporomandibular joint input to medullary dorsal horn neurons in a lamina-specific manner in female rats

Estrogen status and psychological stress contribute to the expression of several chronic pain conditions including temporomandibular muscle and joint disorders (TMJD). Sensory neurons that supply the temporomandibular joint (TMJ) region terminate in laminae I and V of the spinal trigeminal nucleus (Vc/C1–2 region); however, little is known about lamina-specificity and environmental influences on the encoding properties of TMJ brainstem neurons. To test the hypothesis that Vc/C1–2 neurons integrate both interoceptive and exteroceptive signals relevant for TMJ nociception, we recorded TMJ-evoked activity in superficial and deep laminae of ovariectomized rats under high and low estradiol (E2) and stress conditions. Rats received daily injections of low (LE) or high (HE) dose E2 and were subjected to forced swim (FS) or sham swim conditioning for 3days. The results revealed marked lamina-specificity in that HE rats displayed enhanced TMJ-evoked activity in superficial, but not deep, laminae independent of stress conditioning. By contrast, FS conditioned rats displayed increased background firing and TMJ-evoked activity of neurons in deep, but not superficial, laminae independent of E2 status. FS also enhanced TMJ-evoked masseter muscle activity and suggested the importance of deep dorsal horn neurons in mediating evoked jaw muscle activity. In conclusion, E2 status and psychophysical stress play a significant role in modifying the encoding properties of TMJ-responsive medullary dorsal horn neurons with a marked lamina-specificity.

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.

CYP19 gene variants affect the assisted reproduction outcome of women with polycystic ovary syndrome

Objective: Cytochrome P450 aromatase catalyzes the irreversible transformation of androgens into estrogens. The association of CYP19(TTTA)n polymorphism with the hormonal profile and the assisted reproduction outcome of women with polycystic ovary syndrome (PCOS) was explored.Methods: One hundred and thirty-two women with PCOS and 200 with male-factor infertility, as controls, participated in the current study. The CYP19(TTTA)n polymorphism was genotyped, while the hormonal profile was determined at the third day of the menstrual cycle. During oocyte retrieval, the follicular size, the follicle and oocyte numbers were recorded.Results: Genotype analysis revealed 6 CYP19(TTTA)n alleles with 7–12 repeats. In PCOS women, the CYP19(TTTA)7 allele presence was associated with lower serum E2 levels at the third day of the menstrual cycle (p < 0.009), lower large follicle (p < 0.02) and total oocyte numbers (p = 0.006), but with significantly higher pregnancy rates after assisted reproduction (p < 0.004).Conclusions: Potential associations of the CYP19(TTTA)7 allele with ovarian response to standard gonadotrophin stimulation and with assisted reproduction outcome were found in PCOS women, probably due to androgen/estrogen ratio alterations.

Five years' experience using oocyte vitrification to preserve fertility for medical and nonmedical indications

To evaluate the results of controlled ovarian hyperstimulation (COH) for oocyte vitrification to preserve fertility for medical and nonmedical indications. A retrospective, multicenter, observational study performed between March 2007 and June 2012. University-affiliated infertility clinics. Of 560 nononcological patients and 475 oncological patients, we performed 1,080 oocyte vitrification cycles, 725 for nonmedical reasons and 355 in patients affected with cancer. Cycle outcome is presented, including 30 women who returned to use their frozen eggs with, 20 pregnancies obtained, 6 newborns, and 8 ongoing pregnancies. Controlled ovarian hyperstimulation, oocyte retrieval, warming of oocytes, and ET in those who already came back. Days of stimulation, total dose of gonadotropins, estrogen (E) and P levels, number of oocytes retrieved and vitrified, pregnancy rate (PR). Comparable results were obtained in both groups of patients, with lower total dose of gonadotropins used and lower serum E(2) levels in patients affected with cancer. Frozen/thawed oocytes performed similarly in both groups. Patients who vitrify eggs for medical or nonmedical reasons perform similarly, as observed in this large series. This technique offers realistic expectations to both groups of patients to have a child with their own eggs. These data could be used to adequately counsel our patients.

