Fundamental role of BMP15 in human ovarian folliculogenesis revealed by null and missense mutations associated with primary ovarian insufficiency.
Hum Mutat. 2020 Jan 20;:
Authors: Rossetti R, Ferrari I, Bestetti I, Moleri S, Brancati F, Petrone L, Finelli P, Persani L
BMP15 encodes an oocyte factor with a relevant role for folliculogenesis as homodimer or cumulin heterodimer (BMP15-GDF9). Heterozygous BMP15 variants in the precursor or mature peptide had been associated with primary ovarian insufficiency (POI), but the underlying mechanism remains elusive and a double dose of BMP15 was suggested to be required for adequate ovarian reserve. We uncovered two homozygous BMP15 null variants found in two girls with POI and primary amenorrhea. Both heterozygous mothers reported physiological menopause. We then performed western blot, immunofluorescence and reporter assays to investigate how previously reported missense variants, p.Y235C and p.R329C, located in the precursor or mature domains of BMP15, may affect protein function. The p.R329C variant demonstrates an impaired colocalization with GDF9 at confocal images and diminished activation of the SMAD pathways at western blot and reporter assays in COV434 follicular cell line. In conclusion, BMP15 null mutations cause POI only in the homozygous state, thus discarding the possibility that isolated BMP15 haploinsufficiency can cause evident ovarian defects, Alternatively, heterozygous BMP15 missense variants may affect ovarian function by interfering with cumulin activity. Our data definitely supports the fundamental role of BMP15 in human ovarian folliculogenesis. This article is protected by copyright. All rights reserved.
PMID: 31957178 [PubMed - as supplied by publisher]
Calcium Supplement Use Is Associated With Less Bone Mineral Density Loss, But Does Not Lessen the Risk of Bone Fracture Across the Menopause Transition: Data From the Study of Women's Health Across the Nation.
JBMR Plus. 2020 Jan;4(1):e10246
Authors: Bailey RL, Zou P, Wallace TC, McCabe GP, Craig BA, Jun S, Cauley JA, Weaver CM
Diet is a modifiable factor that is related to bone mass and risk for fractures; however, the use of calcium supplements for bone health is controversial, with little scientific agreement. The purpose of this analysis was to estimate the change in lumbar spine and femoral neck BMD and the risk of bone fracture by the use of calcium supplements among the Study of Women's Health Across the Nation (SWAN) participants. SWAN is a multicenter, multiethnic, community-based longitudinal cohort designed to examine the health of women across the menopause transition (n = 1490; aged 42 to 52 years at baseline in 1996 to 1997 and followed annually until 2006 to 2008). A mixed-effect model for repeated measures was used to estimate annualized BMD change across time between supplement users and nonusers, unadjusted or fully adjusted (age, race, height, weight, menopausal status [pre-, early peri-, late peri-, and postmenopausal], DXA scanner mode, alcohol intake, vitamin D supplement use, smoking, and physical activity) and a log-linear model with repeated measures was used to estimate the relative risk of fracture by calcium supplement use. All models were also stratified by baseline menopausal status. In fully adjusted models, calcium supplement use was associated with less annualized loss of femoral neck BMD (-0.0032 versus -0.0040 g/cm2/year; p < .001) and lumbar spine BMD (-0.0046 versus -0.0053 g/cm2/year, p = 0.021) in the complete cohort. However, this protective association of calcium supplement use with BMD loss was significant only among premenopausal women (femoral neck: -0.0032 versus -0.0042 g/cm2/year; p = 0.002; lumbar spine: -0.0038 versus -0.0050 g/cm2/year, p = 0.001); no significant differences in BMD were observed among women who were early perimenopausal by calcium supplement use at baseline. No significant differences in the relative risk of fracture were observed, regardless of baseline menopausal status. The use of calcium supplements was associated with less BMD loss over more than a decade, but was not related to the risk of incident bone fracture across the menopause transition. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
PMID: 31956850 [PubMed]
Is Obesity Hypoventilation Syndrome A Postmenopausal Disorder?
