Premenopausal women recover from COVID-19 disease better than postmenopausal women: the Role of DHEA-S

Objectives: We aimed to demonstrate the difference between the premenopausal and postmenopausal women in respect of the clinical course and outcome of the Covid-19 disease. In addition, we investigated the epidemiological and hormonal factors which may have an influence on the progression, severity and mortality of the disease. Study design: A cross-sectional study. Main Outcome Measure(s): Our primary outcome was to demonstrate the poor clinical course and outcome of the Covid-19 disease in the postmenopausal women. Our secondary outcome was to establish the contribution of the hormonal status of the patients to the clinical course of the Covid-19 disease. Result(s): In our cohort, 86 women had mild, 128 women had moderate and 53 women had severe Covid-19 disease. 101 women were at premenopausal state while 152 women were at postmenopausal state. There was a statistically significant difference between the patients with mild, moderate and severe Covid-19 disease with respect to age, BMI, gravidity, parity, smoking, co-morbidities, being in pre-menopausal period, O2 saturation, diastolic blood pressure, parameters of complete blood count, biochemical tests, LH, FSH, E2, DHEA-S, length of hospital stay, body temperature, and the percentage of patients with dyspnea. In the total group, being one year younger decreased the odds of having severe Covid-19 disease 0.338 fold relative to the mild disease (CI: 0.164-0.697, p=0.003). Even though statistically less significant, younger age has a positive impact for the postmenopausal group (OR: 0.378, CI: 0.157-0.910, p=0.030). In the total group, the decrease in the serum DHEA-S level was associated with a 2.604 fold increase in the odds of having severe Covid-19 disease relative to the mild disease (CI:1.254-5.410, p=0.010). For the pre-menopausal group of patients, the decrease in serum DHEA-S level increased the odds of having severe disease by 3.864 fold (CI: 1.269-11.764, p=0.017). In the total group, 1 unit increase in the level of serum LH increased the odds of having mild disease compared to severe disease by 2.821 fold (CI:1.002-5.410, p=0.050). Conclusion(s): The prognosis of Covid-19 disease is more favorable in the premenopausal women with higher serum E2 levels compared to the postmenopausal women. The age and serum levels of DHEA-S and LH are important predictors of the severity of Covid-19 infection for women.Copyright © 2023

The effects of exogenous estrogen in women with SAR-CoV-2 infection: a systematic review and meta-analysis.

STUDY QUESTION: Does exogenous estrogen use affect COVID-19-related mortality in women? SUMMARY ANSWER: Menopausal hormone therapy (MHT) was associated with a lower likelihood of all-cause fatality related to COVID-19 in postmenopausal women (odds ratio (OR) 0.28, 95% CI 0.18, 0.44; 4 studies, 21 517 women) but the combined oral contraceptive pill in premenopausal women did not have a significant effect (OR 1.00, 95% CI 0.42-2.41; 2 studies, 5099 women). WHAT IS KNOWN ALREADY: Men are much more likely to die from COVID-19 than women. STUDY DESIGN, SIZE, DURATION: In this systematic meta-analysis, a literature search was conducted using the following search terms related toCOVID-19 and estrogen, sex hormones, hormonal replacement, menopause, or contraception. The PubMed, Scopus, Cochrane Library, and EMBASE databases were searched to identify relevant studies published between December 2019 and December 2021. We also searched MedRxiv as a preprint database and reviewed the reference lists of all included studies and clinical trial registries for ongoing clinical studies until December 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: All comparative studies that compared the rates mortality and morbidity (hospitalization, intensive care unit (ICU) admission, and ventilation support) due to COVID-19 in women using exogenous estrogen to a control group of women (nonusers) were included. A review of the studies for inclusion, extraction of data, and assessment of the risk of bias was performed independently by two reviewers. The ROBINS-I tool and the RoB 2 tool were used for bias assessment of the included studies. Pooled odds ratios (ORs) with 95% CIs were calculated using Review Manager V5.4.1. The I2 statistic was used to quantify heterogeneity. The quality of the evidence was assessed using GRADE criteria. MAIN RESULTS AND THE ROLE OF CHANCE: After searching the databases, we identified a total of 5310 studies. After removing duplicate records, ineligible studies, and ongoing studies, a total of four cohort studies and one randomized controlled trial comprising 177 809 participants were included in this review. There was a moderate certainty of evidence that MHT was associated with a lower likelihood of all-cause fatality related to COVID-19 (OR 0.28, 95% CI 0.18, 0.44; I2 = 0%; 4 studies, 21 517 women). The review indicated a low certainty of evidence for other outcomes. The mortality rate of premenopausal women in the combined oral contraceptive pill group did not differ significantly from the control group (OR 1.00, 95% CI 0.42-2.41; 2 studies, 5099 women). MHT marginally increased the rate of hospitalization and ICU admission (OR 1.37, 95% CI 1.18-1.61; 3 studies, 151 485 women), but there was no significant difference in the need for respiratory support between MHT users and nonusers (OR 0.91, 95% CI 0.52-1.59; 3 studies, 151 485 women). Overall, the tendency and magnitude of the effects of MHT in postmenopausal women with COVID-19 were consistent across the included studies. LIMITATIONS, REASONS FOR CAUTION: The certainty of the evidence for other outcomes of this review may be limited, as all included studies were cohort studies. In addition, the dosages and durations of exogenous estrogen used by postmenopausal women varied from study to study, and combined progestogen administration may have had some effect on the outcomes. WIDER IMPLICATIONS OF THE FINDINGS: The findings of this study can aid in counseling postmenopausal women taking MHT when they are diagnosed with COVID, as they have a lower chance of death than those not taking MHT. STUDY FUNDING/COMPETING INTEREST(S): Khon Kaen University provided financial support for this review and had no involvement at any stage of the study. The authors have no conflicts of interest to declare. REGISTRATION NUMBER: PROSPERO, CRD42021271882.

