Climacteric

Endocrine consequences of breast cancer therapy and survivorship

Endometriosis-associated cancer

Endometriosis will affect about 10% of the female population and not only can it significantly impact adversely on quality of life and result in infertility, but data are accumulating that malignant transformation is an important consideration. Endometriosis can be histologically typical or atypical, ovarian, superficial peritoneal or deep infiltrating. The precursor for malignant transformation appears to be the ovarian atypical endometriosis component. Ovarian cancer is the most important associated cancer, primarily endometrioid and clear cell cancer. These are the only subtypes wherein a direct clonal relationship between endometriosis, as a direct precursor, and cancer has been made. There is no substantive evidence to support an altered association of borderline cancers of the ovary, serous ovarian cancers and breast, endometrial or cervical cancers. This review provides an overview of the prevailing data pertaining to the molecular and genetic aberrations that accompany the transformation of atypical endometriosis to malignancy and the accumulated epidemiologic evidence which supports the association.

COVID-19 vaccination and postmenopausal bleeding: a retrospective cohort study

COVID-19 vaccination has been related to menstrual irregularities; however, the effect on postmenopausal women is unknown. The aim of this study was to analyze the prevalence of postmenopausal bleeding (PMB) after COVID-19 vaccination. A retrospective study was conducted in the Department of Gynecology in Hospital del Mar. Consecutive postmenopausal women with data available and endometrial biopsy were included between February 2021 and January 2022. Patients were stratified between COVID-19 vaccinated and unvaccinated groups. PMB after 30 days from last vaccine dose was considered unrelated to vaccine. Endometrial pathology diagnoses were stratified into benign or malignant. Univariable and multivariable of regression analysis on variables potentially associated with PMB was performed. A total of 381 patients were included, 91 in the vaccinated group and 290 in the unvaccinated group. Prevalence of PMB in the vaccinated group was 75.8% compared to 59.0% in the unvaccinated group ( A higher prevalence of PMB was associated with COVID-19 vaccine. Endometrial histological results showed no association with COVID-19 vaccination, but endometrial biopsy should be performed for PMB.

Systemic hormone therapy after breast and gynecological cancers: an Italian expert group consensus opinion

The specific Italian Group of Study of the Menopause formulated a consensus opinion on the use of estrogen therapy (ET) or combined estro-progestin hormone therapy (HT) after breast and gynecological cancers. This consensus is based on the risk of recurrence of the specific cancer during ET/HT, the presence of steroid receptors in cancer cells, the use of adjuvant hormone therapies and data on the use of ET/HT after cancer. The following positions were reached. ET/HT can be used after vulvar cancers and melanoma, but with great caution after the rare adenocarcinomas. ET/HT can be used after cervical cancer, but ET should be used with caution after adenocarcinomas. ET/HT can be used after International Federation of Obstetrics and Gynecology (FIGO) stage I-II estrogen-dependent endometrial cancers, except in Black women, and can probably be used after estrogen-independent endometrial cancers. ET/HT cannot be administered or should be used with great caution after most uterine sarcomas. ET/HT can probably be used after ovarian neoplasms except for granulosa cell tumors, and with great caution after low-grade serous ovarian carcinoma and serous borderline ovarian tumors. ET/HT can be used with great caution in women after estrogen receptor (ER)/progesterone receptor (PR)-positive breast cancer and is probably allowed after ER/PR-negative breast cancer.

