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1.
FASEB J ; 37(5): e22931, 2023 05.
Article in English | MEDLINE | ID: mdl-37086099

ABSTRACT

Premature ovarian failure (POF) is a complication of ovarian dysfunction resulting from the depletion or dysfunction of primordial follicles (PFs) in the ovaries. However, residual follicles that have the potential to be activated are present in POF or aged women. Little is known about the mechanisms by which the remaining dormant PFs in POF patients are activated. Using mass spectrometry, we screened differentially generated peptides extracted from the ovarian cortical tissue biopsies of patients with or without POF, during which we identified PFAP1, a peptide that significantly promoted the activation of PFs in the ovaries of 3 dpp mice in vitro. PFAP1 reversed age-related fertility damage in vivo to a certain extent, promoted estrogen (E2) and anti-mullerian hormone (AMH) production (p < .05), and decreased the levels of follicle-stimulating hormone (FSH) (p < .05). In newborn mouse ovaries, PFAP1 could bind to the protein minichromosome maintenance protein 5 (MCM5) and inhibit its ubiquitination and degradation. In addition, PFAP1 promoted the proliferation of GCs, probably by regulating the function and production of MCM5. In conclusion, PFAP1 could promote the activation of PFs in the ovaries of newborn mice, partially restore the ovarian function of aged mice, and increase the proliferation of primary granulosa cells (GCs) by regulating the function of MCM5. PFAP1 is a promising novel peptide that may be developed into a new therapeutic agent for POF and other ovarian diseases.


Subject(s)
Menopause, Premature , Ovarian Diseases , Ovarian Follicle , Peptides , Primary Ovarian Insufficiency , Animals , Female , Mice , Anti-Mullerian Hormone , Cell Cycle Proteins/drug effects , Cell Cycle Proteins/metabolism , Follicle Stimulating Hormone/metabolism , Granulosa Cells/metabolism , Menopause, Premature/metabolism , Ovarian Diseases/drug therapy , Ovarian Diseases/pathology , Ovarian Follicle/drug effects , Ovarian Follicle/metabolism , Primary Ovarian Insufficiency/metabolism , Peptides/pharmacology
2.
Cell Transplant ; 31: 9636897221129171, 2022.
Article in English | MEDLINE | ID: mdl-36282038

ABSTRACT

Premature ovarian insufficiency (POI) can cause multiple sequelae and is currently incurable. Mesenchymal stem cell (MSC) transplantation might provide an effective treatment method for POI. However, the clinical application of systemic MSC transplantation is limited by the low efficiency of cell homing to target tissue in vivo, including systemic MSC transplantation for POI treatment. Thus, exploration of methods to promote MSC homing is necessary. This study was to investigate the effects of low-intensity pulsed ultrasound (LIPUS) on the migration and homing of transplanted human amnion-derived MSCs (hAD-MSCs) to ovaries in rats with chemotherapy-induced POI. For LIPUS treatment, hAD-MSCs were exposed to LIPUS or sham irradiation. Chemokine receptor expressions in hAD-MSCs were detected by polymerase chain reaction (PCR), Western blot, and immunofluorescence assays. hAD-MSC migration was detected by wound healing and transwell migration assays. Cyclophosphamide-induced POI rat models were established to evaluate the effects of LIPUS on the homing of systemically transplanted hAD-MSCs to chemotherapy-induced POI ovaries in vivo. We found that hAD-MSCs expressed chemokine receptors. The LIPUS promoted the expression of chemokine receptors, especially CXCR4, in hAD-MSCs. SDF-1 induced hAD-MSC migration. The LIPUS promoted hAD-MSC migration induced by SDF-1 through SDF-1/CXCR4 axis. SDF-1 levels significantly increased in ovaries induced by chemotherapy in POI rats. Pretreating hAD-MSCs with LIPUS increased the number of hAD-MSCs homing to ovaries in rats with chemotherapy-induced POI to some extent. However, the difference was not significant. Both hAD-MSC and LIPUS-pretreated hAD-MSC transplantation reduced ovarian injuries and improved ovarian function in rats with chemotherapy-induced POI. CXCR4 antagonist significantly reduced the number of hAD-MSCs- and LIPUS-pretreated hAD-MSCs homing to POI ovaries, and further reduced their efficacy in POI treatment. According to these findings, pretreating MSCs with LIPUS before transplantation might provide a novel, convenient, and safe technique to explore for improving the homing of systemically transplanted MSCs to target tissue.


