Supraphysiological Estrogen Levels Research Articles

Autologus Platelet Rich Plasma (PRP) in Vitro Fertilization Antagonist Protocol Caused Homeobox A 10 (HOXA10) Expression in the Endometrium of Wistar Strained Rats Higher Than Without Autologous PRP

Endometrial receptivity is highly correlated with the implantation rate, whereby in Indonesia, the implantation rate among in vitro fertilisation programs is still low, around 19.3%. Antagonist ovarian stimulation protocol can disrupt physiological endocrine milieu by the presence of supra-physiological levels of estrogen and progesterone, both of which are thought to indirectly affect the expression of adhesion molecule cells. Homeobox A 10 (HOXA10) is among one of the biomarkers used to assess endometrial receptivity. The role of HOXA10 is critical during the stage of endometrial development and embryo implantation, both in mice and human. This molecule is thought to work optimally by administering autologous platelet rich plasma (PRP) to the damaged endometrium. The aim of this study was to prove that administration of PRP in an antagonist protocol HOXA10 expression in the endometrium of Wistar rats higher than without PRP. This research was an experimental study. The design for this study was randomized posttest only controlled group, using female Wistar-strain rats type. A total of 40 Wistar rats whose ovary were stimulated by the GnRH antagonist protocol were divided into 2 groups, 20 rats as intervention group in which PRP administration was done and 20 rats as control group. It was found that during the study, there was no significant difference between intervention and control group regarding age and body weight of the Wistar rats, both at the start and at the end of the study. The results of HOXA10 H-score in the intervention group was 3.15 (2.86-3.52) and in the control group was 1.68 (1.43-2.18) (p <0.05). Administration of PRP to ovarian stimulation with an antagonist protocol showed significantly higher expression of endometrial HOXA10 in Wistar rats than without PRP administration.

Oocyte and embryo cryopreservation before gonadotoxic treatments: Principles of safe ovarian stimulation, a systematic review.

Objective:Review the safety of fertility preservation through ovarian stimulation with oocyte or embryo cryopreservation, including cycle and medication options.Evidence review:A systematic review of peer-reviewed sources revealed 2 applicable randomized control trials and 60 cohort studies as well as 20 additional expert opinions or reviews.Results:The capacity for future family building is important for the majority of reproductive age people, despite life-altering medical or oncologic diagnosis. Modern fertility preservation generates a high rate of oocyte yield while utilizing protocols that can be started at multiple points in the menstrual cycle and suppressing supra-physiologic levels of estrogen. Finally, more than one quarter of fertility preservation patients will return to later utilize fertility services.Conclusion:For most patients, fertility preservation can safely be pursued and completed within 2 weeks without affecting disease severity or long-term survival.

Venlafaxine-induced adrenergic signaling stimulates Leydig cells steroidogenesis via Nur77 overexpression: A possible role of EGF

Venlafaxine, a norepinephrine and serotonin reuptake inhibitor, impairs rat sperm parameters, spermatogenesis and causes high intratesticular estrogen and testosterone levels, indicating that Leydig cells (LCs) may be a venlafaxine target. We evaluated the effect of venlafaxine treatment on rat LCs, focusing on adrenergic signaling, EGF immunoexpression and steroidogenesis. Germ cells mitotic/meiotic activity and UCHL1 levels were also evaluated in the seminiferous epithelium. Eighteen adult male rats received 30 mg/kg of venlafaxine (n = 9) or distilled water (n = 9). The seminiferous tubules, epithelium and LCs nuclear areas were measured, and the immunoexpression of Ki-67, UCHL1, StAR, EGF, c-Kit and 17β-HSD was evaluated. UCHL1, StAR and EGF protein levels and Adra1a, Nur77 and Ndrg2 expression were analyzed. Malondialdehyde (MDA) and nitrite testicular levels, and serum estrogen and testosterone levels were measured. Venlafaxine induced LCs hypertrophy and Ndrg2 upregulation in parallel to increased number of Ki-67, c-Kit- and 17β-HSD-positive interstitial cells, indicating that this antidepressant stimulates LCs lineage proliferation and differentiation. Upregulation of Adra1a and Nur77 could explain the high levels of StAR and testosterone levels, as well as aromatization. Enhanced EGF immunoexpression in LCs suggests that this growth fact is involved in adrenergically-induced steroidogenesis, likely via upregulation of Nur77. Slight tubular atrophy and weak Ki-67 immunoexpression in germ cells, in association with high UCHL1 levels, indicate that spermatogenesis is likely impaired by this enzyme under supraphysiological estrogen levels. These data corroborate the unchanged MDA and nitrite levels. Therefore, venlafaxine stimulates LCs steroidogenesis via adrenergic signaling, and EGF may be involved in this process.