Postmenopausal hyperandrogenism

Postmenopausal hyperandrogenism is a state of relative or absolute androgen excess originating from the adrenal glands and/or ovaries clinically manifested by the presence of terminal hair in androgen-dependent areas of the body, and other manifestations of hyperandrogenism such as acne and alopecia or the development of virilization. In such circumstances, physicians must exclude the possibility of rare but serious androgen-producing tumors of the adrenal glands or ovaries. Worsening of undiagnosed hyperandrogenic disorders such as polycystic ovary syndrome, congenital adrenal hyperplasia, ovarian hyperthecosis, Cushing syndrome and iatrogenic hyperandrogenism should be considered for differential diagnosis. Elevated serum testosterone not only causes virilizing effects, but also will lead to hypercholesterolemia, insulin resistance, hypertension and cardiac disease. An ovarian androgen-secreting tumor, which is diagnosed in 1-3 of 1000 patients presenting with hirsutism, comprises less than 0.5% of all ovarian tumors. Adrenal tumors, including non-malignant adenomas and malignant carcinomas, are less common than ovarian tumors but cause postmenopausal virilization. Measurement of serum testosterone, sex hormone-binding globulin, dehydroepiandrosterone sulfate, androstenedione and inhibin B is necessary in postmenopausal women with the complaints and signs of hyperandrogenism. Some tests to discard Cushing syndrome should also be done. After an etiological source of androgen hypersecretion has been suspected, we recommend performing magnetic resonance imaging of the adrenal glands or ovaries. Medical management with gonadotropin-releasing hormone agonist/analogues or antagonists has been reported for women who are either unfit for surgery or in whom the source of elevated testosterone is unidentified.

Hormone replacement therapy and cervical cancer: a systematic review of the literature

Gynecological tumor treatment, including cervical cancer (CC) treatment, often leads to iatrogenic premature menopause. This highlights the critical importance of investigating indications for hormone replacement therapy (HRT), as most patients, thanks to the improvement in diagnosis and treatment, have to deal with the sequelae of their cancer treatments for many years. This systematic review aims to provide an overview of the current knowledge regarding the risks of HRT and CC. In particular, we aim to investigate whether the use of HRT can increase CC incidence, and evaluate its risk in CC survivors. A systematic review, in agreement with PRISMA guidelines, of the English literature present in PubMed and SCOPUS has been performed. A total of 2805 articles have been screened, of which 10 were considered eligible. Several studies reported a significantly reduced risk of developing cervical squamous cell carcinoma in postmenopausal women treated with HRT, while a weak increase in the incidence of adenocarcinoma has been shown. No evidence reports a harmful effect of HRT on CC oncological outcome, while several benefits, in terms of reduced metabolic risk and increased quality of life, have been described, thus concluding that HRT should be offered to young CC survivors for the management of early menopause.

Hyperandrogenism after menopause: diagnostic evaluation

The use of hysteroscopy in endometrial cancer: old questions and novel challenges

Endometrial cancer is the most common gynecological malignancy with a relatively good overall prognosis. It traditionally has two subtypes: type 1 (endometrioid carcinoma) and type 2 (non-endometrioid carcinoma). The prognosis is excellent for stage I endometrioid cancer, with a 5-year survival rate of 96%. However, the prognosis is much worse for women with high-risk endometrial cancer. Effective preoperative staging is important in order to tailor treatment and achieve optimal long-term survival. The majority of asymptomatic polyps detected by ultrasound are treated surgically. Conventionally, dilatation and curettage was performed to obtain a histological diagnosis, but nowadays hysteroscopy with biopsy is starting to be considered as the gold standard. Hysteroscopic resection seems to reduce the risk of underdiagnosed (atypical endometrial hyperplasia) endometrial cancer. To avoid the spread of malignant cells, hysteroscopy should be performed with concern to keep intrauterine pressure low. In comparison with cervical injection, the hysteroscopic method has a better detection rate in the para-aortic area during sentinel lymph node mapping. In the assessment of cervical involvement, the accuracy of magnetic resonance imaging is significantly higher than the accuracy of hysteroscopy. In fertility-sparing cases, hysteroscopic endometrium resection with progesterone therapy is an acceptable option.

