Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
- MeSH
- alely MeSH
- celogenomová asociační studie MeSH
- checkpoint kinasa 1 genetika MeSH
- checkpoint kinasa 2 genetika MeSH
- diabetes mellitus 2. typu MeSH
- dieta MeSH
- dlouhověkost genetika MeSH
- dospělí MeSH
- fertilita genetika MeSH
- genetická predispozice k nemoci MeSH
- kosti a kostní tkáň metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- menopauza genetika MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- ovarium metabolismus MeSH
- předčasná menopauza genetika MeSH
- primární ovariální insuficience genetika MeSH
- protein FMRP genetika MeSH
- stárnutí genetika MeSH
- uterus MeSH
- zdravé stárnutí genetika MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Dálný východ etnologie MeSH
- Evropa etnologie MeSH
- Názvy látek
- checkpoint kinasa 1 MeSH
- checkpoint kinasa 2 MeSH
- Chek1 protein, mouse MeSH Prohlížeč
- Chek2 protein, mouse MeSH Prohlížeč
- FMR1 protein, human MeSH Prohlížeč
- protein FMRP MeSH
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.
- Klíčová slova
- Childhood cancer survivor, GWAS, Genetic variations, Late effects, SNPs,
- MeSH
- antimülleriánský hormon analýza MeSH
- celogenomová asociační studie MeSH
- dospělí traumatizovaní v dětství MeSH
- jednonukleotidový polymorfismus * MeSH
- lidé MeSH
- předčasná menopauza genetika metabolismus MeSH
- přežívající onkologičtí pacienti MeSH
- průzkumy a dotazníky MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- protokol klinické studie MeSH
- Názvy látek
- antimülleriánský hormon MeSH
Ovarian suppression or ovarian ablation used in treatment of breast carcinoma results in temporary or permanent menopause and associated menopausal symptoms - most frequently vasomotoric symptoms (hot flashes, sweats), vaginal atrophy, sleep disturbances. Patients can also experience frequent decrease in bone density (osteopenia, osteoporosis), mood swings or depression, less frequently cardiac toxicity. Managements of these symptoms is complex. As hormonal replacement therapy (estrogens or combined estrogen/gestagen therapy) is contraindicated in women with breast carcinoma, other available options include non-hormonal pharmacological or non-pharmacological methods or their combinations. Women should be advised about cooling techniques and how to avoid known triggers; these measures should be combined with other non-pharmacological and pharmacological intervention. Non-pharmacological methods include the use of acupuncture or cognitive behavioral therapy. Some tips to help stay cool and decrease hot flashes - avoid hot beverages, spicy food, limit coffee or alcohol intake, dress in layers of clothing that can be removed if necessary. Pharmacological options include most frequently antidepressants - SSRI (selective serotonin reuptake inhibitor), SNRI (serotonin norepinephrin reuptake inhibitor), or alternatively gabapentin or pregabali. A very promising drug is paroxetine with a lot of clinical trials. Only this drug has FDA approval for the indication of hot flashes. Paroxetine can lead to disproportional changes in plasma levels of drug in CYP2D6 metabolism and thus it is not suitable for combination of paroxetine with tamoxifen. Several studies demonstrated the effectiveness of the newer generation of SSRI - citalopram, escitalopram, sertralin and duloxetin in ameliorating hot flashes. Venlafaxine in dose 75 or 150 mg has been associated with a 61% reduction in hot flashes frequency if compared to 27% reduction with placebo. Medroxyprogesterone acetate and megestrol acetate were investigated especially in patients with breast cancer history and both drugs demonstrate an effect in hot flashes treatment. Management of vaginal atrophy is challenging. Vaginal dryness/atrophy can be relieved with use of topical lubricants/gels or possibly in highly symptomatic patients with short term use of topical estrogens. As these symptoms require highly complex management, multidisciplinary approach is recommended.Key words: breast cancer - postmenopause - ovarian suppression - postmenopausal osteoporosis - therapyThis work was supported by grant of the Czech Ministry of Health - RVO (MOÚ, 00209805).The author declares she has no potential conflicts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 20. 7. 2016Accepted: 10. 8. 2016.