The impact of gender and serum estradiol levels on HDL‐mediated reverse cholesterol transport

Premenopausal women have a lower incidence of cardiovascular disease compared to men of the same age. Endogenous oestrogens, especially estradiol, presumably protect against atherosclerosis by a variety of mechanisms. Reverse cholesterol transport (RCT) mechanisms also provide protection against this disease. RCT is defined as the removal of cholesterol from peripheral macrophage foam cells, via high-density lipoproteins (HDL), and cholesterol transportation to the liver for excretion. We have previously shown in a preliminary study that HDL, isolated from premenopausal women, enhanced macrophage cholesterol efflux compared to HDL derived from age-matched male subjects. Here, we expanded this study by analysing a larger population of healthy volunteers and evaluated the capacity of HDL derived from women with high or low serum E2 concentrations, mainly representing premenopausal and postmenopausal women, respectively, or men (each group consisting of 30 subjects) to facilitate cholesterol removal from human THP-1 macrophages. HDL isolated from serum samples was incubated with [(3)H] cholesterol oleate-loaded macrophages for 16 h, after which cholesterol efflux to HDL was determined. No significant differences in the efflux-promoting ability of HDL existed among the three groups. Relevant plasma factors involved in further steps of RCT, such as cholesterol ester transfer protein (CETP), phospholipid transfer protein (PLTP) and lecithin:cholesterol acyltransferase (LCAT) activities were also analysed, but no differences were observed among the study groups. The results do not support a role for estradiol status or gender in modifying the initial step of RCT as a protective mechanism against cardiovascular disease.

Effect of low dose bisphenol A on the early differentiation of human embryonic stem cells into mammary epithelial cells

It has been previously reported that Bisphenol A (BPA) can disturb the development of mammary structure and increase the risk of breast cancer in experimental animals. In this study, an in vitro model of human embryonic stem cell (hESC) differentiation into mammary epithelial cells was applied to investigate the effect of low dose BPA on the early stages of mammogenesis. A newly established hESC line was directionally differentiated into mammary epithelial cells by a well-established three-dimensional (3D) culture system. The differentiated mammary epithelial cells were characterized by immunofluorescence and western blotting assay, and were called induced differentiated mammary epithelial cells (iDMECs) based on these data. The hESCs were treated with low doses of BPA range 10−9–10−6M during the differentiation process, with DMSO as the solvent control and 17-β-estrodiol (E2) as the estrogen-positive control. Our results showed that low dose BPA and E2 could influence the mammosphere area of iDMECs and upregulate the expression level of Oct4 and Nanog proteins, while only BPA could downregulate the expression of E-cadherin protein. Taken together, this study provides some insights into the effects of low dose BPA on the early differentiation stage of mammary epithelial cells and suggests an easier canceration status of iDMECs under the effect of low dose BPA during its early differentiation stage.

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.

Deficits in latent inhibition induced by estradiol replacement are ameliorated by haloperidol treatment

There are sex differences in the symptomatology of schizophrenia, and in the response to antipsychotic treatments. One hallmark symptom of schizophrenia is a deficit in selective attention. Selective attention can be measured using a latent inhibition (LI) paradigm in humans; LI can be measured in rodents, and is used as an animal model of the selective attention deficits observed in schizophrenia. In the current experiments LI was used to clarify whether selective attention differs between male rats and ovariectomized (OVX) female rats receiving different estradiol (E2) replacement regimens. An additional aim was to determine whether haloperidol’s (HAL) facilitation of LI is enhanced by E2. Males and OVX female rats were trained in a conditioned emotional response LI paradigm. Females received no E2 replacement, a chronic low dose of E2 via silastic capsule, or a high phasic dose of E2 via silastic capsule accompanied by E2 (10 µg/kg subcutaneous (SC)) injections every 4th day. Actual plasma levels of E2 were determined using an enzyme linked immunosorbent assay. Rats were also administered a vehicle treatment, a 0.05 mg/kg, or a 0.1 mg/kg IP injection of HAL. Males and OVX females that did not receive E2 replacement both exhibited LI, but LI was not observed in the low and high E2 replacement groups. HAL restored LI at a lower dose in the females receiving high E2 replacement compared to females receiving low E2 replacement, indicating that E2 replacement facilitates HAL in restoring LI.