Open Respir Med J. 2019;13:51-54
Authors: BaHammam AS, Almeneessier AS
Previous studies have assessed the role of gender and menopause in Obstructive Sleep Apnea (OSA). It is well known that menopause is a major risk factor for OSA. However, analogous studies on obesity Hypoventilation Syndrome (OHS) are limited. Recent studies have suggested that OHS is more prevalent in postmenopausal women. Moreover, women with OHS seem to have excess comorbidities, including hypothyroidism, hypertension, pulmonary hypertension, and diabetes mellitus, compared to men. In the present perspective, we discuss recent data on the prevalence and comorbidities associated with OHS in women, as well as the use of noninvasive ventilation in women with OHS, and try to answer the question, "Is OHS a disorder of postmenopausal women?"
PMID: 31956377 [PubMed]
Risk factors for endometrial carcinoma among postmenopausal women in Sri Lanka: a case control study.
BMC Public Health. 2019 Oct 28;19(1):1387
Authors: Jayawickcrama WIU, Abeysena C
BACKGROUND: Endometrial carcinoma burden is on the rise globally. The objective of this study was to determine the risk factors for endometrial carcinoma among postmenopausal women in Western province in Sri Lanka.
METHODS: A case control study was conducted recruiting 83 incident cases of endometrial carcinoma and 332 unmatched hospital controls from all the secondary and tertiary care hospitals in the province using consecutive sampling technique. A case was defined as a postmenopausal woman who had been residing in the province for at least a period of 1 year, diagnosed to have endometrial carcinoma with histological confirmation within 3 months of the initiation of data collection of the study. Data were collected using validated interviewer administered questionnaire. Risk factor were identified through multiple logistic regression and results were expressed as adjusted odds ratios (AOR) and 95% confidence intervals (CI).
RESULTS: The independent risk factors of endometrial carcinoma are having family history of any type of cancer among first degree relative (AOR = 12.6; 95% CI:5.14-30.9), generalized obesity (BMI ≥25 kg/m2) (AOR = 11.85; 95% CI:5.12-27.4), never conceived (AOR = 3.84; 95% CI:1.37-10.7), age at menarche ≤11 years (AOR = 4.07; 95% CI:1.16-14.2), age > 55 years (AOR = 4.69; 95% CI:2.16-10.2), monthly family income of ≤20,000 Rupees (AOR = 2.65; 95% CI:1.31-5.39), sub-optimal consumption of deep fried food (AOR = 0.17; 95% CI:0.06-0.46), and low level household activities (AOR = 2.82; 95% CI:1.34-5.92).
CONCLUSIONS: There were eight independent risk factors of endometrial carcinoma specific for Sri Lankan postmenopausal women identified. Some modifiable risk factors such as generalized obesity, sub-optimal dietary practices and low level physical activities need to be addressed at primary prevention level.
PMID: 31660927 [PubMed - indexed for MEDLINE]
Menstrual Health as a Part of Preventive Health Care.
Obstet Gynecol Clin North Am. 2019 Sep;46(3):441-453
Authors: Matteson KA, Zaluski KM
Menstrual health assessment facilitates identification of pathologic conditions (eg, abnormal uterine bleeding, endometriosis), offers the opportunity to educate women on what menstrual symptoms may be normal or abnormal, and provides the opportunity to initiate treatment for women who are suffering because of problems with menstrual bleeding or associated symptoms. Heavy bleeding, pain, fatigue, and mood changes significantly affect a woman's physical, social, and emotional quality of life. Promptly identifying and treating these disorders by incorporating their assessment into routine well-woman care has the potential to positively affect the lives of a substantial number of women.
PMID: 31378287 [PubMed - indexed for MEDLINE]
Maternal caregivers have confluence of altered cortisol, high reward-driven eating, and worse metabolic health.
