Baseline Estradiol Research Articles

Effects of obesity on clinical outcomes in diminished ovarian reserve patients undergoing intracytoplasmic sperm injection cycles.

The aim of this study is to evaluate the effects of obesity on clinical outcomes in diminished ovarian reserve (DOR) patients undergoing intracytoplasmic sperm injection cycles. In this retrospective observational cross-sectional study, women admitted to current clinic with DOR undergoing intracytoplasmic sperm injection were divided into 2 groups according to the obesity. Patient age, body mass index, anti-mullerian hormone, baseline follicle stimulating hormone and baseline estradiol levels, antral follicle count, total gonadotropin dose, day of stimulation, number of mature (MII) oocytes, and clinical pregnancy were evaluated. There were no statistically significant differences between groups in terms of age, anti-mullerian hormone, baseline follicle stimulating hormone, baseline estradiol levels, antral follicle count, and clinical pregnancy (P > .05). Total gonadotropin dose, the days of ovarian stimulation were higher and number of MII oocyte were less in the obese group (P < .05). Logistic regression analyses also revealed that the days of ovarian stimulation and number of MII oocyte were significant factors in the study group. ROC curve analysis showed obesity is a negatively affecting factor in DOR patients. Obesity causes more gonadotropin dose longer days of stimulation, and less number of MII oocyte. However clinical pregnancy rate is not negatively affected by obesity according to the current study.

Abstract PS10-03: Impact of Baseline Oestradiol and Testosterone on the Preventive Effect of Anastrozole

Abstract It is well known that serum levels of oestradiol and testosterone, esp free hormone levels, influence the risk of developing breast cancer in postmenopausal women (Thomas et al 1997, Hankinson et al 1998, Kaaks et al 2005, Tin Tin et al 2021). However very little is known about how these hormone levels influence the effectiveness of aromatase inhibitors. In the IBIS-II Prevention Trial we compared anastrozole to placebo in 3864 women at high risk of breast cancer (Cuzick et al 2020). Of these women 3644 (94.3%) had a baseline blood sample. In those with a valid blood sample, 72 in the anastrozole arm and 142 in the placebo arm developed breast cancer (including DCIS) after 12.9 years of follow up (OR = 0.49, 95% CI 0.37–0.66 P&amp;lt; 0.0001). For each case two controls were selected, matched on age, treatment arm and follow up longer than the matching case. In these women oestradiol (E2), testosterone (Testo) and SHBG were measured by liquid chromatography – tandem mass spectroscopy, and E2/SHBG and Testo/SHBG ratios were computed to approximate free hormone levels, and analysed in quartiles. Hormone replacement therapy was not allowed during the trial, and women with use within 3 months prior to entry or outlier hormone values were excluded from these analyses. In the placebo arm higher levels of both of these ratios were associated with a higher breast cancer rate (OR per quartile 1.25 (1.04-1.59), P=0.018) for E2/SHBG and (OR per quartile 1.22 (1.02-1.47), P = 0.032) for Testo/SHBG), whereas no significant effect was seen in the anastrozole arm (OR = 1.05 (0.81-1.37), and 1.16 (0.90-1.49), resp) (Table). Neither treatment interaction was significant. Absolute numbers of cases were similar between the anastrozole and placebo arms in the lowest quartile of E2/SHBG (18 anastrozole, 22 placebo), but higher numbers were seen in the placebo arm for the other quartiles. Similar results were seen for testo/SHBG, and supportive, but weaker results were seen for these two hormones without an SHBG adjustment, SHBG and BMI at entry. Adjusting for other risk factors had no influence on these findings. Effect sizes were similar during the 5 year treatment period and thereafter. There were too few ER negative cases to compare results by receptor status. Vasomotor side effects were higher with increasing E2/SHBG levels in both arms, but no other hormone showed an effect, and no hormone level was significantly associated with gynaecologic or musculoskeletal side effects. As aromatase inhibitors effectively eliminate the production of oestradiol in postmenopausal women, these results suggest they may be more effective in postmenopausal women with high oestradiol or testosterone levels, and raise questions about their value in women in the lower quartile of serum levels for these hormones for prevention and possibly adjuvant treatment. Table: Risk of breast cancer by quartiles of the oestradiol/SHBG in ratio high risk women treated with anastrozole or placebo. Citation Format: Jack Cuzick, Kim Chu, Brian Keevil, Antony Howell, Bernardo Bonanni, Evans Gareth, Kaija Holli, Sibylle Loibl, Nicholas Zdenkowski, Steven Cummings, Mitch Dowsett. Impact of Baseline Oestradiol and Testosterone on the Preventive Effect of Anastrozole [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS10-03.

Abstract PO5-02-01: Concerning Discrepancies in Estradiol Levels in Premenopausal Women Receiving Abemaciclib and Ovarian Function Suppression