Subjective cognitive changes following premenopausal risk-reducing bilateral salpingo-oophorectomy

Women at high risk of ovarian cancer are commonly advised to undergo risk-reducing bilateral salpingo-oophorectomy (BSO) prior to natural menopause. Cognitive symptoms during natural menopause transition are frequently reported; however, very few studies have examined cognitive changes following surgical menopause. To address this gap, we explored the cognitive experiences of women within 24 months post BSO. This observational cross-sectional sub-study is part of a larger project, the Early Menopause and Cognition Study (EM-COG). We investigated perceived cognitive experiences in Australian women ( Fifteen out of 16 participants (93.75%) reported changes to cognition within 24 months post BSO. The key cognitive symptoms reported were brain fog, memory and retrieval difficulties, slower processing speed as well as attention difficulties. Five participants (31.3%) experienced negative mood symptoms post BSO. Findings from this study suggest that women experience subjective cognitive changes within 24 months post BSO. This period could be a vulnerable time for women's cognitive health. While these findings need to be confirmed by a large prospective study, our research indicates that psychoeducation and awareness will be helpful in managing cognitive symptoms after surgical menopause.

Adjuvant treatment with tamoxifen for estrogen receptor-positive breast cancer and gynecological risks in premenopausal and perimenopausal women – a systematic review

Tamoxifen (TMX) is known to increase the risk of endometrial cancer (EC) in postmenopausal women, but data on the effects in premenopausal and perimenopausal women remain inconsistent and not well illuminated. This study aimed to evaluate whether TMX increases the risks of gynecological symptoms and EC in premenopausal and perimenopausal women receiving adjuvant therapy for estrogen receptor-positive breast cancer. Systematic searches in PubMed, Cochrane and Web Of Science yielded 319 relevant articles, of which 38 were analyzed after excluding duplicates and non-qualifying studies. The Oxford Criteria were used to ensure consistent evaluation before final inclusion. No meta-analysis was conducted due to study heterogeneity. Ten studies (two meta-analyses, one systematic review, four retrospective cohort studies, one retrospective comparative study, one prospective cohort study and one case-control study) were included. TMX was associated with an increased risk of EC in premenopausal and perimenopausal women (mean relative risk 2.25; standard deviation 0.9) compared to no treatment or treatment with raloxifene or aromatase inhibitors. Risk appeared in some studies to increase with treatment duration and persisted for ≥5 years post treatment. TMX also significantly increased the risk of gynecological symptoms, benign and premalignant endometrial pathology, intrauterine procedures and hysterectomy ( TMX seems to increase EC risk and significantly increase the risk of gynecological symptoms in premenopausal and perimenopausal women, with risk persisting years following treatment cessation. Healthcare professionals should counsel these women on potential risks and emphasize prompt evaluation of gynecological symptoms.

Effectiveness of different methods for polypectomy in the menopause: a retrospective study

To treat or not to treat? An evidence-based practice guide for the management of endometrial polyps

Endometrial polyps are a common finding, with a prevalence of about 40%, and are usually diagnosed incidentally as most are asymptomatic. Symptomatic polyps usually present with abnormal uterine bleeding and/or sub-fertility. About 25% of polyps resolve spontaneously if managed conservatively. The usual management of endometrial polyps, symptomatic or asymptomatic, is polypectomy, performed primarily to exclude malignancy within the polyp despite the overall risk of malignancy being low (about 3%). The main risk factors for malignancy are menopause and abnormal uterine bleeding, with hypertension, obesity, diabetes mellitus, and tamoxifen use thought to play a lesser role. Transvaginal ultrasonography is the primary diagnostic tool for endometrial polyps although visualization by hysteroscopy is the gold standard for diagnosis. There is no proven preventative or medical treatment, with complete polyp removal under hysteroscopic guidance the recommended surgical treatment. Some women may decline surgical endometrial polyp management due to the small inherent risks. Conservative management is an option for asymptomatic premenopausal and postmenopausal women, whilst polypectomy is recommended for all women with abnormal uterine bleeding. Management should be individualized and made in consultation with the patient.