Changes in preferences for ovarian cancer prevention strategies during the COVID-19 pandemic: Results of a discrete choice experiment

Background: The COVID-19 pandemic influenced patient health care decisions, but there is little information about the pandemic's impact on decisions about cancer risk reduction. This includes women at elevated risk of breast or ovarian cancer considering risk-reducing salpingooophorectomy (RRSO), risk-reducing salpingectomy (RRS), or other preventive measures. During the pandemic patients needed to balance their concerns about cancer risk reduction with their risks associated with elective health procedures, a risk which changed as vaccines became available. Method(s): To address the impact of the COVID-19 pandemic on cancer prevention decision making, we recruited N=396 pre-menopausal women with a personal history of breast cancer or familial history suggestive of increased breast and/or ovarian cancer risk between 4/2019 and 3/2022. We conducted a discrete choice experiment in which patients were asked to choose between two scenarios that specified type of surgery (RRSO, RRS vs. non-surgical surveillance), age of menopause (natural versus immediate), quality of menopausal symptoms (mild, moderate, severe), and risk of ovarian cancer, heart disease, or osteoporosis. Risk of ovarian cancer for the scenarios provided varied in discrete intervals from 0% to 40%. We examined temporal trends during the pandemic using interactions with time coinciding approximately with the beginning of pandemic, peak vaccination period, and the Omicron wave. Result(s): We identified significant temporal interactions on a woman's prevention decisions. In 2019, women at higher risk of ovarian cancer were more likely to choose prevention scenarios that favored lower ovarian cancer risk (odds ratio [OR] = 0.48;95% CI = 0.37, 0.69 per 10% increase in ovarian cancer risk difference). This association decreased through the pre-vaccine period of 2020 by OR=2.61/month (95% CI = 1.21, 5.65). By June 2020, the effect of a 10% increase in ovarian cancer risk on intervention choice had attenuated substantially (OR=0.84, 95% CI 0.67, 1.00). By January 2022, the effect strengthened (OR= 0.69, 95% CI .49, .88), but had not reached pre-pandemic levels. Before 3/2020, natural age of menopause (versus immediate) had a strong impact on the choice of a scenario (OR=3.56, 95% CI 1.65-7.65). At the beginning of the pandemic, the effect was reduced by 0.47/month (95% CI 0.22-0.99). The rate of attenuation slowed over time, such that the effect of having a natural age of menopause on choice was OR= 1.56 (95% CI 0.65, 2.46) by January 2022. Tests for temporal interactions were statistically significant for both ovarian cancer risk and age of menopause. Conclusion(s): Our results suggest that over the course of the pandemic, women seemed more accepting of higher risks of ovarian cancer and immediate (post treatment) menopause when considering preventive options. There was an inverse U shape curve of the effect of ovarian cancer risk on choices over time (Figure A), but the strength of the relationship had not reached prepandemic levels by January 2022. This may reflect patient tolerance for side effects as the pandemic evolved. These results suggest that factors such as ovarian cancer risk and delay of menopause influenced personal prevention choices, but that these choices were influenced by events related to events that hallmarked the COVID-19 pandemic.