Abstract Background: Adjuvant abemaciclib in combination with endocrine therapy improves outcomes for patients with high-risk, hormone receptor-positive (HR+), HER2-negative early-stage breast cancer. In premenopausal women, the use of an aromatase inhibitor (AI) requires chemical or surgical ovarian function suppression (OFS). Our published case report of a premenopausal woman receiving adjuvant abemaciclib with elevated estradiol levels measured by the Abbott Alinity chemiluminescent microparticle immunoassay (CMIA) despite bilateral salpingo-oophorectomy (BSO) but low estradiol levels using liquid chromatography-mass spectrometry (LC-MS/MS) suggested an interference of abemaciclib with the immunoassay (PMID: 37124155). The aim of this study was to determine discrepancies in estradiol levels using CMIA compared to LC-MS/MS and subsequent treatment changes in a larger patient population. Methods: We conducted an IRB-approved retrospective review of premenopausal women with early-stage HR+ breast cancer treated with adjuvant OFS and abemaciclib at our institution from October 2021 to April 2023 who had at least 1 CMIA estradiol level drawn during abemaciclib therapy. Pathology, treatment plans, and lab data were abstracted from medical records. Postmenopausal estradiol levels were based on reference ranges of &amp;lt; 41 pg/mL using CMIA or &amp;lt; 15 pg/mL using LC-MS/MS. We utilized descriptive statistics to describe the population and management. Results: We identified 22 patients who met criteria for our review. The average age was 42.3 years, all had positive axillary nodes, 6 (27%) received neoadjuvant chemotherapy, and 15 (68%) received adjuvant chemotherapy. There were 14 (64%) patients who received leuprolide and 8 (36%) received goserelin, whereas 19 (86%) received AI and 3 (14%) received tamoxifen as their initial oral antiestrogen therapy. The majority of patients did not have baseline estradiol levels when starting OFS though after starting abemaciclib, 20 patients had CMIA estradiol levels in the premenopausal range, 9 of which had estradiol monitored by both CMIA and LC-MS/MS (Table 1). The average length of time from starting OFS to starting abemaciclib was 144.6 days with 1 patient switching from tamoxifen to OFS and AI after starting abemaciclib. Due to elevated CMIA estradiol, treatment changes included increased OFS dosage (5 patients), change of OFS (2 patients), and change to tamoxifen (3 patients). There were 6 patients who underwent BSO, 3 due to persistently elevated CMIA estradiol levels, 2 due to patient preference, and 1 due to a BRCA mutation. Following surgery, 2 patients had persistently elevated CMIA estradiol but low LC-MS/MS estradiol. The remainder of these patients did not have estradiol levels measured by CMIA. Conclusions: Our retrospective review demonstrated the likely interference of abemaciclib with the Abbott Alinity immunoassay as shown by 9 patients treated with OFS and abemaciclib with simultaneous premenopausal range CMIA estradiol levels and postmenopausal range LC-MS/MS estradiol levels. As up to 91% of patients in our study may have had a false positive estradiol level erroneously suggesting inadequate OFS, monitoring of estradiol levels using the CMIA assay in patients receiving adjuvant abemaciclib in addition to OFS could lead to changes in therapy that may be unnecessary. It is recommended that the LC-MS/MS assay be used when monitoring of estradiol levels is indicated in patients receiving abemaciclib concurrently with OFS. Table 1: Estradiol levels in patients receiving OFS and abemaciclib who had both CMIA and LC-MS/MS assays Citation Format: Alaina Kessler, Rima Patel, Emily Gallagher, Tianxiang Sheng, Damodara Rao Mendu, Amy Tiersten, Paula Klein, Aarti Bhardwaj, Anupama Goel, Joseph Sparano, Theresa Shao, Julie Fasano. Concerning Discrepancies in Estradiol Levels in Premenopausal Women Receiving Abemaciclib and Ovarian Function Suppression [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-02-01.

Abstract CT205: Neoadjuvant (Z)-endoxifen in premenopausal ER+, HER2- breast cancer: Evaluation of the first pharmacokinetic cohort of the EVANGELINE trial

Abstract Background: Ovarian function suppression (OFS) combined with tamoxifen (TAM) or an aromatase inhibitor (AI) is standard for premenopausal (PM) ER+, HER2- breast cancer (BC). However, &amp;gt; 40% PM patients (pts) are intolerant of OFS. For these pts, TAM is the only FDA approved option. In the neoadjuvant endocrine setting, pts with endocrine sensitive disease (ESD) (Ki-67 ≤ 10% at 4 weeks) have 5yr dDFS &amp;gt; 97%; however, only 45% of TAM pts vs &amp;gt;75% with AI+OFS achieve 4 wk ESD (Nitz JCO 2022). (Z)-endoxifen (ENDX) is a potent anti-estrogen superior to TAM and AI in xenograft models and with antitumor activity in endocrine-resistant postmenopausal pts. ENDX additionally targets protein kinase C beta 1 (PKCβ1) at concentrations &amp;gt;500 ng/mL, resulting in AKT inhibition and apoptosis (Jayaraman npj Breast Cancer 2023). We hypothesize that ENDX dual targeting of ERα and PKCβ1 will obviate the need for OFS and be non-inferior to AI plus OFS for PM pts with ER+/HER2- BC. Methods: EVANGELINE (NCT05607004) is an ongoing phase 2 multicenter neoadjuvant study with pharmacokinetic (PK) run-in assessing ENDX in PM women with ER+/HER2- BC. The primary objective for the PK run-in is to identify a dose (40 or 80 mg/day) resulting in ENDX steady state concentrations (Css) of 500-1000 ng/mL (to target both ERα and PKCβ1) without significant toxicity. Following PK run-in, the randomized phase II goal is to assess whether the ESD rate with ENDX is non-inferior to exemestane plus goserelin. Women with ESD at wk4 continue treatment for 24 weeks followed by surgery. Here we report the results from the 40 mg/day PK run-in. Results: Seven PM women (6 White, 1 Asian) aged 28-51 (median 46) received ENDX 40 mg/day. Pt characteristics on study were: ER &amp;gt; 90% (all pts), median Ki-67 = 13 (range 4-33%), cTstage (cT2: 6 pts, cT3: 1 pt), and tumor grade (G1: 1 pt, G2: 6 pts). The median ENDX 28 day Css (ng/mL) was 263.6 (range 180.3-376.6). One pt discontinued due to wk4 Ki-67 remaining &amp;gt; 10%. The remaining 6 had ESD, with either wk4 Ki-67 remaining ≤ 10% (3 pts) or decreasing to ≤ 10% (3 pts) and after 24 wks underwent surgery with surgical Ki-67 ≤ 3% (range 0-3%). MRI central review (wk12 and wk24) demonstrated target lesion decreases in all pts with 1 CR, 1 PR and 4 SD (RECIST). Treatment related toxicities included grade 3 headache (n=1), grade 2 amenorrhea (n=1), and grade 2 hot flashes (n=1). The median (range) baseline estrone (n=5) was 54 pg/mL (19-114) with median (range) fold increase from baseline of 9.0 (1.3-23.2) at wk4 and 4.7 (0.4 - 25.9) at wk24. The median baseline estradiol level (n=5) was 29 pg/mL (19-209) with median fold increases from baseline of 17.9 (0.4-57.0) at wk4 and 8.1 (0.04 - 56.6) at wk24. Additional surgical and blood biomarker data will be presented at the meeting. Conclusions: ENDX (40 mg/day) exhibits promising antitumor activity for PM ER+/HER2- BC but with ENDX Css below target. Enrollment is ongoing to the 80 mg/day dose level. Citation Format: Matthew P. Goetz, Vera J. Suman, Heather Fraser, Lida Mina, Pooja Advani, Roberto Leon-Ferre, Karthik Giridhar, Felipe Batalini, Katie N. Hunt, Swaathi Jayaraman, James Jakub, Patricia Cronin, Mara Piltin, Amy Degnim, James N. Ingle, Judy C. Boughey, Sarah Buhrow, Joel Reid, Matthew Schellenberg, John Hawse, Steven Quay. Neoadjuvant (Z)-endoxifen in premenopausal ER+, HER2- breast cancer: Evaluation of the first pharmacokinetic cohort of the EVANGELINE trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT205.