Subject(s)
Antineoplastic Agents , Menopause, Premature , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Primary Ovarian Insufficiency , Female , Rats , Humans , Animals , Amnion/metabolism , Mesenchymal Stem Cells/metabolism , Primary Ovarian Insufficiency/chemically induced , Primary Ovarian Insufficiency/therapy , Mesenchymal Stem Cell Transplantation/methods , Receptors, CXCR4/metabolism , Menopause, Premature/metabolism , Ultrasonic Waves , Cyclophosphamide
3.
Obstet Gynecol ; 138(6): 950-960, 2021 12 01.
Article in English | MEDLINE | ID: mdl-34794166

ABSTRACT

SUMMARY: With an estimated 3.8 million breast cancer survivors in the United States, obstetrician-gynecologists often are on the front lines of addressing survivorship issues, including the hypoestrogenic-related adverse effects of cancer therapies or early menopause in survivors (1). Although systemic and vaginal estrogen are used widely for symptomatic relief of genitourinary syndrome of menopause in the general population, among individuals with a history of hormone-sensitive cancer, there is uncertainty about the safety of hormone-based therapy, leading many individuals with bothersome symptoms to remain untreated, with potential negative consequences on quality of life (2). An effective management strategy requires familiarity with a range of both hormonal and nonhormonal treatment options, knowledge about the pharmaceutical mechanisms of action, and the ability to tailor treatment based on individual risk factors. This clinical consensus document was developed using an a priori protocol in conjunction with two authors specializing in urogynecology and gynecologic oncology. This document has been updated to review the safety and efficacy of newer hormonal treatment options as well as nonhormonal modalities.


Subject(s)
Estrogens/administration & dosage , Female Urogenital Diseases/drug therapy , Gynecology/standards , Hormone Replacement Therapy/standards , Urology/standards , Breast Neoplasms/complications , Breast Neoplasms/metabolism , Cancer Survivors , Consensus , Estrogens/metabolism , Female , Female Urogenital Diseases/etiology , Female Urogenital Diseases/metabolism , Humans , Menopause, Premature/metabolism
5.
FASEB J ; 35(8): e21753, 2021 08.
Article in English | MEDLINE | ID: mdl-34233068

ABSTRACT

Ovarian infertility and subfertility presenting with premature ovarian insufficiency (POI) and diminished ovarian reserve are major issues facing the developed world due to the trend of delaying childbirth. Ovarian senescence and POI represent a continuum of physiological/pathophysiological changes in ovarian follicle functions. Based on advances in whole exome sequencing, evaluation of gene copy variants, together with family-based and genome-wide association studies, we discussed genes responsible for POI and ovarian senescence. We used a gene-centric approach to sort out literature deposited in the Ovarian Kaleidoscope database (http://okdb.appliedbioinfo.net) by sub-categorizing candidate genes as ligand-receptor signaling, meiosis and DNA repair, transcriptional factors, RNA metabolism, enzymes, and others. We discussed individual gene mutations found in POI patients and verification of gene functions in gene-deleted model organisms. Decreased expression of some of the POI genes could be responsible for ovarian senescence, especially those essential for DNA repair, meiosis and mitochondrial functions. We propose to set up a candidate gene panel for targeted sequencing in POI patients together with studies on mitochondria-associated genes in middle-aged subfertile patients.


Subject(s)
Ovary/metabolism , Primary Ovarian Insufficiency/genetics , Animals , DNA Repair/genetics , Databases, Genetic , Female , Genome-Wide Association Study , Humans , Meiosis/genetics , Menopause, Premature/genetics , Menopause, Premature/metabolism , Models, Genetic , Ovarian Reserve/genetics , Primary Ovarian Insufficiency/metabolism , Transcription Factors/genetics , Exome Sequencing
6.
Maturitas ; 148: 33-39, 2021 Jun.
Article in English | MEDLINE | ID: mdl-34024349

ABSTRACT

OBJECTIVE: . To compare the metabolic profile of women with spontaneous premature ovarian insufficiency (POI) with that of age-matched healthy controls. STUDY DESIGN: . A cross-sectional case-control study was conducted using 1:1 matching by age. Women below the age of 40 with spontaneous POI who did not receive any medication (n = 303) and age-matched healthy women (n = 303) were included in this study. MAIN OUTCOME MEASURES: . Metabolic profiles, including serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), glucose, uric acid, urea and creatinine, were compared between women with POI and controls. For women with POI, factors associated with the metabolic profile were analyzed. RESULTS: . Women with POI were more likely to exhibit increased serum levels of TG (ß, 0.155; 95% CI, 0.086, 0.223) and glucose (0.067; 0.052, 0.083), decreased levels of HDL-C (-0.087; -0.123, -0.051), LDL-C (-0.047; -0.091, -0.003) and uric acid (-0.053; -0.090, -0.015), and impaired kidney function (urea [0.070; 0.033, 0.107]; creatinine [0.277; 0.256, 0.299]; eGFR [-0.234; -0.252, -0.216]) compared with controls after adjusting for age and BMI. BMI, parity, gravidity, FSH and E2 levels were independent factors associated with the metabolic profile of women with POI. CONCLUSION: . Women with POI exhibited abnormalities in lipid metabolism, glucose metabolism, and a decrease in kidney function. In women with POI, early detection and lifelong management of metabolic abnormalities are needed.