PLoS One. 2019;14(5):e0216541
Authors: Radin RM, Mason AE, Laudenslager ML, Epel ES
Animal models have shown that chronic stress increases cortisol, which contributes to overeating of highly palatable food, increased abdominal fat and lower cortisol reactivity. Few studies in humans have simultaneously examined these trajectories. We examined premenopausal women, either mothers of children with a diagnosis of an autism spectrum disorder (n = 92) or mothers of neurotypical children (n = 91). At baseline and 2-years, we assessed hair cortisol, metabolic health, and reward-based eating. We compared groups cross-sectionally and prospectively, accounting for BMI change. Caregivers, relative to controls, had lower cumulative hair cortisol at each time point, with no decreases over time. Caregivers also had stable levels of poor metabolic functioning and greater reward-based eating across both time points, and evidenced increased abdominal fat prospectively (all ps ≤.05), independent of change in BMI. This pattern of findings suggest that individuals under chronic stress, such as caregivers, would benefit from tailored interventions focusing on better regulation of stress and eating in tandem to prevent early onset of metabolic disease, regardless of weight status.
PMID: 31075126 [PubMed - indexed for MEDLINE]
Mammographic breast density and its association with urinary estrogens and the fecal microbiota in postmenopausal women.
PLoS One. 2019;14(5):e0216114
Authors: Jones GS, Spencer Feigelson H, Falk RT, Hua X, Ravel J, Yu G, Flores R, Gail MH, Shi J, Xu X, Goedert JJ
BACKGROUND: Breast density, as estimated by mammography, is a strong risk factor for breast cancer in pre- and postmenopausal women, but the determinants of breast density have not yet been established. The aim of this study was to assess if urinary estrogens or gut microbiota alterations are associated with mammographic density in postmenopausal women.
METHODS: Among 54 cancer-free, postmenopausal controls in the Breast and Colon Health study, we classified low- versus high-density women with Breast Imaging Reporting and Data System (BI-RADS, 5th edition) mammographic screening data, then assessed associations with urinary estrogens and estrogen metabolites (determined by liquid chromatography/tandem mass spectrometry), and fecal microbiota alpha and beta diversity (using Illumina sequencing of 16S rRNA amplicons).
RESULTS: Multiple logistic regression revealed no significant association between breast density and fecal microbiota metrics (PD_tree P-value = 0.82; un-weighted and weighted UniFrac P = 0.92 and 0.83, respectively, both by MiRKAT). In contrast, total urinary estrogens (and all 15 estrogens/estrogen metabolites) were strongly and inversely associated with breast density (P = 0.01) after adjustment for age and body mass index.
CONCLUSION: Mammographic density was not associated with the gut microbiota, but it was inversely associated with urinary estrogen levels.
IMPACT: The finding of an inverse association between urinary estrogens and breast density in cancer-free women adds to the growing breast cancer literature on understanding the relationship between endogenous estrogens and mammographic density.
PMID: 31067262 [PubMed - indexed for MEDLINE]
High prevalence of benign mammary tumors in a rat model of polycystic ovary syndrome during postmenopausal period.
Gynecol Endocrinol. 2019 Aug;35(8):679-684
Authors: Noroozzadeh M, Behboudi-Gandevani S, Mosaffa N, Tohidi M, Ramezani Tehrani F
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in reproductive-age women. Significant associations between PCOS and benign breast diseases (BBD) and a possibly potential association between PCOS and breast cancer have been reported. The etiology of these events of mammary glands in PCOS remains unclear. Animal models that show BBD and breast cancer may contribute to further understanding about these diseases. We aimed to examine the spontaneous occurrence of mammary tumors, their prevalence, and type in our rat model of PCOS. Prenatal androgen-induced PCOS rats and controls were examined in later life. Benign mammary tumors were observed in 75% and 33.33% of PCOS rats and controls during the postmenopausal period, respectively (p = .0158). Mammary tumors were non-invasive, margins of excision were normal and tumors were freely movable, in both groups. After microscopic evaluations of tumors, proliferative breast lesions and adenomas with a tubular growth pattern were observed in both groups. However, in PCOS rats, of benign tumors two had a mixed pattern of fibroadenoma/fibroma and cysts. High prevalence of benign mammary tumors was observed in our rat model of PCOS during the postmenopausal period, possibly due to hormonal imbalances during their reproductive lifespan; this model may contribute to current data available regarding the events of mammary glands in PCOS.