The association of menopausal hormone levels with progression-related biomarkers in multiple sclerosis

BackgroundMultiple sclerosis (MS) progression coincides temporally with menopause. However, it remains unclear whether the changes in disease course are related to the changes in reproductive hormone concentrations. We assessed the association of menopausal hormonal levels with progression-related biomarkers of MS and evaluated the changes in serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels during menopausal hormone therapy (MHT) in a prospective baseline-controlled design. MethodsThe baseline serum estradiol, follicle stimulating hormone, and luteinizing hormone levels were measured from menopausal women with MS (n = 16) and healthy controls (HC, n = 15). SNfL and sGFAP were measured by single-molecule array. The associations of hormone levels with sNfL and sGFAP, and with Expanded Disability Status Scale (EDSS) and lesion load and whole brain volumes (WBV) in MRI were analyzed with Spearman's rank correlation and age-adjusted linear regression model. Changes in sNfL and sGFAP during one-year treatment with estradiol hemihydrate combined with cyclic dydrogesterone were assessed with Wilcoxon Signed Ranks Test. ResultsIn MS group, baseline estradiol had a positive correlation with WBV in MRI and an inverse correlation with lesion load, sNfL and sGFAP, but no correlation with EDSS. The associations of low estradiol with high sGFAP and low WBV were independent of age. During MHT, there was no significant change in sNfL and sGFAP levels in MS group while in HC, sGFAP slightly decreased at three months but returned to baseline at 12 months. ConclusionOur preliminary findings suggest that low estradiol in menopausal women with MS has an age-independent association with more pronounced brain atrophy and higher sGFAP and thus advanced astrogliosis which could partially explain the more rapid progression of MS after menopause. One year of MHT did not alter the sGFAP or sNfL levels in women with MS.

Effect of baseline oestradiol serum concentration on the efficacy of anastrozole for preventing breast cancer in postmenopausal women at high risk: a case-control study of the IBIS-II prevention trial

An increased risk of breast cancer is associated with high serum concentrations of oestradiol and testosterone in postmenopausal women, but little is known about how these hormones affect response to endocrine therapy for breast cancer prevention or treatment. We aimed to assess the effects of serum oestradiol and testosterone concentrations on the efficacy of the aromatase inhibitor anastrozole for the prevention of breast cancer in postmenopausal women at high risk. In this case-control study we used data from the IBIS-II prevention trial, a randomised, controlled, double-blind trial in postmenopausal women aged 40-70 years at high risk of breast cancer, conducted in 153 breast cancer treatment centres across 18 countries. In the trial, women were randomly assigned (1:1) to receive anastrozole (1 mg/day, orally) or placebo daily for 5 years. In this pre-planned case-control study, the primary analysis was the effect of the baseline oestradiol to sex hormone binding globulin (SHBG) ratio (oestradiol-SHBG ratio) on the development of all breast cancers, including ductal carcinoma in situ (the primary endpoint in the trial). Cases were participants in whom breast cancer was reported after trial entry and until the cutoff on Oct 22, 2019, and who had valid blood samples and no use of hormone replacement therapy within 3 months of trial entry or during the trial. For each case, two controls without breast cancer were selected at random, matched on treatment group, age (within 2 years), and follow-up time (at least that of the matching case). For each treatment group, we applied a multinominal logistic regression likelihood-ratio trend test to assess what change in the proportion of cases was associated with a one-quartile change in hormone ratio. Controls were used only to determine quartile cutoffs. Profile likelihood 95% CIs were used to indicate the precision of estimates. A secondary analysis also investigated the effect of the baseline testosterone-SHBG ratio on breast cancer development. We also assessed relative benefit of anastrozole versus placebo (calculated as 1 - the ratio of breast cancer cases in the anastrozole group to cases in the placebo group). The trial was registered with ISRCTN (number ISRCTN31488319) and completed recruitment on Jan 31, 2012, but long-term follow-up is ongoing. 3864 women were recruited into the trial between Feb 2, 2003, and Jan 31, 2012, and randomly assigned to receive anastrozole (n=1920) or placebo (n=1944). Median follow-up time was 131 months (IQR 106-156), during which 85 (4·4%) cases of breast cancer in the anastrozole group and 165 (8·5%) in the placebo group were identified. No data on gender, race, or ethnicity were collected. After exclusions, the case-control study included 212 participants from the anastrozole group (72 cases, 140 controls) and 416 from the placebo group (142 cases, 274 controls). A trend of increasing breast cancer risk with increasing oestradiol-SHBG ratio was found in the placebo group (trend per quartile 1·25 [95% CI 1·08 to 1·45], p=0·0033), but not in the anastrozole group (1·06 [0·86 to 1·30], p=0·60). A weaker effect was seen for the testosterone-SHBG ratio in the placebo group (trend 1·21 [1·05 to 1·41], p=0·011), but again not in the anastrozole group (trend 1·18 [0·96 to 1·46], p=0·11). A relative benefit of anastrozole was seen in quartile 2 (0·55 [95% CI 0·13 to 0·78]), quartile 3 (0·54 [0·22 to 0·74], and quartile 4 (0·56 [0·23 to 0·76]) of oestradiol-SHBG ratio, but not in quartile 1 (0·18 [-0·60 to 0·59]). These results suggest that serum hormones should be measured more routinely and integrated into risk management decisions. Measuring serum hormone concentrations is inexpensive and might help clinicians differentiate which women will benefit most from an aromatase inhibitor. Cancer Research UK, National Health and Medical Research Council (Australia), Breast Cancer Research Foundation, and DaCosta Fund.

