STUDY QUESTION: What is the impact of the EuroNet-PHL-C2 treatment for boys with classical Hodgkin lymphoma (cHL) on semen parameters? SUMMARY ANSWER: More than half of the patients (52%, n = 16/31) had oligozoospermia or azoospermia at 2 years from cHL diagnosis; particularly boys treated for advanced-stage cHL had low sperm counts and motility. WHAT IS KNOWN ALREADY: Chemotherapy and radiotherapy to the inguinal region or testes can impair spermatogenesis and result in reduced fertility. The EuroNet-PHL-C2 trial aims to minimize radiotherapy in standard childhood cHL treatment, by intensifying chemotherapy. The present study aims to assess the (gonadotoxic) impact of this treatment protocol on semen parameters and reproductive hormones in boys aged ≤18 years. STUDY DESIGN, SIZE, DURATION: This international, prospective, multi-centre cohort study was an add-on study to the randomized phase-3 EuroNet-PHL-C2 trial, where the efficacy of standard cHL treatment with OEPA-COPDAC-28 (OEPA: vincristine, etoposide, prednisone, and doxorubicin; COPDAC-28: cyclophosphamide, vincristine, prednisone, and dacarbazine) was compared to intensified OEPA-DECOPDAC-21 chemotherapy (DECOPDAC-21: COPDAC with additional doxorubicin and etoposide and 25% more cyclophosphamide). Patients were recruited between January 2017 and September 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligibility criteria included male patients, diagnosed with classical HL before or at the age of 18 years, and treated according to the EuroNet-PHL-C2 protocol in any of the 18 participating sites in the Netherlands, Germany, Belgium, Czech Republic, and Austria. Sperm parameters (sperm concentration, progressive motility, sperm volume, and calculated total motile sperm count) were assessed at diagnosis and 2 years after diagnosis in (post)pubertal boys. Laboratory measurements (serum follicle-stimulating hormone (FSH) and inhibin B) were performed in samples drawn at diagnosis, during treatment (2-3 times), and at 2 years post-diagnosis, and (age-adjusted) analyses were conducted separately for pre-pubertal and (post)pubertal boys. Outcomes were compared between the treatment levels (TL1, TL2, and TL3) and consolidation treatment schemes (COPDAC-28 and DECOPDAC-21). MAIN RESULTS AND THE ROLE OF CHANCE: In total, 101 boys were included in the present analysis: 73 were (post)pubertal (median age 15.4 years, (IQR 14.4; 16.6), 10 TL1, 29 TL2, 34 TL3, 62% of TL2/3 patients received COPDAC-28) and 28 boys were pre-pubertal (median age 9.6 years (IQR 6.6; 11.4), 4 TL1, 7 TL2, 17 TL3, 38% of TL2/3 patients received COPDAC-28). The study included six boys who had received pelvic radiotherapy; none were irradiated in the inguinal or testicular area. At diagnosis, 48 (post)pubertal boys delivered semen for cryopreservation; 19 (40%) semen samples were oligospermic and 4 (8%) were azoospermic. Low sperm concentration (<15 mil/ml) appeared to be related to the HL disease itself, with a higher prevalence in boys who presented with B symptoms (76% vs 26%, aOR 2.3 (95% CI 1.0; 3.8), P = 0.001) compared to those without such symptoms. At 2 -years post-diagnosis, 31 boys provided semen samples for analysis, of whom 12 (39%) boys had oligozoospermia and 4 (13%) had azoospermia, while 22 boys (71%) had low total motile sperm counts (TMSC) (<20 mil). Specifically, the eight boys in the TL3 group treated with DECOPDAC-21 consolidation had low sperm counts and low progressive motility after 2 years (i.e. median sperm count 1.4 mil/ml (IQR <0.1; 5.3), n = 7 (88%), low sperm concentration, low median progressive motility 16.5% (IQR 0.0; 51.2), respectively). Age-adjusted serum FSH levels were significantly raised and inhibin B levels (and inhibin B:FSH ratios) were decreased during chemotherapy in (post)pubertal boys, with subsequent normalization in 80% (for FSH) and 60% (for inhibin B) of boys after 2 years. Only 4 out of the 14 (post)pubertal boys (29%) with low sperm concentrations after 2 years had elevated FSH (>7.6 IU/l), while 7 (50%) had low inhibin B levels (<100 ng/l). In pre-pubertal boys, reproductive hormones were low overall and remained relatively stable during chemotherapy. LIMITATIONS, REASONS FOR CAUTION: The present analyses included sperm and laboratory measurements up to 2 years post-diagnosis. Long-term reproductive outcomes and potential recovery of spermatogenesis remain unknown, while recovery was reported up to 5- or even 10-year post-chemotherapy in previous studies.Boys who were pre-pubertal at diagnosis were still too young and/or physically not able to deliver semen after 2 years and we could not assess a potential difference in gonadotoxicity according to pubertal state at the time of treatment. Overall, the statistical power of the analyses on sperm concentration and quality after 2 years was limited. WIDER IMPLICATIONS OF THE FINDINGS: Results of the semen analyses conducted among the 31 boys who had provided a semen sample at 2 years post-treatment were generally poor. However, additional long-term and adequately powered data are crucial to assess the potential recovery and clinical impact on fertility. The participating boys will be invited to deliver a semen sample after 5 years. Until these data become available, benefits of intensified chemotherapy in cHL treatment to reduce radiotherapy and lower risk for development of secondary tumours should be carefully weighed against potentially increased risk of other late effects, such as diminished fertility due to the increased chemotherapy burden. Boys with newly diagnosed cHL should be encouraged to deliver sperm for cryopreservation whenever possible. However, patients and clinicians should also realize that the overall state of disease and inflammatory milieu of cHL can negatively affect sperm quality and thereby reduce chance of successful fertility preservation. Furthermore, the measurement of FSH and inhibin B appears to be of low value in predicting low sperm quality at two years from cHL treatment. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Dutch charity foundation KiKa (project 257) that funds research on all forms of childhood cancer. C.M.-K., D.K., W.H.W., D.H., MC, A.U., and A.B. were involved in the development of the EuroNet-PHL-C2 regimen. The other authors declare no potential conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