BRCA carriers after risk-reducing bilateral salpingo-oophorectomy: menopausal hormone therapy knowledge gaps, and the impact of physicians’ recommendations

Female carriers of BRCA1/2 gene mutations are at an increased lifetime risk for breast and ovarian cancers. They are recommended to undergo risk-reducing surgery, including bilateral salpingo-oophorectomy (RR-BSO), upon completion of childbearing. RR-BSO surgery decreases morbidity and mortality but results in early menopause. Menopausal hormone therapy (MHT) is under-utilized despite being shown as safe for carriers. We aim to evaluate the factors associated with decision-making regarding MHT use following RR-BSO in healthy BRCA mutation carriers. Female carriers aged <50 years who underwent RR-BSO and were followed in a multidisciplinary clinic completed online multiple-choice and free-text questionnaires. A total of 142 women met the inclusion criteria and filled the questionnaire: 83 were MHT users and 59 were non-users. MHT users underwent RR-BSO earlier than non-users (40.82 ± 3.91 vs. 42.88 ± 4.34; Post-RR-BSO outcomes, including the effects on women's quality of life and its possible mitigation through MHT use, need to be addressed pre surgery by healthcare providers.

Treatment of women with BRCA mutation

The cumulative risk for breast and ovarian cancer is high in

Menopausal hormone therapy: what are the problems in the perception of Chinese physicians?

This study aimed to investigate Chinese physicians' perception and attitudes toward menopausal hormone therapy (MHT). This nationwide online survey was conducted in China. Physicians registered in the WeChat groups of the Gynecological Endocrinology Committee of China's Maternal and Child Health Care Association received a message invitation to complete this anonymous online survey from April 2020 to July 2020. Physicians' knowledge of and attitudes toward MHT were surveyed. In total, 4672 questionnaires were submitted; only completed questionnaires could be submitted. The message was sent to 6021 doctors, so the response rate was 77.6%. Overall, 77.9-92.9% of physicians knew the common indications and contraindications to MHT. Additionally, 90.6%, 85.4%, 80.7% and 37.5% of physicians thought that MHT would increase the risk of venous thrombosis, breast cancer, endometrial cancer and weight gain, respectively. In total, 58.1% of the physicians mistakenly believed that a sex hormone test was one of the necessary examinations to reassess MHT prescription during follow-up visits. We found that 68.5% of physicians would consider using MHT themselves or recommend MHT to their partners in the future, and 11.4% were currently using MHT. Most Chinese physicians have basic knowledge of MHT. Their misunderstandings about MHT mainly centered on the risks of endometrial cancer, weight gain and the necessary examinations during follow-up visits. These misunderstandings need to be clarified in future professional training programs.

Impact of risk-reducing salpingo-oophorectomy on lipid determinants, HbA1c and CRP

Risk-reducing salpingo-oophorectomy (RRSO) is advised before 40-45 years of age for BRCA1/2 mutation carriers. This study describes the effect of RRSO on lipid determinants, hemoglobin A1c (HbA1c) and C-reactive protein (CRP). A total of 142 women with increased risk of ovarian cancer were included, 92 premenopausal and 50 postmenopausal. Serum levels of low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol and total cholesterol, triglycerides, HbA1c and CRP were determined at three points in time: before (T0) and 6 weeks (T1) and 7 months (T2) following RRSO. The Hot Flush Rating Scale was administered at the same time points. In premenopausal women, levels of HDL-cholesterol, the cholesterol ratio and HBA1c increased significantly over time, although still staying within the reference range. In this group, hot flushes increased over time ( Seven months after RRSO, the lipid profile in premenopausal women had changed, although still staying within the reference range. For postmenopausal women, we did not observe any significant changes. Our results do not suggest a worsening of cardiovascular risk within 7 months of RRSO.