Sex- and age-based comparison of serum immunoglobulins following liver transplantation

BackgroundOver a quarter of organ transplant recipients have low immunoglobulin levels in their early post-transplant course, which is associated with increased risk of infection and mortality. Although immunoglobulin level varies by sex among healthy individuals, it is unknown how such differences are affected by transplant-related immunosuppression. This study compared post-liver transplant immunoglobulin G (IgG) between sexes at varying ages. MethodsSerum specimens from a prospective cohort of 130 liver transplant recipients were analyzed. IgG was measured at time of transplant and from one-month post-transplant samples. Post-transplant IgG was compared between sexes using multivariable linear regression. Four age and sex categories were created (women<50, women≥50, men<50, men≥50) and the model repeated with this as the explanatory variable. The relationship between sex hormone concentrations and post-transplant IgG was also explored. Infection type and incidence were examined within groups. ResultsThe cohort included 99 men, 31 women (mean age 53). In adjusted linear regression, post-transplant IgG was not significantly different by sex (p = 0.92). However, when broken into four categories by age and sex, the contrast in IgG levels between younger versus older patients was strikingly greater among women than among men. An interaction term including age and sex was statistically significant (p = 0.03). The combined age-sex categorical variable was also significantly associated with post-transplant IgG (p = 0.01). Finally, an association was identified between baseline estradiol level and post-transplant change in IgG (p = 0.04). ConclusionsSex and age have an important relationship with post-transplant IgG with older women demonstrating lowest concentrations. Immunoglobulin levels have previously demonstrated association with post-transplant outcomes.

Abstract GS4-08: 10-year results of a phase 3 trial of low-dose tamoxifen in non-invasive breast cancer

Abstract We have previously shown in a phase 3 trial that tamoxifen 5 mg/day for 3 years decreased by 52% the incidence of recurrence of invasive breast cancer or DCIS after a median follow-up of 5.1 years in women with excised non invasive breast disease, including atypical ductal hyperplasia, DCIS or LCIS (DeCensi et al. JCO 2019; 37:1629). Toxicity was negligible with only an extra hot flash per day in the tamoxifen arm compared with the placebo arm. These findings were incorporated into the ASCO clinical practice guidelines for breast cancer risk reduction as an alternative option to standard doses and duration of tamoxifen or aromatase inhibitors in women with non-invasive disease (Visvanathan et al. JCO 2019; 37:3152). In the present study we update the findings on breast cancer recurrence after a median of 9.14 years (interquartile range, IQR, 7.16-10.73) and a total of 10.57 person years of follow up to see if the treatment effect is retained with more events and after a median of approximately 6 years from treatment cessation. We conducted a national multicenter randomized trial of tamoxifen, 5 mg/d or placebo administered for 3 years after surgery in women with hormone-sensitive or unknown breast intraepithelial neoplasia, including atypical ductal hyperplasia and lobular or ductal carcinoma in situ. The primary end point was the incidence of invasive breast cancer or ductal carcinoma in situ. Between November 1, 2008, and March 31, 2015, 1,160 women were screened and 500 aged 75 years of age or younger were included in the study. Women with high-grade or comedo/necrotic DCIS received adjuvant radiotherapy of 50 Gy in 25 courses. The mean age was 54 years (standard deviation, 9 years), and 55% of participants were postmenopausal. The mean (SD) body mass index, kg/m2, was 25.7 (4.8) on tamoxifen and 25.3 (4.2) on placebo. Twenty percent had ADH, 11% had LCIS, and the remaining 69% had DCIS. After a median follow-up of 9.14 years, there were 22 neoplastic events (invasive breast cancer or DCIS) with tamoxifen and 37 with placebo (annual rate 11.09, 95% CI, 7-30-16.84 on T vs 19.71, 95% CI, 14.28-27.21 on P per 1,000 person-years; hazard ratio, 0.56; 95% CI, 0.33 to 0.95; P = .03), which resulted in a 5-year number needed to treat of 18. Overall, 71% of the recurrences were invasive breast cancer. The follow-up was updated with the most recent visit within 12 months in two thirds of the participants, so an update of all participants will be performed by Sept 30th with full analysis of neoplastic events, annual risk rate ratio, serious adverse events and deaths. Moreover, an updated analysis of potential effect modifiers will be conducted, including menopausal status, baseline estradiol levels, menopausal symptoms, BMI, smoking status and Ki-67 of the primary lesion. In conclusion, our findings indicate that low dose tamoxifen given for 3 years still significantly prevents recurrences from non-invasive breast cancer after a median of 6 years from treatment cessation, providing a valid prevention/interception option in this disease group. Supported by Ente Ospedaliero Ospedali Galliera, Genova, Italy, the Italian Ministry of Health (RFPS-2006-1-339898), the Italian Association for Cancer Research (IG 2008 Grant No. 5611), and the Italian League against Cancer (LILT 7-08). Citation Format: Andrea De Censi, Matteo Lazzeroni, Matteo Puntoni, Luca Boni, Aliana Guerrieri Gonzaga, Tania Buttiron Webber, Marianna Fava, Irene Maria Briata, Livia Giordano, Maria Digennaro, Laura Cortesi, Fabio Falcini, Franca Avino, Francesco Millo, Katia Cagossi, Elisa Gallerani, Alessia De Simone, Anna Cariello, Giuseppe Aprile, Maria Renne, Bernardo Bonanni. 10-year results of a phase 3 trial of low-dose tamoxifen in non-invasive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-08.