Predictor for supraphysiologic serum estradiol elevation on hCG triggering day of controlled ovarian stimulation using letrozole and gonadotropins in women with estrogen-dependent cancers.

The objective of this study was to evaluate predicting factors for supraphysiologic serum estradiol elevation during controlled ovarian stimulation (COS) with administration of letrozole and gonadotropins in patients with estrogen-dependent cancer. Use of aromatase inhibitors is recommended to prevent the potential effects of elevated serum estradiol levels and recurrence of tumor in patients with estrogen-dependent cancers during COS. Although previous studies reported that letrozole have shown an effective lowering of peak estrogen levels, a part of patients shows supraphysiologic levels of estrogen associated with ovarian stimulation despite the administration of letrozole. From January 2009 to December 2019, patients with estrogen-dependent cancer who underwent COS with antagonist protocol using a letrozole (5 mg/ day) to keep estrogen levels low were included in this study. Early monitoring serum estradiol was measured in all patients on the 4-6th day of stimulation. Subjects were classified into two groups according to the serum estradiol level on hCG triggering day, physiologic estradiol group (≤400 pg/mL) and supraphysiologic estradiol group (>400 pg/mL). A total of 96 COS cycles were retrospectively analyzed. Supraphysiologic level of serum estradiol was found in 21.9% of the patients. Mean age, AMH, duration of stimulation, total dose of gonadotropins administered were not different between the two groups. However, early monitoring serum estradiol level was significantly higher in the supraphysiologic estradiol group (67.1±47.9 vs. 115.6±78.1, p = 0.001) and was associated with the occurrence of supraphysiologic elevation of serum estradiol on hCG triggering day. Patients with early monitoring serum estradiol ≥84.5 pg/mL had an odds ratio of 5.376 [95% CI, 1.613–17.913] for supraphysiologic elevation of serum estradiol compared to those with early monitoring serum estradiol below 84.5 pg/mL. In conclusion, early monitoring serum estradiol is an independent predicting factor for supraphysiologic level of serum estradiol on hCG triggering day in the COS cycles using letrozole and gonadotropins.

Neonatal Estrogen Causes Irreversible Male Infertility via Specific Suppressive Action on Hypothalamic Kiss1 Neurons.