- MeSH
- ablace * MeSH
- antitumorózní látky hormonální terapeutické užití MeSH
- lidé MeSH
- menopauza * MeSH
- nádory prsu * MeSH
- návaly MeSH
- ovarektomie MeSH
- ovarium * účinky léků účinky záření chirurgie MeSH
- předčasná menopauza MeSH
- selektivní inhibitory zpětného vychytávání serotoninu MeSH
- tamoxifen terapeutické užití MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antitumorózní látky hormonální MeSH
- selektivní inhibitory zpětného vychytávání serotoninu MeSH
- tamoxifen MeSH
Radical hysterectomy for early stage cervical cancer has satisfactory results in terms of survival, but may impact negatively on a patient's quality of life, which may include sexual dysfunctions. Female sexual dysfunctions (FSD) represent a frequent morbidity but often remain unrecognized and undertreated. Although discussions regarding sexuality are found by many medical doctors to be sensitive and embarrassing, psychosexual counseling is an essential component of comprehensive care for gynecological cancer patients and their partners. The goal of this article is to summarize and discuss available relevant data on FSD in women who have undergone radical hysterectomy for an early stage of cervical cancer.
- MeSH
- dyspareunie etiologie patofyziologie psychologie MeSH
- hladké svalstvo inervace MeSH
- hysterektomie škodlivé účinky metody psychologie MeSH
- kvalita života MeSH
- libido MeSH
- lidé MeSH
- lymfadenektomie MeSH
- lymfedém etiologie psychologie MeSH
- nádory děložního čípku chirurgie MeSH
- ovarektomie škodlivé účinky psychologie MeSH
- pooperační komplikace etiologie psychologie MeSH
- poranění periferního nervu MeSH
- předčasná menopauza MeSH
- představa o vlastním těle MeSH
- relaxace svalu MeSH
- sexuální dysfunkce fyziologická etiologie patofyziologie psychologie MeSH
- vagina inervace MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: Several studies suggest that changes in estrogens and androgens during menopause play a role in the regulation of leptin production. Some authors present hypothesis that sex hormone replacement therapy can modulate leptin levels but up to date evidence shows that the influence of endogenous estrogens, androgens levels and sex hormone therapy on leptin concentration remains uncertain. AIM: To evaluate the influence of surgically induced menopause on serum leptin levels and the influence of different types of hormonal therapy on serum leptin concentrations. METHODS: 58 women with surgically induced menopause were divided into three groups. Women who did not receive any hormonal substitution (group 1), women who received Estradiol l mg per day (group 2) and women who received Tibolone 2,5 mg per day (group 3). The levels of leptin, estradiol, testosterone, testosterone, dehydroepiandrosterone sulfate, FSH, LH and progesterone were measured in all subjects on the 5th day and after 3 months following the surgical procedure. RESULTS: Mean serum leptin concentrations did not differ statistically in any of the studied groups in the beginning and in the end of the study. There was no correlations between serum leptin and estradiol, LH, FSH, progesterone, testosterone, free testosterone and DHEAS concentrations in any of groups before and after treatment. CONCLUSION: Changes in sex hormone concentrations caused by ovariectomy do not influence serum leptin concentrations. Also the short term administration of low dose estrogen therapy or tibolone in postmenopausal subjects does not change serum leptin levels.
- MeSH
- dospělí MeSH
- estradiol terapeutické užití MeSH
- estrogenní substituční terapie * MeSH
- hysterektomie MeSH
- leptin krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- modulátory estrogenních receptorů terapeutické užití MeSH
- norpregneny terapeutické užití MeSH
- ovarektomie škodlivé účinky MeSH
- předčasná menopauza krev MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- estradiol MeSH
- leptin MeSH
- modulátory estrogenních receptorů MeSH
- norpregneny MeSH
- tibolone MeSH Prohlížeč
BACKGROUND: The purpose of the present study was to determine changes of plasminogen activator inhibitor-1 (PAI-1) as biochemical cardiovascular risk factor during the use of different administration methods in the early estrogen replacement therapy. METHODS AND RESULTS: In a 12-week prospective, randomized, interventional, cross-over trial, oestradiol was administered orally in a dose of 2 mg daily or transdermally in a dose of 0.05 mg daily. Forty-five healthy postmenopausal women were included into the study within 12 weeks after the hysterectomy and ovariectomy (surgical castration). Forty-one women completed the study and their data were analyzed. The average age was of 49 +/- 6 years. PAI-1 was determined by bioimmunoassay (Chromolyze PAI-1). The PAI-1 level decreased statistically significantly (p = 0.001) after the oral oestrogen therapy from 11.39 +/- 12.02 IU/l to 5.0 +/- 5.27 IU/l. Changes are also significant compared with non-significant changes after the transdermal therapy. CONCLUSIONS: The oral therapy reduced statistically significantly PAI-1 levels compared with the transdermal method of administration. This change is beneficial from the view of cardiovascular risk.