Subject(s)
Biomarkers/metabolism , Menopause, Premature/metabolism , Metabolome , Primary Ovarian Insufficiency/metabolism , Adult , Case-Control Studies , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Cross-Sectional Studies , Female , Humans , Primary Ovarian Insufficiency/pathology , Triglycerides/blood , Young Adult
7.
PLoS One ; 16(3): e0247398, 2021.
Article in English | MEDLINE | ID: mdl-33690615

ABSTRACT

BACKGROUND: Several forms of pulmonary hypertension (PH) disproportionately affect women. Animal and human studies suggest that estradiol exerts mixed effects on the pulmonary vasculature. Whether premature menopause represents a risk factor for PH is unknown. METHODS AND FINDINGS: In this cohort study, women in the UK Biobank aged 40-69 years who were postmenopausal and had complete data available on reproductive history were included. Premature menopause, defined as menopause occurring before age 40 years. Postmenopausal women without premature menopause served as the reference group. The primary outcome was incident PH, ascertained by appearance of a qualifying ICD code in the participant's UK Biobank study record. Of 136,715 postmenopausal women included, 5,201 (3.8%) had premature menopause. Participants were followed up for a median of 11.1 (interquartile range 10.5-11.8) years. The primary outcome occurred in 38 women (0.73%) with premature menopause and 409 (0.31%) without. After adjustment for age, race, ever-smoking, body-mass index, systolic blood pressure, antihypertensive medication use, non-high-density lipoprotein cholesterol, cholesterol-lowering medication use, C-reactive protein, prevalent type 2 diabetes, obstructive sleep apnea, heart failure, mitral regurgitation, aortic stenosis, venous thromboembolism, forced vital capacity (FVC), the forced expiratory volume in 1 second-to-FVC ratio, use of menopausal hormone therapy, and hysterectomy status, premature menopause was independently associated with PH (hazard ratio 2.13, 95% CI 1.31-3.23, P<0.001). In analyses of alternate menopausal age thresholds, risk of PH appeared to increase progressively with younger age at menopause (Ptrend <0.001), with 4.8-fold risk in women with menopause before age 30 years (95% CI 1.82-12.74, P = 0.002). Use of menopausal hormone therapy did not modify the association of premature menopause with PH. CONCLUSIONS: Premature menopause may represent an independent risk factor for PH in women. Further investigation of the role of sex hormones in PH is needed in animal and human studies to elucidate pathobiology and identify novel therapeutic targets.


Subject(s)
Gonadal Steroid Hormones/metabolism , Hypertension, Pulmonary/epidemiology , Menopause, Premature/metabolism , Adult , Aged , Biological Specimen Banks , Cohort Studies , Female , Humans , Hypertension, Pulmonary/etiology , Incidental Findings , Middle Aged , Risk Factors , United Kingdom/epidemiology
8.
Gynecol Endocrinol ; 36(8): 687-692, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32429709

ABSTRACT

Objective: We aimed to investigate the relationship between oxidative stress (OS) and subclinical atherosclerosis in patients with premature ovarian insufficiency (POI), by analyzing the dynamic thiol/disulfide homeostasis (TDH) parameters as an OS marker and carotid intima-media thickness (CIMT).Materials and methods: A total of 69 women, 34 with POI and 35 healthy controls were included in this prospective cross-sectional study. TDH parameters (plasma native thiol, total thiol, disulfide, disulfide/native thiol, native thiol/total thiol, and disulfide/total thiol ratios) and CIMT were measured and compared between the two groups.Results: In primary ovarian insufficiency group, native thiol (p=.009) and total thiol (p=.010) levels were significantly decreased, and CIMT values were significantly increased (p= <.001). CIMT values were negatively correlated with native thiol (r=-0.553, p=.001) and total thiol levels (r=-0.565, p=.001); and positively correlated with age (r = 0.457, p=.007), BMI (r = 0.408, p=.017), and total cholesterol (r = 0.605, p<.001) in POI group.Conclusions: Decreased native thiol and total thiol levels demonstrate the defective anti-oxidant mechanism in POI. Negative correlation between native thiol, total thiol levels, and CIMT means the presence of abnormal anti-oxidant mechanisms may play a role in the development of subclinical atherosclerosis in patients with POI. This is a novel report on the mechanism of subclinical atherosclerosis in women with POI, which needs to be supported with further studies evaluating the pathophysiology of OS.