Aberrant exposure to estrogen-like compounds during the critical developmental period may cause improper hypothalamic programming, thus resulting in reproductive dysfunction in adulthood in male mammals. Kisspeptin-neurokinin B-dynorphin A (KNDy) neurons in the arcuate nucleus (ARC) have been suggested to govern tonic GnRH/gonadotropin release to control reproduction in male mammals. In this study, we report that chronic exposure to supraphysiological levels of estrogen during the neonatal period caused an irreversible suppression of KNDy genes in the ARC, resulting in reproductive dysfunction in male rats. Daily estradiol benzoate (EB) administration from days 0 to 10 postpartum caused smaller seminiferous tubules, abnormal spermatogenesis, and a decrease in plasma testosterone in adult male rats. The neonatal EB treatment profoundly suppressed LH pulse and ARC KNDy gene expression at adulthood, but it failed to affect the number of GnRH gene-expressing cells in male rats. The EB treatment failed to affect gene expression of other neuropeptides, such as GHRH, proopiomelanocortin, and agouti-related protein in the ARC, suggesting that ARC KNDy neurons would be a specific target of neonatal estrogen to cause male reproductive dysfunction. Because LH secretory responses to kisspeptin challenge and GnRH expression were spared in male rats with the EB treatment, LH pulse suppression is most probably due to ARC KNDy deficiency. Taken together, the current study indicates that chronic exposure to estrogenic chemicals in the developing brain causes a defect of ARC KNDy neurons, resulting in an inhibition of pulsatile GnRH/LH release and the failure of spermatogenesis and steroidogenesis.

Mole modifications following controlled ovarian stimulation for assisted reproduction technologies

The role of estrogens on moles biology remains undefined although estrogenic receptors have been found on melanocytes. It has been postulated that supraphysiological estrogen levels could promote the progression of moles to melanoma. Women undergoing controlled ovarian stimulation (COS) for assisted reproductive technologies (ART) are exposed to high levels of estrogens, produced by the ovary in response to exogenous gonadotropin administration. The aim of this study is to assess whether COS for ART may have an impact on mole structure and/or characteristics. Women undergoing to ART for various infertility conditions were included in the study. Personal and clinical data were collected. Dermatoscopic features and scores (total dermoscopy score--TDS) were statistically compared before COS and after a 6-month follow-up period. Statistical correlation was performed between estradiol, FSH blood levels and relative variation in moles dimensions. A total of 46 patients were included in the study. One hundred and seventy-five melanocytic lesions from 31 patients were evaluated at both time points. Although statistically significant differences were found in mole dimension and TDS between the two time points, these differences had no relevance in the clinical setting not suggesting the need for mole excision. Moreover, the only statistically significant correlation with estradiol blood concentration on hCG administration day was found with one-axis dimensional variation. To our knowledge this is the first work to evaluate the effect of COS on moles. The obtained results do not support a causal relation between the supraphysiological hormone levels stimulation and worsening of clinical and dermoscopical features of moles. Further study is needed to clarify whether estrogens plays a role in melanoma.

High-Dose Estradiol-Replacement Therapy Enhances the Renal Vascular Response to Angiotensin II via an AT2-Receptor Dependent Mechanism.

Physiological levels of estrogen appear to enhance angiotensin type 2 receptor- (AT2R-) mediated vasodilatation. However, the effects of supraphysiological levels of estrogen, analogous to those achieved with high-dose estrogen replacement therapy in postmenopausal women, remain unknown. Therefore, we pretreated ovariectomized rats with a relatively high dose of estrogen (0.5 mg/kg/week) for two weeks. Subsequently, renal hemodynamic responses to intravenous angiotensin II (Ang II, 30–300 ng/kg/min) were tested under anesthesia, while renal perfusion pressure was held constant. The role of AT2R was examined by pretreating groups of rats with PD123319 or its vehicle. Renal blood flow (RBF) decreased in a dose-related manner in response to Ang II. Responses to Ang II were enhanced by pretreatment with estradiol. For example, at 300 ng kg−1 min−1, Ang II reduced RBF by 45.7 ± 1.9% in estradiol-treated rats but only by 27.3 ± 5.1% in vehicle-treated rats. Pretreatment with PD123319 blunted the response of RBF to Ang II in estradiol-treated rats, so that reductions in RBF were similar to those in rats not treated with estradiol. We conclude that supraphysiological levels of estrogen promote AT2R-mediated renal vasoconstriction. This mechanism could potentially contribute to the increased risk of cardiovascular disease associated with hormone replacement therapy using high-dose estrogen.