OPTIMA, a prospective randomized trial to validate the clinical utility and cost-effectiveness of gene expression test-directed chemotherapy decisions in high clinical risk early breast cancer

Background: Multi-parameter tumor gene expression assays (MPAs) are used to estimate individual patient risk and guide chemotherapy use in hormone-sensitive, HER2-negative early breast cancer. The TAILORx trial supports MPA use in a node-negative population. Evidence for MPA use in postmenopausal node-positive breast cancer has been provided by the RxPONDER trial interim analysis but this relies on the absence of superiority in an analysis where >50% of events were unrelated to breast cancer. There is much uncertainty about MPA use for premenopausal patients. OPTIMA (Optimal Personalised Treatment of early breast cancer usIng Multi-parameter Analysis) (ISRCTN42400492) is a prospective international randomized controlled trial designed to validate MPAs as predictors of chemotherapy sensitivity in a largely node-positive breast cancer population. Method(s): OPTIMA is a partially blinded study with an adaptive two-stage design. The trial recruits women and men age 40 or older with resected ER-positive, HER2-negative invasive breast cancer and up to 9 involved axillary lymph nodes. Randomization is to standard management (chemotherapy and endocrine therapy) or to MPA-directed treatment using the Prosigna (PAM50) test. Those with a Prosigna tumor Score (ROR-PT) >60 receive standard management whilst those with a low score (<=60) tumor are treated with endocrine therapy alone. Endocrine therapy for premenopausal women includes ovarian suppression for all participants unless they experience a chemotherapy-induced menopause. Adjuvant abemaciclib is permitted. The trial will be analyzed for (1) non-inferiority of recurrence according to randomization and (2) cost-effectiveness. The key secondary outcome is non-inferiority of recurrence for patients with low ROR-PT score tumors. The efficacy analyses will be performed Per Protocol using Invasive Breast Cancer Free Survival (IBCFS) as the primary outcome measure to limit the risk of a false non-inferiority conclusion. Recruitment of 4500 patients over 8 years will permit demonstration of up to 3% non-inferiority of test-directed treatment with at least 83% power, assuming 5-year IBCFS is 87% with standard management. An integrated qualitative recruitment study addresses challenges to consent and recruitment, building on experience from the feasibility study which found that a multidisciplinary approach is important for recruitment success. OPTIMA is strongly supported by a patient group which has helped design all patient documents and which is represented on the TMG. Result(s): The OPTIMA main trial opened in January 2017 and has continued to recruit throughout the COVID-19 pandemic. Overall recruitment as of 1 July 2022 was 2814 (2593 from UK, 221 from Norway). Patient characteristics are well balanced between the trial arms. Currently 95% of randomized participants are eligible for inclusion in the PP analysis. 66% of the MPA-directed arm participants have been allocated to endocrine therapy only. The test failure rate is < 1%. Conclusion(s): OPTIMA will provide robust unbiased evidence on test-directed chemotherapy safety for both postmenopausal and premenopausal women with 1-3 involved nodes as well as for patients with 4-9 involved nodes and for patients treated with abemaciclib.

Pulmonary benign metastasizing leiomyoma (PBML) - A rare cause of lung tumor

Introduction: Benign metastasizing leiomyoma (BML) is a rare disorder that usually occur in premenopausal women with uterine leiomyoma. The commonest metastasis site is the lungs. Diagnosis and treatment are challenging and there is no standardized treatment for BML. Case Description: We report a case of a 66-year-old menopausal lady who presented to Sarawak General Hospital in October 2021 for Covid-19 infection, with incidental finding of pulmonary benign metastasizing leiomyoma (PBML). She experienced one-year history of weight loss. Chest X-ray on admission revealed a solitary right lung nodule (2 x 2cm). CT thorax revealed a right perihilar lesion with multiple smaller lung nodules. Tuberculosis was excluded. The histopathology result of lung biopsy surprisingly showed spindle cell neoplasm with smooth muscle differentiation. There was no palpable abdominal mass. Ultrasound showed irregular endometrial mass about 3.9 x2 cm. Repeated CT thorax and abdomen in April 2022 showed the lung lesion has enlarged to 4 x 4 cm. Patient is planned for a hysterectomy and bilateral salpingo-oophorectomy following a multidisciplinary meeting among Respiratory Physician, Oncologist and Gynae-oncologist. Discussion: Benign metastasizing leiomyoma is rare and not well understood. It usually occurs in premenopausal women with history of myomectomy or hysterectomy. Only few cases have been reported among postmenopausal women without prior history of leiomyoma. Lung biopsy is crucial in excluding serious causes such as malignancy and achieving the correct diagnosis. As there is no established treatment and monitoring guideline, treatment should be individualized and guided by a multidisciplinary team.