Dynorphin-Kappa Opioid Receptor Signaling Partly Mediates Estrogen Negative Feedback Effect on LH Pulses in Female Rats

Accumulating evidence suggests that the arcuate nucleus (ARC) kisspeptin/neurokinin B (NKB)/dynorphin (KNDy) neurons play a role in estrogen negative feedback action on pulsatile gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) release. The present study aimed to determine if dynorphin (Dyn) is involved in estrogen negative feedback on pulsatile GnRH/LH release. The effect of the injection of nor-binaltorphimine (nor-BNI), a kappa-opioid receptor (KOR) antagonist, into the third cerebroventricle (3V) on LH pulses was determined in ovariectomized (OVX) adult female rats with/without replacement of negative feedback levels of estradiol (low E2). The mean LH concentrations and baseline levels of LH secretion in nor-BNI-injected, low E2-treated rats were significantly higher compared with vehicle-treated controls. On the other hand, the nor-BNI treatment failed to affect any LH pulse parameters in OVX rats without low E2 treatment. These results suggest that Dyn is involved in the estrogen negative feedback regulation of pulsatile GnRH/LH release. The low E2 treatment had no significant effect on the numbers of ARC Pdyn (Dyn gene)-,Kiss1- and Tac2 (NKB gene)-expressing cells. The treatment also did not affect mRNA levels of Pdyn and Oprk1 (KOR gene) in the ARC-median eminence region, but significantly increased the ARC kisspeptin immunoreactivity. These findings suggest that the negative feedback level of estrogen suppresses kisspeptin release from the ARC KNDy neurons through an unknown mechanism without affecting the Dyn and KOR expressions in the ARC. Taken together, the present result suggests that Dyn-KOR signaling is a part of estrogen negative feedback action on GnRH/LH pulses by reducing the kisspeptin release in female rats.

The Occurrence of Glaucoma and Association with Serum Estradiol Level in Postmenopausal Women

Objectives: To investigate the occurrence of glaucoma and association with the serum estradiol (E2) level in postmenopausal women. Methods: We evaluated the serum E2 level, female reproductive factors and glaucoma related risk factors including intraocular pressure and optical coherence tomography (OCT) findings in 30 postmenopausal women who visited Obstetrics and Gynecology outpatient clinic. Patients who showed abnormal findings on the glaucoma screening test were classified to the glaucoma suspect group (group-G), and underwent a glaucoma confirmatory test. Serum E2 level, female reproductive and other menopausal healthrelated factors such as lipid profiles and bone mineral densities were analyzed in the group-G and non glaucomatous group (group-N). Results: Eight out of thirty participants (26.7%) were classified to the group-G. One of them was diagnosed as having glaucoma that required treatment, and the other two were found to have early glaucomatous changes. Compared to the group-G, the group-N had a higher level of serum E2 (19.40 ± 4.79 vs. 13.95 ± 4.55 pg/mL) The difference, however, was not statistically significant (P = 0.525). The proportion of glaucoma suspect patients in the groups with a higher serum E2 level (≥ 20 pg/mL) and a lower serum E2 level (< 20 pg/mL) was similar (25.0 and 27.3%, P = 0.645). Multiple logistic regression analysis showed that no female reproductive factors were associated with the risk of glaucoma. Conclusion: Comprehensive glaucoma screening using an OCT in postmenopausal women could detect more glaucoma patients than prevalence in the similar age group. Statistical significance was not found in the association between serum E2 level and the risk of glaucoma. (J Korean Soc Menopause 2013;19:106-111)