Seeing the Future: Epigenetic Biomarkers of Postpartum Depression

Postpartum depression (PPD) affects between 10 and 20% of women in the general population, but the risk is much higher in women with a history of major depression (MDD) or bipolar disorder (BP) with at least 30% developing PPD (Payne et al, 2007). There is evidence that women with a history of PPD are affectively susceptible to hormonal change: Bloch et al (2000) demonstrated that women with a history of PPD developed mood symptoms in response to a blinded withdrawal of supraphysiological levels of estrogen and progesterone compared to none of controls. We used a cross-species translational design to identify estrogen-mediated epigenetic changes associated with PPD (Guintivano et al, 2013). DNA methylation profiles were generated from whole blood using methylation microarrays in a sample of PPD high-risk women who were followed prospectively through pregnancy and after delivery. These profiles were cross-referenced with syntenic locations, which demonstrated murine hippocampal DNA methylation changes in response to long-term treatment with 17β-estradiol (E2). Initially, we investigated only DSM-4 defined PPD where women suffered a major depressive episode within 4 weeks of delivery. Using this group, we identified two biomarker loci at HP1BP3 and TTC9B, which predicted PPD with an area under the receiver operator characteristic curve (AUC) of 0.87. In a replication analysis, these biomarkers also functioned to segregate PPD status in women who developed depression during the antenatal period with 88% accuracy; however intriguingly, the prediction was in the opposite direction. There is controversy in the literature as to whether PPD as defined by DSM-4 is a unique entity from depression that begins during pregnancy and continues postpartum. In light of previous reports demonstrating depression-associated changes in white blood cell type compositions (Lutgendorf et al, 2008), we compared the two groups and found a decrease in the ratio of monocytes to lymphocytes and granulocytes in the antenatally depressed women that correlated with HP1BP3 DNA methylation status. Incorporation of cellular composition into the model enabled a prediction of PPD status with an AUC of 82% independent of antenatal depression status. Our results further suggested that there is an enhanced sensitivity to estrogen-based DNA methylation reprogramming in the hippocampus in those at risk for PPD, independent of antenatal depression status. Our findings are consistent with the hypotheses of hormone sensitivity-mediated PPD risk put forth by Bloch et al, as well as previous work implicating an increased sensitivity of the stress system with antenatal depression (Katz et al, 2012). As estrogen is closely tied to both the hypothalamic pituitary adrenal (HPA) axis as well as inflammation, it is conceivable that our findings represent a first step in unifying the disparate definitions of PPD into a common etiology of estrogen sensitivity and possibly a continuum of vulnerability to its downstream consequences. Whether our identified biomarkers represent a mere proxy of estrogen sensitivity or are involved in PPD pathophysiology will require further study. TTC9B may be linked to regulation of AMPA receptor levels, which in turn have been shown to be associated with resilience or vulnerability to stress (Schmidt et al, 2010). If the molecular changes exhibited by the biomarkers indicate a biological vulnerability, these may interact with stress occurring in the postnatal period and ultimately lead to depression. The use of animal models to either alter brain biomarker expression or to simulate hormone sensitivity differences may be used to test these mechanistic hypotheses. Further research will be needed to determine whether the identified biomarkers will display PPD predictive alterations at periods of low circulating estrogen in non-pregnant women; however, as high estrogen levels are a feature of normal pregnancy, these biomarkers are capable of early screening for PPD during pregnancy independent of whether they represent trait or state biological variation. In conclusion, we have identified biomarkers for postpartum mood status that correctly identify whether or not a woman will be depressed during the postpartum time period, regardless of whether or not she is depressed during pregnancy. Future work is needed to confirm these findings and to determine whether identification of women at risk will allow successful prevention of PPD.