• MeSH
• analýza spermatu MeSH
• azoospermie farmakoterapie   MeSH
• cyklofosfamid * terapeutické užití   MeSH
• dakarbazin terapeutické užití   MeSH
• dítě MeSH
• doxorubicin terapeutické užití   škodlivé účinky   MeSH
• etoposid terapeutické užití   aplikace a dávkování   MeSH
• folikuly stimulující hormon krev   MeSH
• Hodgkinova nemoc * farmakoterapie   MeSH
• inhibiny krev   MeSH
• lidé MeSH
• mladiství MeSH
• motilita spermií účinky léků   MeSH
• oligospermie farmakoterapie   MeSH
• počet spermií MeSH
• prednison terapeutické užití   aplikace a dávkování   MeSH
• předškolní dítě MeSH
• prospektivní studie MeSH
• protokoly antitumorózní kombinované chemoterapie * terapeutické užití   škodlivé účinky   MeSH
• vinkristin terapeutické užití   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

This study hypothesized that SCFA, acetate impacts positively on hypothalamic pyroptosis and its related abnormalities in experimentally induced PCOS rat model, possibly through NrF2/HIF1-α modulation. Eight-week-old female Wister rats were divided into groups (n = 5), namely control, PCOS, acetate and PCOS + acetate groups. Induction of PCOS was performed by administering 1 mg/kg body weight of letrozole for 21 days. After PCOS confirmation, the animals were treated with 200 mg/kg of acetate for 6 weeks. Rats with PCOS were characterized with insulin resistance, leptin resistance, increased plasma testosterone as well as degenerated ovarian follicles. There was also a significant increase in hypothalamic triglyceride level, triglyceride-glucose index, inflammatory biomarkers (SDF-1 and NF-kB) and caspase-6 as well as plasma LH and triglyceride. A decrease was observed in plasma adiponectin, GnRH, FSH, and hypothalamic GABA with severe inflammasome expression in PCOS rats. These were accompanied by decreased level of NrF2/HIF1-α, and the alterations were reversed when treated with acetate. Collectively, the present results suggest the therapeutic impact of acetate on hypothalamic pyroptosis and its related comorbidity in PCOS, a beneficial effect that is accompanied by modulation of NrF2/HIF1-α.