Subject(s)
Atherosclerosis/etiology , Carotid Intima-Media Thickness , Oxidative Stress/physiology , Primary Ovarian Insufficiency/complications , Adult , Asymptomatic Diseases , Atherosclerosis/complications , Atherosclerosis/diagnosis , Atherosclerosis/metabolism , Biomarkers/analysis , Biomarkers/blood , Cardiometabolic Risk Factors , Case-Control Studies , Cross-Sectional Studies , Disulfides/blood , Female , Humans , Menopause, Premature/metabolism , Menopause, Premature/physiology , Primary Ovarian Insufficiency/metabolism , Primary Ovarian Insufficiency/pathology , Primary Ovarian Insufficiency/physiopathology , Sulfhydryl Compounds/blood , Young Adult
9.
PLoS One ; 15(3): e0229576, 2020.
Article in English | MEDLINE | ID: mdl-32134933

ABSTRACT

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in women worldwide. The cardiovascular risk profile deteriorates after women enter menopause. By definition, women diagnosed with premature ovarian insufficiency (POI) experience menopause before 40 years of age, which may render these women even more susceptible to develop CVD later in life. However, prospective long-term follow up data of well phenotyped women with POI are scarce. In the current study we compare the CVD profile and risk of middle aged women previously diagnosed with POI, to a population based reference group matched for age and BMI. METHODS AND FINDINGS: We compared 123 women (age 49.0 (± 4.3) years) and diagnosed with POI 8.1 (IQR: 6.8-9.6) years earlier, with 123 population controls (age 49.4 (± 3.9) years). All women underwent an extensive standardized cardiovascular screening. We assessed CVD risk factors including waist circumference, BMI, blood pressure, lipid profile, pulse wave velocity (PWV), and the prevalence of diabetes mellitus, metabolic syndrome (MetS) and carotid intima media thickness (cIMT), in both women with POI and controls. We calculated the 10-year CVD Framingham Risk Score (FRS) and the American Heart Association's suggested cardiovascular health score (CHS). Waist circumference (90.0 (IQR: 83.0-98.0) versus 80.7 (IQR: 75.1-86.8), p < 0.01), waist-to-hip ratio (0.90 (IQR: 0.85-0.93) versus 0.79 (IQR: 0.75-0.83), p < 0.01), systolic blood pressure (124 (IQR 112-135) versus 120 (IQR109-131), p < 0.04) and diastolic blood pressure (81 (IQR: 76-89) versus 78 (IQR: 71-86), p < 0.01), prevalence of hypertension (45 (37%) versus 21 (17%), p < 0.01) and MetS (19 (16%) versus 4 (3%), p < 0.01) were all significantly increased in women with POI compared to healthy controls. Other risk factors, however, such as lipids, glucose levels and prevalence of diabetes were similar comparing women with POI versus controls. The arterial stiffness assessed by PWV was also similar in both populations (8.1 (IQR: 7.1-9.4) versus 7.9 (IQR: 7.1-8.4), p = 0.21). In addition, cIMT was lower in women with POI compared to controls (550 µm (500-615) versus 684 µm (618-737), p < 0.01). The calculated 10-year CVD risk was 5.9% (IQR: 3.7-10.6) versus 6.0% (IQR: 3.9-9.0) (p = 0.31) and current CHS was 6.1 (1.9) versus 6.5 (1.6) (p = 0.07), respectively in POI versus controls. CONCLUSIONS: Middle age women with POI presented with more unfavorable cardiovascular risk factors (increased waist circumference and a higher prevalence of hypertension and MetS) compared to age and BMI matched population controls. In contrast, the current study reveals a lower cIMT and similar 10-year cardiovascular disease risk and cardiovascular health score. In summary, neither signs of premature atherosclerosis nor a worse cardiovascular disease risk or health score were observed among middle age women with POI compared to population controls. Longer-term follow-up studies of women of more advanced age are warranted to establish whether women with POI are truly at increased risk of developing CVD events later in life. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02616510.


Subject(s)
Cardiovascular Diseases/physiopathology , Cardiovascular System/physiopathology , Primary Ovarian Insufficiency/physiopathology , Atherosclerosis/blood , Atherosclerosis/metabolism , Atherosclerosis/physiopathology , Blood Pressure/physiology , Cardiovascular Diseases/blood , Cardiovascular Diseases/metabolism , Cardiovascular System/metabolism , Case-Control Studies , Diabetes Mellitus/physiopathology , Female , Glucose/metabolism , Humans , Hypertension/blood , Hypertension/metabolism , Hypertension/physiopathology , Lipids/blood , Menopause/blood , Menopause/metabolism , Menopause/physiology , Menopause, Premature/blood , Menopause, Premature/metabolism , Menopause, Premature/physiology , Middle Aged , Primary Ovarian Insufficiency/blood , Primary Ovarian Insufficiency/metabolism , Prospective Studies , Pulse Wave Analysis/methods , Risk Factors , Vascular Stiffness/physiology , Waist Circumference/physiology , Waist-Hip Ratio/methods
10.
Clin Endocrinol (Oxf) ; 91(4): 498-507, 2019 10.
Article in English | MEDLINE | ID: mdl-31218708