Supraphysiological estrogen levels adversely impact proliferation and histone modification in human embryonic stem cells: possible implications for controlled ovarian hyperstimulation assisted pregnancy

Objective Controlled ovarian hyperstimulation (COH) results in supraphysiologic levels of maternal serum estradiol (E 2) during the luteal phase, thus promoting oocyte production at unknown risk to the subsequently developing embryo. Human embryonic stem cells (hESCs) have been identified as a model system to assess the impact of COH on early embryonic development, specifically 17β-estradiol mediated effects on proliferation, gene expression, and histone modification. Study design Cell proliferation and associated factors, such as HDAC1, as well as histone modification patterns were evaluated in ERα and β expressing hESCs after exposure to 17β-estradiol (1 × 10 −10 M to 1 × 10 −7 M), as well as in an untreated control. Results Resultant data revealed that while physiologically relevant E 2 levels (1 × 10 −9 M E 2) induced cell cycle progression from G1 to the proliferation phase, supraphysiologic levels akin to those observed after COH (1 × 10 −7 M E 2) adversely affected hESCs proliferation via down regulation of HDAC1. Modification of H3K9me2, PhH3S10, H4K5ac, and H2A.Z histone patterns were also dependent on 17β-estradiol concentration. Conclusion While physiologic levels of 17β-estradiol induced cell proliferation, possibly via HDAC1 involvement in histone modification, cell proliferation in hESCs was suppressed at supraphysiologic levels.

Impact of high levels of progesterone on α1-integrin distribution in the endometrium of patients with unexplained infertility

Irregular or low expression of integrins, which are cell adhesion molecules, may be associated with infertility. We conducted a prospective controlled study evaluating the effects of supraphysiological levels of estrogen and progesterone created by human menopausal gonadotropins (HMG) and progesterone support on alpha(1)-integrin immunolocalisation in the endometrium. Three groups were enrolled in the study. The first group of patients (group 1) had unexplained infertility and had been treated with HMG and progesterone (n=27). The second group of patients (group 2) was an untreated fertile group (n=24). The third group (group 3) consisted of patients who had unexplained infertility and had received no treatment (n=11). Endometrial biopsy specimens were taken from individuals from each group during the ovulation induction period. alpha(1)-integrin immunohistochemistry was performed. Serum estradiol and progesterone levels were also measured in parallel with histological dating of endometrial biopsies. Group 1 showed no statistical difference from group 2 in alpha(1)-integrin or histological dating. Group 3 showed less alpha(1)-integrin in the glandular epithelium in the secretory phase. We observed that alpha(1)-integrin was specific to the secretory phase. Its localization was denser in group 2 when compared with group 3, which supports the conclusion that alpha(1)-integrin may be a useful marker for luteal phase quality. Moreover, the supraphysiological estrogen and progesterone levels created by HMG and progesterone support may affect the alpha(1)-integrin in the endometrium in the secretory phase in the case of unexplained infertile patients.

Expression of complement system regulatory molecules in the endometrium of normal ovulatory and hyperstimulated women correlate with menstrual cycle phase

The present study describes the temporal expression of complement regulatory molecules membrane cofactor protein (MCP), decay accelerating factor (DAF), CR1, and CD59 in the human endometrium throughout the normal menstrual cycle and in patients submitted to ovarian hyperstimulation. During its proliferative phase, the endometrium expresses MCP, with increased expression during the secretory phase. Phase-dependent expression also was observed for DAF and CD59, mainly in the secretory phase. Expression of CR1 was not detected. These results suggest the presence of complement system activity during the menstrual cycle, with greater expression of regulatory molecules during the secretory phase to protect the epithelial integrity of human endometrium.