Ovarian tissue cryopreservation and transplantation prevents iatrogenic premature ovarian insufficiency: first 10 cases in China

The aim of this study was to report on the first 10 cases of ovarian tissue cryopreservation (OTC) and retransplantation (OTCT) in China. A retrospective descriptive study was performed of 10 Chinese women with different diseases undergoing OTC/OTCT in the first specialized center in China. Patients' ovarian function and fertility were followed up. The 10 cases included five cases of cervical cancer and one case each of endometrial cancer, breast cancer, rectal cancer, myelodysplastic syndrome, and aplastic anemia, respectively. The average age at OTC was 33.70 years; the time from OTC to OTCT was 15 months. The average number of transplanted ovarian tissue pieces was 4.9, with 9.5 pieces remaining cryopreserved. The OTCT position for nine cases was in a right-sided peritoneal pocket of ovarian fossa, and for one patient was in bilateral pockets. The average time from OTCT to restoration of ovarian function was 3.4 months. One year after OTCT, all ovaries were still functioning normally. In the first case, the function now remains preserved for more than 3 years. So far, the woman who wishes to conceive has no pregnancy. Regarding ovarian function, OTC and OTCT were successful and reliable in China's first cryobank. We expect to perform more retransplantations in the near future, which will add to the global data.

Risk of endometrial malignancy in women treated for breast cancer: the BLUSH prediction model – evidence from a comprehensive multicentric retrospective cohort study

This study aimed to evaluate characteristics of endometrial surveillance in women treated for breast cancer to build a clinical prediction model. A multicentric retrospective cohort study was conducted at two tertiary-care university hospitals from January 2020 to June 2023. Perimenopausal and postmenopausal women treated for breast cancer were categorized into two groups: patients with and without diagnosis of endometrial malignancy (endometrial carcinoma) or premalignancy (atypical endometrial hyperplasia). Characteristics of breast cancer and ultrasonographic and hysteroscopic examinations were compared. A prediction model for endometrial malignancy was built using logistic regression. Predictive accuracy was assessed using the receiver operating characteristic (ROC) curve and goodness of fit using the Hosmer-Lemeshow test. One hundred and thirty-two (28 with premalignancy or malignancy and 104 without malignancy) women were analyzed. A nomogram was produced for prediction model development utilizing the presence and duration in months of abnormal uterine (BL)eeding, ultrasound (US) vascular pattern and echogenicity and (H)ysteroscopic appearance of endometrium (BLUSH) as determined by logistic regression. Sensitivity and specificity were 79.17% and 95.19%, respectively, with an area under ROC curve of 0.965, indicating good accuracy. Good goodness of fit and prediction stability were indicated by the calibration curve and Hosmer-Lemeshow test ( Breast cancer survivors undergoing endometrial surveillance might benefit from a potentially useful prediction model based on hysteroscopic appearance, ultrasonographic uniformity of endometrium, Doppler flow and presence of abnormal uterine bleeding.

Recent advances in the management of postmenopausal women with non-atypical endometrial hyperplasia

Non-atypical endometrial hyperplasia is a benign disease without significant somatic genetic changes. Postmenopausal women with non-atypical endometrial hyperplasia have a significant risk of progression to endometrial cancer and persistent endometrial hyperplasia. Most cases of atypical endometrial hyperplasia in postmenopausal women are treated surgically, including hysterectomy. At present, the treatment of postmenopausal women with non-atypical endometrial hyperplasia is still controversial. Correct and timely diagnosis and treatment are of great significance to prevent progression of the lesion. This study mainly provides an updated synthesis of the literature that investigates the etiology, diagnosis and treatment of postmenopausal women with non-atypical endometrial hyperplasia. As of December 2022, a literature search related to postmenopausal non-atypical endometrial hyperplasia was conducted on the PubMed database. For most postmenopausal patients with non-atypical endometrial hyperplasia, regular re-examination should be performed during conservative treatment. For postmenopausal patients with endometrial cancer risk factors, persistent non-atypical endometrial hyperplasia or progesterone contraindications, hysterectomy and bilateral salpingo-oophorectomy should be the first choice.