ABSTRACT

OBJECTIVE: Osteoporosis associated with premature ovarian insufficiency (POI) and early menopause (EM) is a major concern for women. We aimed to (a) identify information and knowledge gaps and behaviours regarding bone health in women with POI/EM and (b) co-design an osteoporosis fact sheet. DESIGN: Mixed-methods study: survey of women and online resource appraisals to develop and refine, using semi-structured interviews, an osteoporosis fact sheet. PATIENTS: Women with POI/EM (menopause before ages 40 and 45 years respectively). MEASUREMENTS: Demographics, comorbidities, information needs, calcium intake, exercise, osteoporosis knowledge (OKAT), beliefs and self-efficacy, DISCERN appraisal (validated scales). ANALYSIS: descriptive statistics, logistic regression and thematic analysis of interviews. RESULTS: Median age of survey respondents (n = 316) was 54(IQR47-63) years, median age of menopause was 40(IQR38-43) years, and osteoporosis diagnosis was reported in 19%. Most reported inadequate dietary calcium intake (99%) and exercise (65%). Median OKAT score 8 [IQR6-10]/19 indicated knowledge gaps regarding risk factors and treatment options. Adjusting for age and education, OKAT predicted calcium intake (OR 1.126 [CI 1.035-1.225]; P = 0.006) and screening (OR 1.186 [CI 1.077-1.305]; P = 0.001); beliefs predicted screening (OR 1.027 [CI 1.004-1.050]; P = 0.019); and self-efficacy predicted calcium intake (OR1.040 (CI 1.013-1.069); P = 0.003] and exercise (OR 1.117 [CI 1.077-1.160]; P < 0.001). Current online resources have deficiencies. Five themes identified from two interview rounds (n = 10/ round) were as follows: content, emotional response, design, perceived usefulness and clinical considerations. The final fact sheet was considered acceptable and useful in addressing knowledge gaps, promoting information-seeking, impacting behaviours and facilitating healthcare discussions. CONCLUSION: A co-designed fact sheet is acceptable and addresses identified osteoporosis knowledge gaps in women with POI/EM.


Subject(s)
Menopause, Premature/metabolism , Menopause, Premature/physiology , Osteoporosis/diagnosis , Osteoporosis/metabolism , Primary Ovarian Insufficiency/metabolism , Primary Ovarian Insufficiency/physiopathology , Adult , Exercise/physiology , Female , Humans , Logistic Models , Middle Aged , Risk Factors
11.
Eur J Endocrinol ; 180(1): 41-50, 2019 Jan 01.
Article in English | MEDLINE | ID: mdl-30400047

ABSTRACT

Objective/Design Menopausal transition has been associated with a derangement of glucose metabolism. However, it is not known if early menopause (EM, defined as age at menopause <45 years) or premature ovarian insufficiency (POI, defined as age at menopause <40 years) are associated with increased risk of type 2 diabetes mellitus (T2DM). To systematically investigate and meta-analyze the best evidence regarding the association of age at menopause with the risk of T2DM. Methods A comprehensive search was conducted in PubMed, CENTRAL and Scopus, up to January 31, 2018. Data are expressed as odds ratio (OR) with 95% confidence intervals (CI). The I 2 index was employed for heterogeneity. Results Thirteen studies were included in the qualitative and quantitative analysis (191 762 postmenopausal women, 21 664 cases with T2DM). Both women with EM and POI were at higher risk of T2DM compared with those of age at menopause of 45-55 years (OR: 1.15, 95% CI: 1.04-1.26, P = 0.003; I 2: 61%, P < 0.002 and OR: 1.50, 95% CI: 1.03-2.19, P = 0.033; I 2: 75.2%, P < 0.003), respectively). Similar associations emerged when women with EM and POI were compared with those of age at menopause >45 years (OR: 1.12, 95% CI: 1.01-1.20, P < 0.02; I 2: 78%, P < 0.001 and OR: 1.53, 95% CI: 1.03-2.27, P = 0.035; I 2: 78%, P < 0.001), respectively). Conclusions Both EM and POI are associated with increased risk of T2DM.


Subject(s)
Diabetes Mellitus, Type 2/etiology , Menopause, Premature/metabolism , Primary Ovarian Insufficiency/complications , Diabetes Mellitus, Type 2/metabolism , Female , Humans , Risk Factors
12.
Fertil Steril ; 110(5): 790-793, 2018 10.
Article in English | MEDLINE | ID: mdl-30316413

ABSTRACT

One in three American women will die from cardiovascular disease (CVD), making it the leading cause of death among women in the United States. Traditionally, CVD has been seen as a disease of postmenopausal women, yet increasingly, risk factors for CVD are being characterized earlier. Although menopause, and its associated hypoestrogenism, has been consistently linked to CVD risk, accelerated ovarian aging among premenopausal patients has become a focus of attempts to identify women with increased CVD risk earlier. We present a review of the evidence for the association between early menopause and diminished ovarian reserve with CVD and its risk factors.