Aromatase Inhibitors in Infertility Treatment: Risks and Benefits

Ovulatory disorders (such as polycystic ovary syndrome [PCOS]) are commonly treated with clomiphene citrate (CC), with rates of ovulation ranging between 50 and 90%. However, even though the majority of pregnancies occur within the first three cycles of treatment [1], the overall pregnancy rates are disappointingly low, ranging from 20–40% [2–4], and the likelihood of miscarriage is relatively high [5]. This discrepancy between high rates of ovulation and low rates of pregnancy is believed to be a consequence of the antiestrogenic effect of CC on peripheral targets, such as the endometrium (affecting its thickness and maturation) and the endocervix (affecting the production and quality of cervical mucus). The problem is compounded by the long half-life of CC and the persistence of an isomer, zuclomiphene, both of which lead to an accumulating antiestrogenic effect with consecutive cycles of treatment [6]. In addition, due to the prolonged occupation of estrogen receptors by CC in the hypothalamus, the circulating amount of estrogen may rise to high levels from ongoing stimulation of the follicles by endogenous follicle-stimulating hormone (FSH) production. Such supraphysiological levels of estrogen may be deleterious to the developing oocyte, sperm and embryo [7]. Consequently, better methods for inducing ovulation are desirable. Studies in animals suggest that aromatase, an enzyme necessary to convert androgens to estrogen, could be a potential target for the inhibition of estrogen production. Aromatase inhibitors (AIs) increased gonadotropin levels and ovarian weight in female rats [8], and have been found to produce multiple ovarian follicles in female primates [9]. The new generation of AIs (anastrozole, letrozole and vorozole) have more specific action, fewer side effects and lower

The Effect of Estrogen on Ovine Anterior Cruciate Ligament Fibroblasts

Estrogen has been implicated as a causal factor for anterior cruciate ligament injuries in women. Studies have demonstrated a decrease in anterior cruciate ligament fibroblast proliferation and collagen synthesis at supraphysiologic levels of estrogen in a rabbit model. Hypothesis The authors hypothesized that physiologic levels of estrogen would have no significant effect on anterior cruciate ligament fibroblast proliferation and collagen synthesis in an ovine model. Methods Anterior cruciate ligament fibroblasts were isolated from sheep knees using routine cell culture methods. The cells were exposed to 17β-estradiol at physiologic concentrations of 2.2, 5, 15, 25, 250, and 2500 pg/ml. Cell proliferation was determined by cell counts on days 4 and 6. Collagen synthesis was determined by 3H-proline incorporation on day 4. Immunohistochemistry was performed to detect estrogen receptors. Results Immunohistochemistry demonstrated the presence of estrogen receptors in ovine anterior cruciate ligament fibroblasts. There was no significant difference in anterior cruciate ligament fibroblast proliferation or collagen synthesis regardless of 17β-estradiol concentration. Conclusions Based on results of this study, and given the low turnover of collagen in ligaments, it is unlikely that a 2- to 3-day per month increase in circulating estrogen would result in rapid, clinically significant alterations in material properties ofthe anterior cruciate ligament in vivo. The etiology of noncontact anterior cruciate ligament injuries is complex and multifactorial in nature, meriting further investigation.

Serum estradiol positively predicts outcomes in patients doing IVF

Objective: In contemporary practice of IVF, controlled ovarian hyperstimulation (COH), monitored by serum levels of estradiol and ultrasound imaging is nearly universally employed to maximize the probability of achieving an ongoing pregnancy. While COH recruits multiple follicles, resulting supraphysiologic levels of estrogen might also adversely affect endometrial receptivity. Thus, high estradiol levels during COH might be associated with favorable or unfavorable outcomes following IVF. We have studied the usefulness of the level of estradiol at the time of administration of hCG as an indicator of pregnancy outcome in both usual and good prognosis patients.

Is high-dose estrogen-induced osteogenesis in the mouse mediated by an estrogen receptor?