Serum estradiol levels decrease after oophorectomy in transmasculine individuals on testosterone therapy.

Transmasculine individuals, considering whether to undergo total hysterectomy with bilateral salpingectomy, have the option to have a concomitant oophorectomy. While studies have evaluated hormone changes following testosterone therapy initiation, most of those patients have not undergone oophorectomy. Data are currently limited to support health outcomes regarding the decision to retain or remove the ovaries. We performed a retrospective chart review of transmasculine patients maintained on high-dose testosterone therapy at a single endocrine clinic in Vancouver, British Columbia, Canada. Twelve transmasculine individuals who underwent bilateral oophorectomy and had presurgical and postsurgical serum data were included. We identified 12 transmasculine subjects as controls, who were on testosterone therapy and did not undergo oophorectomy, but additionally matched to the first group by age, testosterone dosing regimen, and body mass index. There was a statistically significant decrease in the estradiol levels of case subjects postoophorectomy, when compared to presurgical estradiol levels (P = 0.02). There was no significant difference between baseline estradiol levels between control and case subjects; however, the difference in estradiol levels at follow-up measurements was significant (P = 0.03). Total testosterone levels did not differ between control and case subjects at baseline and follow-up (both P > 0.05). Our results demonstrate that oophorectomy further attenuates estradiol levels below what is achieved by high-dose exogenous testosterone alone. Correlated clinical outcomes, such as impacts on bone health, were not available. The clinical implications of oophorectomy versus ovarian retention on endocrinological and overall health outcomes are currently limited.

Accelerated forgetting of a trauma-like event in healthy men and women after a single dose of hydrocortisone

Posttraumatic stress disorder (PTSD) is characterised by dysregulated hypothalamic-pituitary-adrenal axis activity and altered glucocorticoid receptor sensitivity. Early treatment with glucocorticoids may reduce PTSD risk, although the effect of such treatment on the aetiologically critical step of traumatic-memory-formation remains unclear. Here we examine the effects of exogenous cortisol (hydrocortisone) in a preclinical model of PTSD, using a factorial (Drug × Sex), randomised-controlled, double-blind design. Healthy men and women (n = 120) were randomised to receive 30 mg oral hydrocortisone or matched placebo immediately after watching a stressful film. Effects on film-related intrusions were assessed acutely in the lab, and ecologically using daily memory diaries for one week. We found that participants receiving hydrocortisone showed a faster reduction in daily intrusion frequency. Voluntary memory was assessed once, at the end of the week, but was unaffected by hydrocortisone. Exploratory analyses indicated sex-dependent associations between intrusions and baseline estradiol and progesterone levels. In men receiving hydrocortisone, higher baseline estradiol levels were associated with fewer intrusions, whereas women exhibited the opposite pattern. By contrast, progesterone levels were positively associated with intrusions only in men treated with hydrocortisone. The findings suggest that hydrocortisone promotes an accelerated degradation of sensory-perceptual representations underlying traumatic intrusive memories. In addition, while sex alone was not an important moderator, the combination of sex and sex-hormone levels (especially estradiol) influenced hydrocortisone’s effects on involuntary aversive memories. Future well-powered experimental studies may provide a basis for a precision-psychiatry approach to optimising early post-traumatic glucocorticoid treatments that target intrusive memories, based on individual endocrinological profiles.

Ovarian response to follicle-stimulating hormone in women with polycystic ovary syndrome is diminished compared to ovulatory controls.

The mechanisms underlying ovarian dysfunction in polycystic ovary syndrome (PCOS) have not been definitively established. Our objective was to perform a detailed examination of ovarian responses to recombinant follicle-stimulating hormone (rFSH) in women with PCOS and controls. This prospective, crossover, dose-response study included three rFSH stimulation periods. Each stimulation period involved three consecutive, daily, subcutaneous injections of rFSH administered at a single dose. Low, medium and high rFSH doses were weight-adjusted, corresponding to 0.5, 1.1 and 2.2 IU/kg/d, respectively. Stimulation periods occurred in randomized order and were separated by 8-week washouts. Thirty participants (8 PCOS and 22 controls) were studied. PCOS was defined by oligomenorrhea and clinical or biochemical androgen excess, excluding other aetiologies of ovulatory dysfunction. Blood samples were obtained for hormone measurements before and 24 h after each rFSH injection. Participants with PCOS had significantly greater body mass index, antral follicle count and circulating testosterone, anti-mullerian hormone (AMH)and luteinizing hormone concentrations compared with controls participants. Baseline estradiol (E2) concentrations were similar in both groups. At the lowest dose of rFSH, PCOS participants did not demonstrate E2 increments, whereas a significant increase occurred in controls. rFSH-induced E2 production per follicle was significantly reduced in PCOS participants compared with controls at all rFSH doses. Increasing T and decreasing AMH concentrations were associated with augmented E2 production per follicle. Women with PCOS exhibited diminished initial E2 responses to rFSH compared with controls. These findings suggest that the mechanism of anovulation in PCOS may involve altered ovarian response to gonadotropins.