• MeSH
• adiponektin metabolismus   krev   MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa * metabolismus   MeSH
• faktor 2 související s NF-E2 metabolismus   MeSH
• folikuly stimulující hormon krev   MeSH
• GABA metabolismus   MeSH
• hormon uvolňující gonadotropiny metabolismus   MeSH
• hypothalamus * metabolismus   účinky léků   patologie   MeSH
• inzulinová rezistence MeSH
• krysa rodu rattus MeSH
• leptin krev   metabolismus   MeSH
• letrozol farmakologie   MeSH
• luteinizační hormon krev   MeSH
• modely nemocí na zvířatech MeSH
• potkani Wistar * MeSH
• pyroptóza * účinky léků   MeSH
• syndrom polycystických ovarií * chemicky indukované   metabolismus   farmakoterapie   patologie   MeSH
• testosteron krev   MeSH
• triglyceridy krev   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma achieve an event-free survival at 5 years of about 90% after treatment with vincristine, etoposide, prednisone, and doxorubicin (OEPA) followed by cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) and radiotherapy, but long-term treatment effects affect survival and quality of life. We aimed to investigate whether radiotherapy can be omitted in patients with morphological and metabolic adequate response to OEPA and whether modified consolidation chemotherapy reduces gonadotoxicity. METHODS: Our study was designed as a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial, and was carried out at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed intermediate-stage (treatment group 2) and advanced-stage (treatment group 3) classical Hodgkin lymphoma who were younger than 18 years and stratified according to risk using Ann Arbor disease stages IIAE, IIB, IIBE, IIIA, IIIAE, IIIB, IIIBE, and all stages IV (A, B, AE, and BE) were included in the study. Patients with early disease (treatment group 1) were excluded from this analysis. All patients were treated with two cycles of OEPA (1·5 mg/m2 vincristine taken intravenously capped at 2 mg, on days 1, 8, and 15; 125 mg/m2 etoposide taken intravenously on days 1-5; 60 mg/m2 prednisone taken orally on days 1-15; and 40 mg/m2 doxorubicin taken intravenously on days 1 and 15). Patients were randomly assigned to two (treatment group 2) or four (treatment group 3) cycles of COPP (500 mg/m2 cyclophosphamide taken intravenously on days 1 and 8; 1·5 mg/m2 vincristine taken intravenously capped at 2 mg, on days 1 and 8; 40 mg/m2 prednisone taken orally on days 1 to 15; and 100 mg/m2 procarbazine taken orally on days 1 to 15) or COPDAC, which was identical to COPP except that 250 mg/m2 dacarbazine administered intravenously on days 1 to 3 replaced procarbazine. The method of randomisation (1:1) was minimisation with stochastic component and was centrally stratified by treatment group, country, trial sites, and sex. The primary endpoint was event-free survival, defined as time from treatment start until the first of the following events: death from any cause, progression or relapse of classical Hodgkin lymphoma, or occurrence of secondary malignancy. The primary objectives were maintaining 90% event-free survival at 5 years in patients with adequate response to OEPA treated without radiotherapy and to exclude a decrease of 8% in event-free survival at 5 years in the embedded COPDAC versus COPP randomisation to show non-inferiority of COPDAC. Efficacy analyses are reported per protocol and safety in the intention-to-treat population. The trial is registered with ClinicalTrials.gov (trial number NCT00433459) and EUDRACT (trial number 2006-000995-33), and is closed to recruitment. FINDINGS: Between Jan 31, 2007, and Jan 30, 2013, 2102 patients were recruited. 737 (35%) of the 2102 recruited patients were in treatment group 1 (early-stage disease) and were not included in our analysis. 1365 (65%) of the 2102 patients were in treatment group 2 (intermediate-stage disease; n=455) and treatment group 3 (advanced-stage disease; n=910). Of these 1365, 1287 (94%) patients (435 [34%] of 1287 in treatment group 2 and 852 [66%] of 1287 in treatment group 3) were included in the titration trial per-protocol analysis. 937 (69%) of 1365 patients were randomly assigned to COPP (n=471) or COPDAC (n=466) in the embedded trial. Median follow-up was 66·5 months (IQR 62·7-71·7). Of 1287 patients in the per-protocol group, 514 (40%) had an adequate response to treatment and were not treated with radiotherapy (215 [49%] of 435 in treatment group 2 and 299 [35%] of 852 in treatment group 3). 773 (60%) of 1287 patients with inadequate response were scheduled for radiotherapy (220 [51%] of 435 in the treatment group 2 and 553 [65%] of 852 in treatment group 3. In patients who responded adequately, event-free survival rates at 5 years were 90·1% (95% CI 87·5-92·7). event-free survival rates at 5 years in 892 patients who were randomly assigned to treatment and analysed per protocol were 89·9% (95% CI 87·1-92·8) for COPP (n=444) versus 86·1% (82·9-89·4) for COPDAC (n=448). The COPDAC minus COPP difference in event-free survival at 5 years was -3·7% (-8·0 to 0·6). The most common grade 3-4 adverse events (intention-to-treat population) were decreased haemoglobin (205 [15%] of 1365 patients during OEPA vs 37 [7%] of 528 treated with COPP vs 20 [2%] of 819 treated with COPDAC), decreased white blood cells (815 [60%] vs 231 [44%] vs 84 [10%]), and decreased neutrophils (1160 [85%] vs 223 [42%] vs 174 [21%]). One patient in treatment group 2 died of sepsis after the first cycle of OEPA; no other treatment-related deaths occurred. INTERPRETATION: Our results show that radiotherapy can be omitted in patients who adequately respond to treatment, when consolidated with COPP or COPDAC. COPDAC might be less effective, but is substantially less gonadotoxic than COPP. A high proportion of patients could therefore be spared radiotherapy, eventually reducing the late effects of treatment. With more refined criteria for response assessment, the number of patients who receive radiotherapy will be further decreased. FUNDING: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder Gießen, Kinderkrebsstiftung Mainz, Tour der Hoffnung, Menschen für Kinder, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.