PMID: 30990105 [PubMed - indexed for MEDLINE]
Abnormal Uterine Bleeding in Premenopausal Women.
Am Fam Physician. 2019 04 01;99(7):435-443
Authors: Wouk N, Helton M
Abnormal uterine bleeding is a common symptom in women. The acronym PALM-COEIN facilitates classification, with PALM referring to structural etiologies (polyp, adenomyosis, leiomyoma, malignancy and hyperplasia), and COEIN referring to nonstructural etiologies (coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, not otherwise classified). Evaluation involves a detailed history and pelvic examination, as well as laboratory testing that includes a pregnancy test and complete blood count. Endometrial sampling should be performed in patients 45 years and older, and in younger patients with a significant history of unopposed estrogen exposure. Transvaginal ultrasonography is the preferred imaging modality and is indicated if a structural etiology is suspected or if symptoms persist despite appropriate initial treatment. Medical and surgical treatment options are available. Emergency interventions for severe bleeding that causes hemodynamic instability include uterine tamponade, intravenous estrogen, dilation and curettage, and uterine artery embolization. To avoid surgical risks and preserve fertility, medical management is the preferred initial approach for hemodynamically stable patients. Patients with severe bleeding can be treated initially with oral estrogen, high-dose estrogen-progestin oral contraceptives, oral progestins, or intravenous tranexamic acid. The most effective long-term medical treatment for heavy menstrual bleeding is the levonorgestrel-releasing intrauterine system. Other long-term medical treatment options include estrogen-progestin oral contraceptives, oral progestins, oral tranexamic acid, nonsteroidal anti-inflammatory drugs, and depot medroxyprogesterone. Hysterectomy is the definitive treatment. A lower-risk surgical option is endometrial ablation, which performs as well as the levonorgestrel-releasing intrauterine system. Select patients with chronic uterine bleeding can be treated with myomectomy, polypectomy, or uterine artery embolization.
PMID: 30932448 [PubMed - indexed for MEDLINE]
A phase Ib dose allocation study of oral administration of lucitanib given in combination with fulvestrant in patients with estrogen receptor-positive and FGFR1-amplified or non-amplified metastatic breast cancer.
Cancer Chemother Pharmacol. 2019 04;83(4):743-753
Authors: Campone M, Bachelot T, Penault-Llorca F, Pallis A, Agrapart V, Pierrat MJ, Poirot C, Dubois F, Xuereb L, Bossard CJ, Guigal-Stephan N, Lockhart B, Andre F
PURPOSE: The primary objective of this multicentric dose allocation and dose expansion study was to determine the MTD and the DLTs of the lucitanib (a tyrosine kinase inhibitor of the FGFR/VEGFR/PDFGR pathways)/fulvestrant combination.
METHODS: Postmenopausal women with ER+/HER2- mBC, who have relapsed during or after treatment with fulvestrant, were eligible. The study had a dose allocation part to assess the tolerability of the combination followed by a dose expansion part.
RESULTS: Eighteen patients with ER+, mBC were enrolled; median age was 66 years, 50% had a PS: 0 and all had received previous endocrine treatment. The study was prematurely terminated after 18 patients (15 in part 1 and 3 in part 2) based on preclinical experiments that failed to confirm the hypothesis that addition of lucitanib would reverse sensitivity to endocrine treatments. Based on data of global lucitanib development, it was decided to stop the dose allocation at 12.5 mg and to start the dose expansion part at 10 mg/day. The most common grade ≥ 3 toxicities (> 10% of patients) were hypertension (78%) and asthenia (22%). All patients required at ≥ 1 interruption, 13 patients (72%) required ≥ 1 dose reduction. Three patients (72%) withdrew from the study for AEs (at 10 mg). Three patients achieved a confirmed PR (10 mg n = 1; 12.5 mg n = 2).
CONCLUSION: Although the combination is feasible it requires close monitoring of the patients for the management of adverse events. Further investigation is required to better understand the potential role of FGFR inhibition in reversing resistance to endocrine treatment.
PMID: 30684019 [PubMed - indexed for MEDLINE]