Although estrogen is known to induce new bone formation in the long bones of female mice, this response is only thought to occur following administration of high doses, suggesting that it may not be mediated by a conventional estrogen receptor. To address this question further, we first examined the stereospecificity of this response by comparing the potency of 17β-estradiol (E 2) in stimulating cancellous bone formation at the proximal tibial metaphysis of intact female mice with that of the relatively inactive stereoisomer, 17α-estradiol (αE 2). We found that E 2 was significantly more potent than αE 2, as assessed by histomorphometry. To provide further evidence for an estrogen-receptor-mediated process, we examined whether E 2-induced osteogenesis in intact female mice could be inhibited by the estrogen receptor antagonist, ICI 182,780 (ICI). Although ICI itself had no effect on histomorphometric indices of the proximal tibial metaphysis when given alone, it significantly inhibited the osteogenic response to E 2. Finally, we examined the dose dependency of E 2-induced osteogenesis at the proximal tibial metaphysis in intact mice. We found that E 2 stimulated cancellous bone formation in a dose-dependent manner over a wide dose range (i.e., 1–4000 μg/kg per day), with significant increases observed at doses of 4 μg/kg per day and beyond. Our results raise the possibility that estrogen-induced osteogenesis in the mouse represents an estrogen-receptor-mediated response that is not confined solely to supraphysiological estrogen levels.

Supraphysiological level of estrogen exposure in vivo increases lymphoid cell death in mice

Estrogen can enhance or reduce lymphocyte functions in vitro depending on dose and exposure duration. The purpose of this study was to determine the effect of in vivo 17β-estradiol (E2) on apoptosis and necrosis in lymphoid tissue of female C567BL/6 mice. Animals were ovariectomized (OVX), ovariectomized and 17β-estradiol supplemented (OVX+E2; 71 μg E2 per day for 14 days), sham ovariectomized (SHAM), or unhandled controls (CONTROL). Thymus and spleen were removed aseptically, cells dispersed into single cell suspensions in RPMI-1640, and measures of cell damage performed: an annexin V flow cytometric assay for markers of apoptosis and an enzyme-linked immunoassay for measures of DNA fragmentation and necrosis. OVX + E2 mice had 620 ± 72 pg/ml 17β-estradiol in serum in contrast to OVX mice which had 7.6 ± 5 pg/ml, the SHAM mice which had 2.8 ± 1 pg/ml of serum E2, and the CONTROL mice which had 3.9 ± 0.8 pg/ml of serum E2 ( p < 0.001). There was a significantly lower percentage of viable thymocytes in OVX+E2 mice compared to the other treatment conditions ( p < 0.001, respectively). There was also a significantly higher percentage of annexin V positive thymocytes in OVX+E2 mice ( p < 0.005). Measures of DNA fragmentation by ELISA were higher in splenocytes from OVX+E2 mice than in the OVX, SHAM or CONTROL mice ( p < 0.005). These results suggest that supraphysiological levels of estrogen in vivo induce damage in lymphoid cells; however, the impact of estrogen associated lymphoid tissue damage on specific immune functions remains to be determined.

Induced LH surges in the rhesus monkey: strength-duration characteristics of the estrogen stimulus.

The strength—duration characteristics of the increments in circulating estrogen required to elicit LH surges in the rhesus monkey were investigated by implanting (sc) Silastic capsules containing estradiol—17β for varying periods of time during the early follicular phase of the menstrual cycle. The magnitude of the resultant “square—wave” increments in serum estrogen concentration was varied by the number of capsules implanted. It was found that serum estrogen concentrations below 100 pg/ml were ineffective in eliciting LH surges, even when applied for as long as 120 hr. Serum estrogen concentrations of 100– 200 pg/ml had! to be maintained for approximately 42 hr to induce LH discharges, whereas 200–400 pg/ml were effective when applied for 36 hr. Supraphysiological estrogen levels of 1200 to 2000 pg/ml elicited LH surges when sustained for only 24 hr. In all instances, LH surges were initiated before the capsules were removed, showing that this response is not a consequence of estrogen withdrawal. The results further indicate that a stimulus, to be effective, must be applied until the response actually begins and that the initiation of the LH surge in the monkey does not appear to be synchronized with the diurnal light—dark cycle.(Endocrinology92: 1740, 1973)