• MeSH
• cyklofosfamid terapeutické užití   MeSH
• dítě MeSH
• folikuly stimulující hormon krev   MeSH
• Hodgkinova nemoc farmakoterapie   mortalita   radioterapie   MeSH
• lidé MeSH
• mladiství MeSH
• prednison terapeutické užití   MeSH
• prokarbazin terapeutické užití   MeSH
• protokoly antitumorózní kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• staging nádorů MeSH
• vinkristin terapeutické užití   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

Minipuberta je definována jako dočasná postnatální aktivace hypotalamo-hypofyzo-gonadální (HPG) osy. Ke spuštění činnosti HPG osy dochází během života celkem třikrát. Poprvé v polovině gestace, kdy se podílí na vývoji a na dozrávání pohlavních žláz. Následuje tzv. minipuberta, která začíná několik dnů po narození a trvá u chlapců 4–6 měsíců a u dívek 2–4 roky. Po „hormonálně klidovém“ dětství přichází klasické pohlavní dospívání s rozvojem sekundárních sexuálních znaků ve druhé dekádě života a je zakončeno kompletní maturací pohlavních žláz umožňující budoucí reprodukci. Existence minipuberty je známa téměř 50 let, ale stále není objasněn její úplný význam. Hladiny pohlavních hormonů dosahují v tomto období téměř k hodnotám dospělých jedinců. U chlapců roste penis, zvětšují se testes, v nichž proliferují zárodečné buňky, u dívek estradiol stimuluje růst prsních žláz a zrání ovariálních folikulů. Fyziologický průběh minipuberty je významný pro budoucí pohlavní vývoj a fertilitu. Toto období je současně několikaměsíčním „oknem příležitosti“ stanovení diagnózy některých vrozených poruch pohlavního vývoje. U chlapců s hypogonadotropním hypogonadismem i s případnou možností včasné léčby. Zvláštní pozornost zasluhují klinické dopady průběhu minipuberty u předčasně narozených dětí a dětí narozených malých na svůj gestační věk. Minipuberta je považována za reálný „předobraz“ budoucího pohlavního vývoje.