- MeSH
- aplikace kožní MeSH
- aplikace orální MeSH
- estradiol aplikace a dávkování MeSH
- estrogenní substituční terapie * MeSH
- hysterektomie MeSH
- inhibitor aktivátoru plazminogenu 1 krev MeSH
- klinické křížové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- ovarektomie MeSH
- předčasná menopauza MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
- Názvy látek
- estradiol MeSH
- inhibitor aktivátoru plazminogenu 1 MeSH
OBJECTIVE: Evaluation of changes in mammographic and ultrasound images of the breast in women using hormonal substitution therapy (HST). DESIGN: Retrospective clinical study. METHODS: A cohort of 430 women with menopause, who have been using hormonal substitution therapy (HST) for 2-10 years, and the control population of 150 women with menopause not using HST were selected for the study. 304 women used combined HST (an oestrogen and a progestogen combination) and 126 women with surgical menopause used oestrogen hormonal substitution (EST). The mammographic and ultrasound image changes were monitored separately in the women's population with combined and oestrogen hormonal substitution and also in relation to the individual types of breast and relative to the application form of the hormonal preparation. In 105 women with HST, the ultrasound image changes were monitored as well. RESULTS: In women with menopause using HST, there was a statistically significant increase of mammographic image density recorded. It was twice as frequent in the women using the combined HST as in the women using oestrogen monotherapy. In the women using oestrogen substitution, there was a monitorable mammographic density increase in a greater percentage of women with orally used preparation in comparison with the women with intradermal oestrogen administration. The mammographic density increase was more significant in both groups and more frequent in women with a prevalence of fatty breast tissue (type II and III according to Tabár). In ultrasound examination, in women with HST, the incidence of new and enlargement of earlier existing benign formations in the breast was recorded. These ultrasound image changes were twice as frequent in the women with oestrogen monotherapy in comparison with the women with the combined hormonal substitution. Only one woman was diagnosed with carcinoma during HST use. CONCLUSIONS: In the women using the combined as well as oestrogen hormonal substitution, a statistically significant mammographic density increase was shown. The mammography density increase was statistically significantly higher in women using the combined hormonal preparation in comparison with the women with oestrogen monotherapy. Enlargement or incidence was twice as frequent in women with the oestrogen monotherapy.
- MeSH
- dospělí MeSH
- estrogenní substituční terapie * MeSH
- lidé středního věku MeSH
- lidé MeSH
- mamografie * MeSH
- menopauza MeSH
- předčasná menopauza MeSH
- ultrasonografie prsů * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
OBJECTIVE: The main known risk factors for coronary heart disease in women, other than age, which is the most important risk factor of all, are cigarette smoking, raised blood pressure, obesity, diabetes and premature menopause, especially after ovarectomy. DESIGN: Retrospective clinical study. SETTING: Medical building, Prague 7, Department of Obstetrics and Gynecology 3rd Medical Faculty Charles University and Faculty Hospital Vinohrady, Prague 10. METHODS: In 1995 and 1996 we investigated plasma lipid levels and bone density in 75 women, 3 to 5 years after ovarectomy without HRT (group A). The results were compared with a control group (group B) of women of the same age and BMI. This group of women had normal menstruation periods. We investigated age, body mass index, bone density, total cholesterol, HDL and LDL cholesterol, ateroghenic index and triglycerides. RESULTS: When we compared groups A and B, there was a better result in all serum lipid levels in group B, but not significantly. In group A was more women with patological level of HDL-cholesterol. In group A there was a significantly lower level of bone density than in group B and there was an increase in the number of patients with osteoporosis in this group. CONCLUSIONS: Castration in premenopause had no influence in mean levels of parameters of lipid metabolism, but bone density significantly decreased after castration in this period.
- MeSH
- index tělesné hmotnosti MeSH
- kostní denzita MeSH
- lidé středního věku MeSH
- lidé MeSH
- lipidy krev MeSH
- ovarektomie * MeSH
- předčasná menopauza krev MeSH
- retrospektivní studie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- Názvy látek
- lipidy MeSH
The authors report on the results of a follow-up of 64 women aged 25-64 years, to whom oestrogens were administered transdermally by means of the preparation Estraderm TTS 25 or 50 for three months. 55 women were treated for postcastration syndrome and nine women for climacteric syndrome. The authors deal with the problems of dosage of the transdermal oestrogen therapy, study the side-effects of treatment and evaluate the results of therapy. In conclusion, they recommend the transdermal form of treatment by Estraderm TTS because of its very good therapeutic effect, acceptability by the patients, and only minimal local and general side-effects.
- MeSH
- aplikace kožní MeSH
- dospělí MeSH
- estradiol aplikace a dávkování MeSH
- estrogenní substituční terapie metody MeSH
- klimakterium účinky léků MeSH
- lidé středního věku MeSH
- lidé MeSH
- ovarektomie škodlivé účinky MeSH
- předčasná menopauza * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- Názvy látek
- estradiol MeSH