Subject(s)
Aging/metabolism , Cardiovascular Diseases/metabolism , Ovarian Reserve/physiology , Ovary/metabolism , Women's Health/trends , Aging/pathology , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/mortality , Female , Humans , Menopause/metabolism , Menopause, Premature/metabolism , Ovary/pathology , Risk Factors
13.
BMC Cancer ; 18(1): 930, 2018 Sep 26.
Article in English | MEDLINE | ID: mdl-30257669

ABSTRACT

BACKGROUND: Improved risk stratification, more effective therapy and better supportive care have resulted in survival rates after childhood cancer of around 80% in developed countries. Treatment however can be harsh, and three in every four childhood cancer survivors (CCS) develop at least one late effect, such as gonadal impairment. Gonadal impairment can cause involuntary childlessness, with serious consequences for the well-being of CCS. In addition, early menopause increases the risk of comorbidities such as cardiovascular disease and osteoporosis. Inter-individual variability in susceptibility to therapy related gonadal impairment suggests a role for genetic variation. Currently, only one candidate gene study investigated genetic determinants in relation to gonadal impairment in female CCS; it yielded one single nucleotide polymorphism (SNP) that was previously linked with the predicted age at menopause in the general population of women, now associated with gonadal impairment in CCS. Additionally, one genome wide association study (GWAS) evaluated an association with premature menopause, but no GWAS has been performed using endocrine measurements for gonadal impairment  as the primary outcome in CCS. METHODS: As part of the PanCareLIFE study, the genetic variability of chemotherapy induced gonadal impairment among CCS will be addressed. Gonadal impairment will be determined by anti-Müllerian hormone (AMH) levels or alternatively by fertility and reproductive medical history retrieved by questionnaire. Clinical and genetic data from 837 non-brain or non-bilateral gonadal irradiated long-term CCS will result in the largest clinical European cohort assembled for this late-effect study to date. A candidate gene study will examine SNPs that have already been associated with age at natural menopause and DNA maintenance in the general population. In addition, a GWAS will be performed to identify novel allelic variants. The results will be validated in an independent CCS cohort. DISCUSSION: This international collaboration aims to enhance knowledge of genetic variation which may be included in risk prediction models for gonadal impairment in CCS.


Subject(s)
Anti-Mullerian Hormone/analysis , Menopause, Premature/genetics , Polymorphism, Single Nucleotide , Adult Survivors of Child Adverse Events , Cancer Survivors , Female , Genome-Wide Association Study , Humans , Menopause, Premature/metabolism , Surveys and Questionnaires
14.
Actual. osteol ; 14(2): 148-150, Mayo - Ago. 2018. ilus
Article in Spanish | LILACS | ID: biblio-1116417

ABSTRACT

El término "distrofia ósea esclerosante mixta" describe la combinación de las características radiológicas correspondientes a melorreostosis, osteopoiquilosis y osteopatía estriada, como entidades individuales, que ocurren en un mismo paciente. El objetivo de esta comunicación es presentar el caso clínico de una paciente con diagnóstico de distrofia ósea esclerosante mixta y, a partir de este caso, realizar una revisión sobre el tema. (AU)


The term "mixed-sclerosing-bone-dystrophy" describes the combination of the radiological characteristics corresponding to melorheostosis, osteopoikilosis and osteopathia striata, as individual conditions, ocurring in the same patient. The aim of this communication is to present the clinical case of a patient diagnosed with mixed-sclerosing-bone-dystrophy and, based on this case, to undertake a review of this condition. (AU)


Subject(s)
Humans , Female , Adult , Osteopoikilosis/diagnosis , Bone Diseases, Metabolic/diagnosis , Melorheostosis/diagnosis , Osteitis Deformans/diagnosis , Osteitis Deformans/drug therapy , Osteitis Deformans/blood , Osteopoikilosis/blood , Radiology , Tibia/diagnostic imaging , Bone Diseases, Metabolic/blood , Menopause, Premature/metabolism , Femur/diagnostic imaging , Pamidronate/administration & dosage , Melorheostosis/blood
15.
Endocrinol Metab Clin North Am ; 44(3): 543-57, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26316242

ABSTRACT

A heterogeneous disorder, premature menopause is not an uncommon entity, affecting approximately 1% of women younger than 40 years. Multisystem implications are recognized as sequelae to the premature deprivation of ovarian steroids, posing unique health-related challenges in this population. An integrated management approach that addresses both the physical and psychological health concerns and the overall well-being of this relatively chronologically young population is paramount.