Relationship between reproductive hormones and migration distance in a polygynous songbird, the Red-winged Blackbird (Agelaius phoeniceus)

Many bird species migrate to southern overwintering locations to avoid harsh conditions at their breeding grounds, but at the cost of an energetically demanding migration that may delay their spring reproductive development. Previous work on the relationship between migration distance and reproductive readiness has primarily focused on early season baseline testosterone in both males and females. However, for females, testosterone alone may not be the appropriate measurement of reproductive development. Estradiol, a metabolite of testosterone that is essential for breeding behaviors and reproduction, should also be measured. Furthermore, baseline testosterone varies throughout the day and may change due to social interactions that occurred prior to sampling. Injection of gonadotropin-releasing hormone (GnRH) elicits an individual’s maximum potential testosterone production, minimizing daily and social variation. We explored relationships between migration distance and reproductive status after arrival to the breeding ground in Red-winged Blackbirds (Agelaius phoeniceus). We predicted that individuals that travel a shorter distance will have higher levels of reproductive hormones upon arrival given they are able to invest less in migration and more in reproduction. This is important because individuals that breed earlier often have higher reproductive success. In females, we measured baseline estradiol and testosterone. In males, we assessed baseline and GnRH-induced testosterone. Hormone values were related to migration distance, estimated by stable isotope analysis of claw samples collected before breeding began in eastern North Dakota. We found that males with shorter inferred migration distances have higher baseline testosterone upon arrival. However, inferred migration distance was not correlated with GnRH-induced testosterone. Female inferred migration distance was not correlated with baseline testosterone, but it was correlated with baseline estradiol. Females with higher testosterone had lower estradiol, suggesting that testosterone in females is not a reliable indicator of estradiol levels, thus readiness to breed. Our observations suggest that baseline hormone levels were related to migration distance, but baseline testosterone alone may not provide a complete assessment of a male or female’s preparedness to breed following spring migration.

Assessment of Gonadotropin Concentrations Stimulated by Gonadotropin-Releasing Hormone Analog by Electrochemiluminescence in Girls with Precocious Puberty and Premature Thelarche

Objective: The aim of this study is to determine the cutoff values of gonadotropin response to gonadotropin-releasing hormone analogs (GnRHas) corresponding to the activation of the hypothalamic-pituitary-gonadal axis that could differentiate central precocious puberty (CPP) from premature thelarche (PT) and using the electrochemiluminescence assay method. Methods: A total of 49 girls underwent the stimulation test with an intramuscular injection of 3.75 mg leuprolide acetate. Based on the clinical and laboratory characteristics, they were divided into two groups: CPP (n = 22) and PT (n = 27). Baseline estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were collected before GnRHa administration and LH and FSH at 60 and 120 min, respectively, after GnRHa administration. Results: The girls with CPP presented an increased height Z-score, advanced bone age, and higher baseline LH, FSH, estradiol, and LH/FSH ratio in relation to PT (p < 0.001). Stimulated LH differed significantly between the two groups, and the LH cutoff values were ≥4.29 IU/L (p < 0.001) and ≥3.95 IU/L at 60 and 120 min, respectively (p < 0.001). The LH peak was found at 60 min after stimulation. Conclusions: The GnRHa test is effective in distinguishing CPP from PT, and a single sampling, at 60 min, with LH concentrations above 4.29 may be the parameter of choice with the advantage of greater convenience and practicality.

Testosterone and Estradiol as Novel Prognostic Indicators for HBV-Related Acute-on-Chronic Liver Failure.

Background: HBV-related acute-on-chronic liver failure (HBV-ACLF) has a high short-term mortality and urgently needs an early warning system with simplicity and high accuracy. Previous studies show that sex hormones play potential roles in the progression of HBV-related liver diseases.Aims: To explore the effect of testosterone and estradiol on the occurrence and prognosis of HBV-ACLF.Methods: A prospective cohort of 300 chronic hepatitis B (CHB) patients was enrolled among which 108 were diagnosed with HBV-ACLF at admission and 20 developed to HBV-ACLF during hospitalization. We compared the level of serum testosterone and estradiol of patients with varied ACLF background, disease severity and cirrhosis conditions and analyzed the predictive ability of short-term prognosis. A novel prognostic model involving testosterone was developed and further validated in the HBV-ACLF group.Results: The baseline estradiol level of HBV-ACLF group was significantly higher while testosterone was lower than that of non-ACLF group. The estradiol level increased while the testosterone level decreased as the number of organ failures increased. Testosterone had high accuracy in predicting the short-term mortality in HBV-ACLF (AUROC = 0.726) and estradiol did better in predicting the occurrence of ACLF during hospitalization (AUROC = 0.695). The novel prognostic model involving testosterone (TATIM model) was proved to have considerable prediction efficiency in HBV-ACLF cohort with or without cirrhosis.Conclusion: Testosterone could be utilized as short-term prognostic indicator for HBV-related ACLF and estradiol can help to predict its occurrence. TATIM model is a novel prognostic model for HBV-related ACLF with simplicity and good performance irrespectively of liver cirrhosis.Clinical Trial Registration Number: This study was based on a sub-cohort from the prospective multicenter cohort (NCT02457637).

A History of Endometriosis Is Associated With Decreased Peripheral NK Cytotoxicity and Increased Infiltration of Uterine CD68+ Macrophages.