INVESTIGATING IDA: LARGE-SCALE DATA SHOWING PERSISTENT GAPS AT THE FRONT DOOR

Introduction Iron deficiency anaemia (IDA) can be a sign of serious underlying disease but often overlooked. Recently updated guidelines of the British Society of Gastroenterology (BSG) recommend male and postmenopausal female patients with IDA should be screened for coeliac disease and undergo dual endoscopy (or CT). Aims This project looked to assess current adherence to these guidelines at the Queen Elizabeth Hospital in Birmingham. Methods A retrospective audit was performed using health informatics for patients who attended AMU/CDU from April 2018 to March 2021. The number of patients with IDA in this time frame was identified. A further analysis of this group was made to determine the proportion of patients with IDA who had IgA TTG measured as well as those who had OGD and colonoscopy/CT colonoscopy requested. Results There were 67797 patients in this study period. 32422 (47.8%) were anaemic (Hb < 120g/dl for women, <130g/dl for men as per WHO guidelines) of which 6357 (19.6%;9.38% of total) had a microcytic anaemia (MCV <83 as per University Hospitals Birmingham laboratory reference range). Ferritin was tested in 3337 (52.5%) of this group, and of those, 1041 (31.2%) were found to have overt IDA (ferritin <30 mg/mL). Rate of investigation The patient cohort with confirmed IDA comprised 334 males (32.0%), 556 post-menopausal females (53.4%, defined as age ≥45) and 151 pre-menopausal females (14.5%). A further analysis was made to explore how male and postmenopausal female cases were investigated, and if the rate of investigation was affected by the COVID-19 pandemic from 1st March 2020 onwards in this subgroup. Results are shown in the table below. In general, only a minority of patients underwent further investigation with males more likely to undergo OGD than females. Surprisingly, apart from increased TTG check latterly, little difference was seen after onset of the COVID-19 pandemic. Conclusions This large-scale study found that only a small minority of patients with IDA underwent further investigation. Whilst the study period includes the pandemic era, our results don't suggest this made a significant impact on practice. Nevertheless, these findings indicate a strong need for increased awareness and quality improvement about optimising IDA investigation according to BSG guidelines.

Adjuvant decision making in the era of limited nodal information

The increasing use of pre-operative systemic therapy has resulted in more limited information about axillary lymph node status, both from the impact of systemic therapy itself as well as from less extensive axillary surgery. Decisions about the use of adjuvant endocrine therapy have not been majorly affected, but information on the presence and number of involved lymph nodes can have a significant influence on the use of adjuvant chemotherapy and HER-2 targeted therapies. In addition, lymph node information can also impact decisions around radiation therapy, making multidisciplinary discussions highly relevant when planning therapy. Patients with hormone receptor positive breast cancer may be treated with pre-operative endocrine therapy. This strategy was often used in early stage breast cancer during the COVID pandemic due to delays in surgery. Although an effective approach, pre-operative endocrine therapy may impact nodal status at surgery, information which is important when deciding on the use of OncotypeDX testing in premenopausal women. Similarly, in postmenopausal women, the presence and number of lymph nodes involved is a critical factor in determining the appropriateness of OncotypeDx testing. This nodal information may be lost in the setting of pre-operative therapy and would alter decisions regarding adjuvant chemotherapy. For patients with HER2 positive breast cancer, the presence of nodal disease remains critical for adjuvant decision making. In the situation of small (up to 3 cm) node negative cancers, up front surgery is preferred, because pathologic confirmation of the tumor size and node negative status may make patients eligible for a de-escalated approach of adjuvant paclitaxel and trastuzumab. Patients with more advanced HER2 positive disease are good candidates for preoperative chemotherapy and HER2 targeted therapy. If they have residual disease at surgery, they can be offered trastuzumab emtansine, which was shown in the KATHERINE trial to improve outcomes. In both situations, accurate information about the presence of disease in the axillary lymph nodes determines the most effective treatment approach. Finally, accurate information about nodal status is also relevant to decisions in patients with triple negative breast cancer. Patients who are treated with pre-operative chemotherapy and have residual disease in either the breast or axillary lymph nodes may be offered adjuvant capecitabine, based on the CREATE-X study, which indicated improved survival outcomes in those patients with residual disease who received adjuvant capecitabine. As in HER2 positive breast cancer, the presence of residual disease (including in the lymph nodes) after preoperative therapy will influence the adjuvant therapy recommendation. Thus, when considering de-escalation approaches in axillary management, the impact on systemic therapy decision making must be carefully considered, as these additional adjuvant therapies may improve survival for patients. Conflict of Interest: No significant relationships.