Minipuberty is defined as temporary postnatal activation of the hypothalamic-pituitary-gonadal (HPG) axis. The HPG axis is triggered three times during lifetime. The first time in the middle of gestation, when it participates in the development and maturation of the sex glands. This is followed by the so-called minipuberty, which begins a few days after birth and lasts 4-6 months in boys and 2-4 years in girls. After the „hormonally sillent“ childhood comes classical sexual adolescence with the development of secondary sexual signs in the second decade of life and is completed by a complete maturation of the sex glands allowing future reproduction. The existence of mini-puberty has been known for almost 50 years, but its full meaning is still not clarified. Levels of sex hormones reach almost to the values of adult individuals during this period. In boys, the penis grows, testes increase in size, in which germ cells proliferate, in girls, estradiol stimulates the growth of mammary glands and the maturation of ovarian follicles. The physiological course of minipuberty is essential for future sexual development and fertility. At the same time, this period is several months‘ „window of opportunity“ of establishing a diagnosis of some congenital disorders of sexual development. In boys with hypogonadotropic hypogonadism, as well as with the possibility of early treatment. The clinical implications of minipuberty in premature babies and infants born young for their gestational age deserve special attention. Minipuberta is considered a real predicition of future sexual development.

• Klíčová slova
• minipuberta,
• MeSH
• embryonální a fetální vývoj MeSH
• estradiol krev   MeSH
• folikuly stimulující hormon krev   MeSH
• lidé MeSH
• luteinizační hormon krev   MeSH
• novorozenec MeSH
• systém hypotalamus-hypofýza * embryologie   MeSH
• testosteron krev   MeSH
• vývoj dítěte MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• ženské pohlaví MeSH

Obesity increases the incidence of hypogonadism in men, and hypogonadism in turn plays a role in obesity. One of the first mechanisms proposed to explain this was a hypothesis based on the principle that obese men have higher estrogen levels, and that increased estrogens provide feedback to the hypothalamic-pituitary-testicular axis, reducing the secretion of gonadotropins and leading to a decrease of overall testosterone levels. This concept has since been questioned, though never completely disproven. In this study we compared hormone levels in three groups of men with differing BMI levels (between 18-25, 25-29, and 30-39), and found correlations between lowering overall testosterone, SHBG and increased BMI. At the same time, there were no significant changes to levels of free androgens, estradiol or the gonadotropins LH and FSH. These findings are in line with the idea that estrogen production in overweight and obese men with BMI up to 39 kg/m(2) does not significantly influence endocrine testicular function.

• MeSH
• androgeny krev   MeSH
• dospělí MeSH
• estradiol krev   MeSH
• estrogeny krev   MeSH
• folikuly stimulující hormon krev   MeSH
• hypogonadismus krev   epidemiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• luteinizační hormon krev   MeSH
• mladý dospělý MeSH
• obezita krev   epidemiologie   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH

Declines in endothelial function can take place rapidly across the menopause transition, placing women at heightened risk for atherosclerosis. Disturbed patterns of conduit artery shear, characterized by greater oscillatory and retrograde shear, are associated with endothelial dysfunction but have yet to be described across menopause. Healthy women, who were not on hormone therapy or contraceptives, were classified into early perimenopausal, late perimenopausal, and early postmenopausal stage. Resting antegrade, retrograde, and oscillatory shear were calculated from blood velocity and diameter measured in the brachial and common femoral artery using Doppler ultrasound. Serum was collected for measurements of estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone. After adjusting for age, brachial artery oscillatory shear was significantly higher in early postmenopausal women (n = 15, 0.17 ± 0.08 a.u.) than both early (n = 12, 0.08 ± 0.05 a.u., P < 0.05) and late (n = 8, 0.08 ± 0.04 a.u) perimenopausal women, and retrograde shear was significantly greater in early postmenopausal versus early perimenopausal women (-19.47 ± 12.97 vs. -9.62 ± 6.11 sec-1 , both P < 0.05). Femoral artery oscillatory and retrograde shear were greater, respectively, in early postmenopausal women (n = 15, 0.19 ± 0.08 a.u.; -13.57 ± 5.82 sec-1 ) than early perimenopausal women (n = 14, 0.11 ± 0.08 a.u.; -8.13 ± 4.43 sec-1 , P < 0.05). Further, Pearson correlation analyses revealed significant associations between FSH and both retrograde and oscillatory shear, respectively, in the brachial (r = -0.40, P = 0.03; r = 0.43, P = 0.02) and common femoral artery (r = -0.45, P = 0.01; r = 0.56, P = 0.001). These results suggest menopause, and its associated changes in reproductive hormones, adversely influences conduit arterial shear rate patterns to greater oscillatory and retrograde shear rates.

• MeSH
• arterie diagnostické zobrazování   fyziologie   MeSH
• cévní endotel fyziologie   MeSH
• dospělí MeSH
• estradiol krev   MeSH
• folikuly stimulující hormon krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• luteinizační hormon krev   MeSH
• menopauza krev   fyziologie   MeSH
• reologie krve * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Extramural MeSH

• MeSH
• dihydrotestosteron * krev   MeSH
• estradiol * krev   MeSH
• estron * krev   MeSH
• folikuly stimulující hormon krev   MeSH
• globulin vázající pohlavní hormony metabolismus   MeSH
• lidé MeSH
• longitudinální studie MeSH
• luteinizační hormon krev   MeSH
• míra přežití MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• stárnutí * krev   MeSH
• testosteron * krev   MeSH
• zdravotnické přehledy MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• komentáře MeSH
• souhrny MeSH

This study investigated the effect of hormonal changes on semen quality, chromatin status, and assisted reproductive outcomes (intracytoplasmic sperm injection), among infertile men. In this research, 219 infertile men undergoing assisted reproductive treatment were evaluated with reproductive hormone levels (including follicle-stimulating hormone, luteinizing hormone and testosterone), semen parameters, and sperm chromatin integrity and condensation, between 2012 and 2014. Finally, the assisted reproductive outcomes in these infertile men were studied. The low rate of total sperm count, motility and morphology, fertilization and the high percentage of DNA damage, the poor zygote (Z4 grade) and embryo quality (grade D), and spontaneous miscarriage was recorded in men with high levels of follicle-stimulating hormone and luteinizing hormone. In conclusion, the changes in the follicle-stimulating hormone, luteinizing hormone, and testosterone by changes in the sperm quality, and DNA damage may have the effects on assisted reproductive outcomes (e.g., low fertilization, poor zygote and embryo quality, and high miscarriage).

• MeSH
• asistovaná reprodukce * MeSH
• chromatin genetika   MeSH
• dospělí MeSH
• folikuly stimulující hormon krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• luteinizační hormon krev   MeSH
• mladý dospělý MeSH
• motilita spermií MeSH
• mužská infertilita * krev   terapie   MeSH
• počet spermií MeSH
• poškození DNA MeSH
• samovolný potrat MeSH
• těhotenství statistika a číselné údaje   MeSH
• testosteron krev   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• těhotenství statistika a číselné údaje   MeSH
• ženské pohlaví MeSH