Subject(s)
Menopause, Premature/metabolism , Primary Ovarian Insufficiency/diagnosis , Female , Humans , Primary Ovarian Insufficiency/metabolism
16.
Ter Arkh ; 86(8): 75-9, 2014.
Article in Russian | MEDLINE | ID: mdl-25306748

ABSTRACT

AIM: To study the formation of and trends in risk factors (RFs) for cardiovascular disease (CVD), their influence on the occurrence of early (preclinical) atherosclerotic lesions, a combination of these changes with osteoporosis (OP) in women following bilateral oophorectomy depending on whether hormone replacement therapy (HRT) is performed. SUBJECTS AND METHODS: The investigation enrolled 50 women with surgical menopause after bilateral oophorectomy in combination with hysterectomy who received estrogen monotherapy (a study group) and 37 patients who underwent the same operation, but had no HRT (a control group). The study group patients were examined twice (before and 10 years after HRT); the comparison group was examined once in the same period postsurgery. The investigators conducted Doppler study of the great arteries of the head and neck and measured pulse wave velocity, as well as they made dual-energy X-ray densitometry to estimate bone mineral density and a detailed analysis of the most common RFs for CVD. RESULTS: There was an increase in the prevalence of RFs for CVD and a change in their structure, which were particularly marked in the women who received no HRT, their impact on the development of early atherosclerotic changes naturally progressing with the number of RFs. The similar trend was observed for bone tissue changes: a higher incidence of osteopenia and OP during the follow-up. CONCLUSION: The high percentage of a concurrence of osteoporosis and atherosclerosis argues for that there are common pathogenic mechanisms.


Subject(s)
Atherosclerosis/etiology , Estrogen Replacement Therapy/methods , Menopause, Premature/metabolism , Osteoporosis, Postmenopausal/etiology , Ovariectomy , Atherosclerosis/epidemiology , Atherosclerosis/metabolism , Atherosclerosis/prevention & control , Blood Glucose/metabolism , Bone Density , Female , Humans , Lipids/blood , Middle Aged , Osteoporosis, Postmenopausal/epidemiology , Osteoporosis, Postmenopausal/metabolism , Osteoporosis, Postmenopausal/prevention & control , Risk Factors , Time Factors
17.
Maturitas ; 79(3): 306-10, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25085705

ABSTRACT

OBJECTIVE: We designed a prospective case-control study in order to investigate the lipid profiles, insulin sensitivity, presence of metabolic syndrome (MetS) and the abdominal fat distribution in karyotypically normal women with premature ovarian insufficiency (POI). METHODS: Anthropometric measurements, FSH, estradiol, total testosterone (T), sex hormone binding globulin (SHBG), free androgen index (FAI), fasting glucose and insulin, homeostatic model for insulin resistance (HOMA-IR), lipid profile, the prevalence of MetS and ultrasonographic abdominal fat measurements were assessed in 56 women with POI and 59 healthy controls at the same age range. RESULTS: Serum levels of T, SHBG and FAI were not significantly different between both groups. Total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) were higher in women with POI. There were no differences in glucose, insulin, HOMA-IR, low-density lipoprotein cholesterol (LDL-C), triglyceride levels between the two groups. A significant positive correlation was identified between T and TG and also between FAI and LDL-C; SHBG levels were correlated inversely with FSH, and positively with HDL-C in women with POI. The presence of MetS was significantly higher in women with POI. The subcutaneous, preperitoneal and visceral fat thicknesses were not significantly different between the groups. CONCLUSIONS: Early cessation of ovulatory function may associated with higher levels of serum TC and HDL-C, but does not seem to cause differences in abdominal fat distribution in women with POI. POI is associated with higher risk of MetS.


Subject(s)
Abdominal Fat/diagnostic imaging , Metabolic Syndrome/metabolism , Primary Ovarian Insufficiency/metabolism , Abdominal Fat/metabolism , Adult , Body Fat Distribution , Case-Control Studies , Cholesterol/blood , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Comorbidity , Estradiol/blood , Female , Follicle Stimulating Hormone/blood , Humans , Insulin/blood , Insulin Resistance , Lipids/blood , Luteinizing Hormone/blood , Menopause, Premature/metabolism , Metabolic Syndrome/diagnostic imaging , Metabolic Syndrome/epidemiology , Metabolome , Prevalence , Primary Ovarian Insufficiency/diagnostic imaging , Primary Ovarian Insufficiency/epidemiology , Prospective Studies , Sex Hormone-Binding Globulin/metabolism , Testosterone/blood , Ultrasonography
18.
Mol Cell Endocrinol ; 389(1-2): 2-6, 2014 May 25.
Article in English | MEDLINE | ID: mdl-24462786