Women with endometriosis may have a defective immune system. However, evidence of the immune responses of endometriosis patients with a history of endometriosis surgery is lacking, and the association between the location of endometriosis lesions and immune responses is unclear. This retrospective study included 117 females with reproductive failure and a history of endometriosis and 200 females with reproductive failure but without endometriosis to analyze their endometrial and peripheral immune responses. The results show that endometriosis was associated with decreased peripheral natural killer (NK) cytotoxicity and increased uterine macrophages. Peripheral NK cytotoxicity at effector-to-target ratios of 25:1 and 50:1 was significantly reduced in women with a history of endometriosis from that of the control group (26.6% versus 33.3% and 36.1% versus 43.3%, respectively, both P < 0.001). Furthermore, after further division of patients into three subgroups according to the location of endometriosis lesions, we observed that NK cytotoxicity in the endometriosis subgroups, especially the mixed endometriosis group, was strongly decreased from that of the controls (P = 0.001). The endometrial CD68+ macrophage proportion in the mixed endometriosis subgroup was higher than that in the control group (2.8% versus 2.1%, P = 0.043). In addition, the baseline estradiol (E2) level was weakly correlated with the percentage of endometrial macrophages (r = 0.251, P = 0.009), indicating a potential association among the endocrine system, endometrial immune environment, and endometriosis. This study indicated that peripheral NK cytotoxicity and endometrial immune cell profiles could be useful for diagnosing and treating endometriosis and endometriosis-related reproductive diseases.

Blastocyst Transfer: A Risk Factor for Gestational Diabetes Mellitus in Women Undergoing In Vitro Fertilization.

BackgroundThe risk of developing gestational diabetes mellitus (GDM) is higher in women undergoing assisted reproductive treatment than in women conceiving spontaneously.ObjectivesTo determine whether the GDM risk after day-3 embryo transfer differs from the GDM risk after day-5 blastocyst transfer.MethodsProspective observational study in women becoming pregnant after first fresh embryo or blastocyst transfer.ResultsA total of 1579 women got pregnant and had live birth; 1300 women got day-3 embryo transfer only, whereas 279 women received at least 1 blastocyst. Of 1579 women, 252 developed GDM. Age, body mass index, baseline estradiol, baseline high-density lipoprotein, and progesterone on the day of human chorionic gonadotropin injection were not different in women receiving day-3 embryos only vs women receiving at least 1 blastocyst. The number and quality of retrieved oocytes were not different in women receiving day-3 embryo transfer from those receiving blastocysts. Our study confirmed already established GDM risk factors such as age and body mass index, baseline estradiol, and high-density lipoprotein, as well as progesterone after ovarian stimulation. We furthermore demonstrate that the GDM incidence in women receiving day-5 blastocyst transfer was significantly higher than those who received day-3 embryo transfer (21.15% vs 14.85%; P = 0.009). Considering confounding factors, we likewise saw that blastocyst transfer was an independent procedure-related GDM risk factor [P = 0.009, Exp (B): 1.56, 95% CI: 1.12-2.18].ConclusionBlastocyst transfer after in vitro fertilization/intracytoplasmic sperm injection increases the risk of developing GDM.

P–695 Establishing predictors of the mode of conception in fertility patients presenting with a clinical pregnancy

Abstract Study question What are the predictors for pregnancies conceived spontaneously (SC), by ovulation induction+/-insemination (OI±IUI) or via In-Vitro Fertilization(IVF), and what proportion of pregnancies were conceived with each method? Summary answer Pregnancies were conceived by SC(27.7%), OI±IUI(33%) or IVF(39.2%).Unexplained infertility positively-predicted SC and OI±IUI-conceptions. Male factor-infertility demonstrated the opposite trend, positively predicting IVF. Endometriosis negatively-predicted SC. What is known already Spontaneous conception (SC) occurs regularly among infertility patients. Most studies have evaluated predictors of pregnancy among women with infertility who were trying to conceive. Few studies have addressed the role of different factors on the mode of conception in infertility patients who were pregnant. Factors found in some studies to be related with a SC were younger female age, shorter duration of infertility, fewer failed IVF cycles, and diagnosis of unexplained-infertility. Study design, size, duration We conducted a retrospective cohort study at a University fertility-center over a six-month period in 2019 and 2020. We reviewed viability scans of 285-patients. Mode of conception was recorded as Spontaneous, OI±IUI, or IVF. Patients’ demographics, obstetric and fertility diagnosis as well as base-line hormones and ovarian reserve testing were extracted to calculate predictors for the mode of conception. Pregnancy was defined as an intra-uterine fetal sac on a transvaginal ultrasound in the 1st-trimester. Participants/materials, setting, methods Parametric analysis was done using ANOVA and Tukey’s post-hoc test. Nonparametric analysis was performed using the chi-square test. Predictors of the mode of conception were calculated by multivariate regression analysis using the variables not in the equation model including the following parameters: male and female age, gravidity, parity, ectopic-pregnancies, infertility diagnosis, baseline serum: FSH, estradiol, TSH, AMH, and AFC. Data is presented as mean ±SD or percentage. P &amp;lt; 0.05 was significant. IRB approval was obtained. Main results and the role of chance 79 (27.7%) of pregnancies were SC, 94 (33%) resulted from OI±IUI, and 112 (39.2%) from IVF. Demographics didn’t differ between the groups including: female age(p = 0.06), male age(p = 0.79), gravidity (p = 0.47), parity(p = 0.7), ectopic-pregnancies(p = 0.07), baseline serum FSH(p = 0.29), estradiol(p = 0.65), TSH(p = 0.56), AMH(p = 0.42), and AFC(p = 0.06). Infertility diagnoses differed when comparing SC, OI±IUI and IVF conceptions respectively: Unexplained (22.7%, 22.3%, 15.1%, p = 0.03), Male-Factor(MF) (25%, 27.6%, 42.8%, p = 0.042), Tubal-factor (2.5%, 2.1%, 13.4, p = 0.002) and Ovulation-disorders/PCOS (24%, 32%, 12.5% p = 0.002). Endometriosis trended higher in women with IVF (p = 0.09). A positive predictor for SC was unexplained infertility(p = 0.0001). A negative predictor was endometriosis(p = 0.005). SC was sub-significantly less likely in the presence of MF (p = 0.057). Unexplained-infertility was a positive predictor for OI±IUI pregnancies(p = 0.047), whereas MF was a negative predictor(p = 0.0001). As for IVF-conceptions, MF was a positive predictor(p = 0.008), while unexplained-infertility negatively predicted conception by IVF(p = 0.018). Ovulation-disorders/PCOS trended lower in women with IVF (p = 0.052). While baseline serum estradiol levels were similar between groups (means 194–218pmol/L), multivariate regression showed it to be a predictor for OI±IUI and IVF conceptions. The clinical significance of this finding is not clear. Interestingly, female age and ovarian reserve were not found to predict one type of conception over another. Other possible predictors in the model were not significant. Limitations, reasons for caution This retrospective cohort may hide underlying bias. Clinical pregnancies were evaluated and not live birth. Our cohort represents patients that conceived and do not offer information about the entire sub-fertile population that is treated in our center, which is also a strength as it’s a novel way of evaluating predictors. Wider implications of the findings: Among patients that conceived spontaneously, advanced age and ovarian reserve did not play a negative role. Predictors of pregnancy were confirmed as expected with the majority of unexplained infertility conceptions occurring spontaneously or with OI+/-IUI, patients with Male factor infertility often conceived by IVF, and ovulation disorders by OI+/-IUI. Trial registration number NA