Východiska: Inhibitory aromatázy 3. generace (anastrozol, letrozol, exemestan) jsou vzhledem k lepším výsledkům ve srovnání s tamoxifenem již standardní součástí hormonální léčby postmenopauzálních pacientek s hormonálně dependentním karcinomem prsu ve všech indikacích (neoadjuvance, adjuvance, metastatické onemocnění). Inhibitory aromatázy brání inhibicí enzymu aromatázy přeměně cirkulujících androgenů na estrogeny a tím výrazně snižují jejich sérovou hladinu. Jejich podání je kontraindikováno u žen s funkčními ovarii. U mnoha původně premenopauzálních pacientek léčených adjuvantní chemoterapií vymizí menstruace (chemoterapií indukovaná amenorea). Těmto nemocným někdy bývají – bez ohledu na věk – podávány inhibitory aromatázy, které však u nich mohou způsobit obnovení ovariálních funkcí s následným selháním léčby nebo nechtěným těhotenstvím. Techniky měření hormonálních hladin pro ověření menopauzálního stavu dostupné v běžné praxi jsou pro tyto situace často nedostačující. Cíl: Toto sdělení se věnuje především vedlejším nežádoucím účinkům inhibitorů aromatázy, které mohou vést ke špatné adherenci k léčbě nebo jejímu ukončení. Závěr: Mnoho nežádoucích účinků inhibitorů aromatázy je způsobeno estrogenní deprivací. Na druhou stranu tím, že inhibitory aromatázy nemají žádnou estrogenní aktivitu, neprovázejí jejich podání závažné nežádoucí účinky typické pro léčbu tamoxifenem, jako je endometriální karcinom nebo tromboembolická nemoc. Léčba inhibitory aromatázy bývá často spojena s vazomotorickými symptomy (návaly horka), suchostí poševní sliznice, dyspareunií, úbytkem kostní hmoty, artralgiemi a myalgiemi (muskuloskeletální symptomy). Prevence a léčba těchto nežádoucích účinků může pacientkám pomoci pokračovat v léčbě.

Background: The third generation aromatase inhibitors (anastrozole, letrozole, exemestane) have become standard endocrine treatment for postmenopausal estrogen receptor – positive breast cancers in all settings (neoadjuvant, adjuvant, metastatic breast cancer), based on superiority to tamoxifen. Aromatase inhibitors interfere with the conversion of androgens into estrogens by blocking the enzyme aromatase resulting in low estradiol levels. Aromatase inhibitors are contraindicated in women with functional ovaries. Many premenopausal women develop amenorrhea after adjuvant chemoterapy. Aromatase inhibitors may promote recovery of ovarian function which could lead to therapeutic failure or even to unexpected pregnancy. Currently available measures to determine the menopausal status are conflicting. Aim: This paper focuses primarily on adverse effects of aromatase inhibitors which can lead to non-compliance or to discontinuation of treatment. Results: Many side effects of aromatase inhibitors are related to estrogen deprivation. On the other hand as aromatase inhibitors lack estrogenic activity, they are not associated with serious adverse events typical for tamoxifen, such as endometrial cancer and thromboembolic disease. Aromatase inhibitors therapy is often associated with vasomotor symptoms (hot flashes), vaginal dryness, dyspareunia, bone loss, arthralgias and myalgias (musculoskeletal symptoms). Management of these side effects can lead to improved adherence and persistence with therapy.

• Klíčová slova
• obnovení ovariální funkce,
• MeSH
• adjuvantní chemoterapie škodlivé účinky   MeSH
• amenorea chemicky indukované   MeSH
• antitumorózní látky hormonální farmakologie   škodlivé účinky   terapeutické užití   MeSH
• atrofická vaginitida farmakoterapie   chemicky indukované   MeSH
• estradiol krev   MeSH
• folikuly stimulující hormon krev   MeSH
• inhibitory aromatasy * farmakologie   kontraindikace   škodlivé účinky   MeSH
• lidé MeSH
• menstruace účinky léků   MeSH
• muskuloskeletální bolest chemicky indukované   prevence a kontrola   MeSH
• nádory prsu * farmakoterapie   MeSH
• návaly chemicky indukované   terapie   MeSH
• obnova funkce účinky léků   MeSH
• osteoporotické fraktury chemicky indukované   prevence a kontrola   MeSH
• osteoporóza chemicky indukované   prevence a kontrola   MeSH
• ovarium účinky léků   MeSH
• postmenopauza MeSH
• předčasná menopauza MeSH
• věkové faktory MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