ABSTRACT

Since basic scientific studies in the 1990s revealed dramatic gender differences in neurological damage from cerebral ischemia, significant evidence has accumulated for a neuroprotective role of ovarian-derived 17ß-Estradiol (E2). Intriguingly, observational studies have further suggested that early and prolonged loss of ovarian E2 (premature menopause) leads to a doubled lifetime risk for dementia and a fivefold increased risk of mortality from neurological disorders, but some controversy remains. Here, we briefly summarize and analyze clinical cohort studies assessing the detrimental neurological outcomes of premature menopause. Furthermore, we discuss current basic science studies elucidating the molecular mechanisms underlying the enhanced risk of neurological disease in prematurely menopausal women and the "window of opportunity" for estrogen benefit. Finally, we highlight four critical issues in the field that require collaboration between basic scientists and clinicians for successful resolution, with the ultimate goal of maintaining optimal neurological health in prematurely menopausal women.


Subject(s)
Menopause, Premature/physiology , Nervous System Diseases/physiopathology , Cohort Studies , Estrogens/metabolism , Female , Humans , Menopause, Premature/metabolism , Nervous System Diseases/metabolism , Risk , Women's Health
19.
Climacteric ; 17(4): 348-55, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24188285

ABSTRACT

OBJECTIVES: This study aimed to compare metabolic syndrome and its components in naturally and surgically menopausal women. METHODS: This is a longitudinal study, with incident case and control groups, conducted on 446 women participants of the Tehran Lipid and Glucose Study, who experienced surgical or natural menopause over a 10-year period. In both groups, data collection was conducted using questionnaires including information on demographic, reproductive and metabolic characteristics at baseline and again after 3 years. Physical examinations and the biochemical profiles were also assessed. RESULTS: During the follow-up, metabolic syndrome was observed in 28.7% and 32.5% of the naturally menopause and surgically menopausal women, respectively. Mean fasting blood sugar and 2-h plasma glucose were significantly higher in the surgically menopause group, compared to the naturally menopause one, whereas mean systolic blood pressure was significantly higher in naturally menopausal women as compared to surgically menopause ones, after further adjustment for premenopausal status. CONCLUSIONS: Although no difference in the prevalence of metabolic syndrome in naturally menopausal women and in surgically menopausal women was found, the components of metabolic syndrome were more prevalent among those with surgical menopause.


Subject(s)
Menopause, Premature/metabolism , Menopause/metabolism , Metabolic Syndrome , Ovariectomy/adverse effects , Postoperative Complications , Adult , Blood Glucose/analysis , Blood Pressure , Female , Humans , Iran/epidemiology , Lipids/blood , Longitudinal Studies , Metabolic Syndrome/diagnosis , Metabolic Syndrome/epidemiology , Metabolic Syndrome/etiology , Metabolic Syndrome/metabolism , Middle Aged , Postoperative Complications/diagnosis , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Postoperative Complications/metabolism , Prevalence , Socioeconomic Factors , Women's Health
20.
Crit Rev Oncol Hematol ; 89(1): 27-42, 2014 Jan.
Article in English | MEDLINE | ID: mdl-23953684

ABSTRACT

Cytotoxic chemotherapy may variably affect ovarian function depending on age and ovarian reserve at diagnosis, type of chemotherapy and use of tamoxifen. Ascertaining whether a premenopausal patient with endocrine-responsive early breast cancer and chemotherapy-induced amenorrhea has reached menopause is essential not only in order to provide accurate information on residual fertility, but also to appropriately prescribe endocrine therapy. Indeed, aromatase inhibitors are contraindicated in women with residual ovarian reserve. However, the diagnosis of menopause in patients with chemotherapy-induced amenorrhea is challenging, since clinical features, follicle-stimulating hormone and estradiol levels may be inaccurate to this aim. Recent studies demonstrated that the anti-müllerian hormone may improve the assessment of ovarian reserve residual to chemotherapy in women with early breast cancer. Herein, we review the incidence of amenorrhea and menopause induced by cytotoxic chemotherapy in women affected by early breast cancer and the suggested mechanisms that sustain these side-effects. Furthermore, it has been scrutinized the potential of new markers of ovarian reserve that may facilitate the selection of appropriate endocrine treatment for premenopausal women who develop amenorrhea following adjuvant chemotherapy for early breast cancer.


Subject(s)
Amenorrhea/chemically induced , Antineoplastic Agents, Hormonal/adverse effects , Breast Neoplasms/complications , Menopause, Premature/drug effects , Amenorrhea/metabolism , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/therapeutic use , Biomarkers/metabolism , Breast Neoplasms/drug therapy , Chemotherapy, Adjuvant , Female , Fertility Preservation , Humans , Menopause, Premature/metabolism , Ovarian Diseases/chemically induced , Ovarian Diseases/metabolism , Prognosis
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