Endocrinological effects of social exclusion and inclusion: Experimental evidence for adaptive regulation of female fecundity

When current conditions are probabilistically less suitable for successful reproduction than future conditions, females may prevent or delay reproduction until conditions improve. Throughout human evolution, social support was likely crucial to female reproductive success. Women may thus have evolved fertility regulation systems sensitive to cues from the social environment. However, current understanding of how psychological phenomena might affect female ovarian function is limited. In this study, we examined whether cues of reduced social support—social ostracism—impact women's hormone production. Following an in-lab group bonding task, women were randomly assigned to a social exclusion (n = 88) or social inclusion (n = 81) condition. After social exclusion, women with low background levels of social support experienced a decrease in estradiol relative to progesterone. In contrast, socially-included women with low background social support experienced an increase in estradiol relative to progesterone. Hormonal changes in both conditions occurred specifically when women were in their mid-to-late follicular phase, when baseline estradiol is high and progesterone is low. Follow-up analyses revealed that these changes were primarily driven by changes in progesterone, consistent with existing evidence for disruption of ovarian function following adrenal release of follicular-phase progesterone. Results offer support for a potential mechanism by which fecundity could respond adaptively to the loss or lack of social support.

The Role of Endocrine Stress Systems and Sex Hormones in the Enhancing Effects of Stress on Mental Rotation Capabilities

The possible effects of stress and neurobiological stress mechanisms on visuospatial abilities remain largely unknown. In the current study, we examined the combined effect of sex hormones and both the hypothalamic–pituitary–adrenal axis (HPA-A) and the sympathetic nervous system (SNS) on stress-induced changes in visuospatial performance. A total of 107 participants completed a mental rotation task and were subsequently exposed to either to the Trier social stress test (TSST) or to a control condition before completing the mental rotation task again. HPA-A and SNS reactivity of the participants were evaluated by measuring salivary alpha amylase (sAA; an SNS activation marker) and cortisol in four saliva samples. Pre-stress levels of sex hormones (progesterone, estradiol, and testosterone) were also measured. The TSST enhanced mental rotation performance, and this enhancement was negatively correlated with baseline estradiol levels and positively correlated with the level of cortisol reactivity among men. In addition, controlling for baseline levels of testosterone, estradiol, and progesterone diminished this effect of stress. These results imply that the stress-induced facilitation of mental rotation performance is modulated by baseline sex hormones and provide preliminary support to the notion that a complex interaction between sex hormones and neuroendocrine stress mechanisms mediates the influence of stress on visuospatial performance.

Effect of porcine placental extract on menopausal symptoms in postmenopausal women: A prospective, randomized, double-blind, placebo-controlled trial

ObjectivesTo determine the effect of oral administration of porcine placental extract (PPE) on the menopausal symptoms of Korean women. Materials and methodsThis study was a multicenter, randomized double-blind placebo-controlled trial. A hundred menopausal Korean women were randomly allocated either to the PPE 400 mg per day or the control group during 12 weeks of the study period. Menopausal symptoms were evaluated using the Kupperman Index (KMI). ResultsThe KMI decreased after 12 weeks in both groups; however, the difference in the changes was not statistically significant. Among overweight or obese women whose body mass index (BMI) was 23 kg/m2 or higher, the KMI decreased more significantly in the PPE group than placebo group after 12 weeks (−18.52 ± 9.09 vs −11.40 ± 10.68, P < 0.05). Among 49 early menopausal women whose duration of menopause was less than 3 years, the KMI decreased more significantly in the PPE group after 12 weeks (−17.29 ± 9.07 vs −11.29 ± 10.68, P < 0.05). The baseline estradiol level was not statistically different between the two groups before trial, but the estradiol level of the PPE group was significantly increased at 12 weeks (11.13 ± 35.13 pg/m, P < 0.05). ConclusionsOral administration of 400 mg PPE per day decreases menopausal symptoms in women with BMI 23 kg/m2 or higher or in early menopausal women. PPE may be considered as a short-term complementary treatment to reduce menopausal symptoms, especially in overweight or early menopausal women.