Inhibitory aromatázy v adjuvantním podání zlepšily léčebné výsledky u postmenopauzálních pacientek s časným karcinomem prsu. Neměly by však být používané u premenopauzálních pacientek. Menopauzální stav je jedním z nejdůležitějších kritérií pro výběr adjuvantní hormonální léčby. Mezi menopauzálním stavem a funkcí ovarií nemusí být přímý vztah, i pacientky s amenoreou můžou mít premenopauzální hladiny estradiolu. Složitější je situace u pacientek užívajících tamoxifen, který může zvyšovat hladiny estradiolu i u pacientek s amenoreou. Při změně adjuvantní hormonální léčby je proto u těchto pacientek nutné změřit hladiny estradiolu. Další skupinou pacientek, u kterých je třeba opatrnosti při indikaci inhibitorů aromatázy, jsou premenopauzální pacientky, u kterých byl menopauzální stav navozen chemoterapií. K obnovení ovariálních funkcí po podání chemoterapie může dojít po různě dlouhé době. V průměru to je 12 měsíců (4−59) a ne vždy musí být doprovázeno obnovením menstruace. Před nasazením inhibitorů aromatázy je proto důležité změřit hladiny estradiolu nejlépe opakovaně v odstupu 3−4 měsíců. U žen mladších 40 let je vysoká pravděpodobnost obnovení ovariálních funkcí, a proto by neměly být léčené inhibitory aromatázy samotnými. Z tohoto důvodu je sledování cirkulujících hladin estradiolu před léčbou inhibitory aromatázy hlavně u žen mezi 40. a 50. rokem života důležité.

Adjuvant treatment with aromatase inhibitors improves outcomes in postmenopausal women with hormone-sensitive early breast cancer; however, they should not be used in premenopausal women. Menopausal status is the most important factor in the choice of the hormonal treatment. There is no direct correlation between amenorrhea and ovarian function, as even the patients with amenorrhea may present with premenopausal plasma estradiol levels. The evaluation of hormonal status becomes more complicated in patients taking tamoxifen, which might lead to further increase of plasma estradiol levels. Therefore, its evaluation before and during the treatment with aromatase inhibitors is clinically important. There is a considerable caution needed when indicating aromatase inhibitors in patients with menopause caused by previous adjuvant chemotherapy, while recovery of ovarian function may appear after a certain period. This could take from 4 to 59 months (12 months on average) and it might not be accompanied by menses. This happens typically in women younger than 40 years, who should, therefore, not be treated by aromatase inhibitors alone. This supports the notion that monitoring of plasma estradiol levels is crucial in women from 40 to 50 years of age, especially before the start of aromatase inhibitors treatment.

• MeSH
• adjuvantní chemoterapie škodlivé účinky   MeSH
• amenorea chemicky indukované   MeSH
• antitumorózní látky hormonální kontraindikace   škodlivé účinky   terapeutické užití   MeSH
• estradiol krev   MeSH
• folikuly stimulující hormon krev   MeSH
• inhibitory aromatasy * kontraindikace   škodlivé účinky   terapeutické užití   MeSH
• kontraceptiva orální hormonální MeSH
• lidé středního věku MeSH
• lidé MeSH
• menopauza * krev   účinky léků   MeSH
• menstruace účinky léků   MeSH
• nádory prsu * farmakoterapie   MeSH
• obnova funkce účinky léků   MeSH
• ovarium účinky léků   MeSH
• postmenopauza krev   MeSH
• premenopauza krev   MeSH
• referenční hodnoty MeSH
• tamoxifen terapeutické užití   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH
• práce podpořená grantem MeSH
• přehledy MeSH