Radosław Słopień

Influence of hormonal replacement therapy on the regional cerebral blood flow in postmenopausal women

OBJECTIVES The aim of this study was evaluation of the influence of hormonal replacement therapy (HRT) on the regional cerebral blood flow in postmenopausal women. METHODS The study group were 20 postmenopausal women, mean age 48.7 years (S.D. +/- 4.9 years). The control group were ten regularly menstruating women, mean age 32.6 years (S.D. +/- 13.2 years). In the studied group we measured the severity of climacteric syndrome with the use of Kupperman index and serum FSH and 17beta-estradiol level with the use of radioimmunological method. Cerebral blood flow was measured at rest using Single Photon Emission Computed Tomography (SPECT). Tracer accumulation evaluation was performed in three slices defined as: cerebellar slice, thalamic slice and ventricular slice, the reference region was delineated in the cerebellum. In ten women with an impairment in the cerebral blood flow at the beginning of the study all the tests were repeated after 12 months of HRT. RESULTS Before HRT mean value of the Kupperman index in the study group was 29.8 points (S.D. +/- 7.1 points); 17beta-estradiol 27 pg/ml (S.D. +/- 2 pg/ml); FSH 56 IU/l (S.D. +/- 49.5 IU/l); SPECT study revealed cerebral blood flow impairment in ten women. In all the studied slices cerebral blood flow was lower in the study group than in the controls. After 12 months of HRT the mean value of the Kupperman index in the study group was 13.2 points (S.D. +/- 2.1 points) (P < 0.05); 17beta-estradiol 44 pg/ml (S.D. +/- 25 pg/ml); FSH 36.4 IU/l (S.D. +/- 57.3 ng/ml); we found cerebral blood flow increase in all studied slices: right cerebellar slice: 5.2%; left cerebellar slice: 4.1%; right thalamic slice: 3.8%; left thalamic slice: 3.3%; right ventricular slice: 7.5%*; left ventricular slice: 6.7%* (* P < 0.05). CONCLUSIONS Cerebral blood flow is lower in the postmenopausal women than in regularly menstruating women. HRT increases regional cerebral blood flow and this improvement coexists with an increase of serum 17beta-estradiol level.

Polymorphic variants of genes encoding MTHFR, MTR, and MTHFD1 and the risk of depression in postmenopausal women in Poland

OBJECTIVE Disturbances in the folate-dependent one-carbon metabolism have been reported in depression. Polymorphic variants of genes encoding key enzymes of folate and methionine metabolism may have an impact on catecholamine catabolism conducted by catechol-O-methyltransferase. METHODS The distribution of polymorphisms of genes encoding methylenetetrahydrofolate reductase (MTHFR); methionine synthase (MTR); 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase (MTHFD1) was examined in postmenopausal women with (n=83) and without depression (n=89). RESULTS We found a significant contribution of the MTHFR 677C>T polymorphic variants to depression in postmenopausal women. Odds ratio (OR) for women with depression and MTHFR TT genotype was 3.478 (95% CI=1.377-8.783), P=0.0096 and OR of the TT and CT genotypes was 2.345 (95% CI=1.258-4.373), P=0.0086. Moreover, after stratification based on depression severity in postmenopausal women, we found that the MTHFR TT genotype displayed a 4.831-fold increased risk of moderate and severe depression (95% CI=1.975-11.820, P=0.0008). We did not observe statistical differences in the distribution of MTR 2756A>G and MTHFD1 1958G>A polymorphic variants in groups of postmenopausal women with and without depression. However, the MTR GG genotype exhibited a 5.750-fold increased risk of moderate and severe depression in postmenopausal women (95% CI=1.547-21.379, P=0.013). CONCLUSIONS Our findings indicate a significant role of folate and possible methionine metabolism involvement in the development of depression in postmenopausal women.

Aromatase inhibitors in the treatment of endometriosis

Endometriosis is a chronic inflammatory condition in which foci of endometrial tissue grow outside of the uterine cavity. Endometriosis was estimated to affect 176 million women of childbearing potential all over the world in 2010. The presence of extrauterine endometrial tissue is associated with pain and infertility. Typical symptoms of endometriosis include dysmenorrhoea, dyspareunia, heavy menstrual periods (menorrhagia), pelvic pain that is not related to menstrual cycles, dysuria, and chronic fatigue. Medical treatments for endometriosis include combined oral contraceptive pills, danazol, gestrinone, medroxyprogesterone acetate, and gonadotropin-releasing hormone agonists (aGnRHs). A new class of medications called aromatase inhibitors has been identified in recent years as potential therapeutic agents for endometriosis. This article provides general information about aromatase inhibitors, their use in gynaecology, and their adverse effects. In particular, the paper discusses the use of aromatase inhibitors in the treatment of endometriosis in postmenopausal women. Unlike oral contraceptives, gestagens, aGnRHs, and danazol, which suppress ovarian oestrogen synthesis, aromatase inhibitors inhibit mainly extra-ovarian synthesis of oestrogens. Therefore, the use of aromatase inhibitors seems to be particularly relevant in older patients, as most of the bodys oestrogen is produced outside the ovaries after menopause. The paper discusses also the use of aromatase inhibitors in the treatment of pain associated with endometriosis and infertility caused by endometriosis.

The MAOA, COMT, MTHFR and ESR1 gene polymorphisms are associated with the risk of depression in menopausal women

OBJECTIVE The aim of the study was assessment of a possible relationship between the polymorphisms of the candidate genes participating in the etiology of some neurological and psychiatric disorders and the risk of depression in perimenopausal and postmenopausal women. METHODS A total of 167 (54 perimenopausal and 113 postmenopausal) Caucasian women from western Poland, aged 42-67, were recruited as the patient group in the study because of depressive symptoms, and another 321 healthy women (102 perimenopausal and 219 postmenopausal) served as the controls. All study participants were evaluated for climacteric and depressive disorders according to the Kupperman index and Hamilton rating scale for depression (HRSD), respectively. The following candidate genes were selected for the study: 5HTR2A, 5HTR1B, 5HTR2C, TPH1, TPH2, MAOA, COMT, NET, GABRB1, ESR1, MTHFR, MTR and MTHFD1. In each group the frequencies of the polymorphisms were determined using PCR-RFLP analysis. RESULTS After correcting for Bonferroni multiple tests, we found associations between the MAOA c.1460C>T (SNP 1137070), COMT c.472G>A (SNP 4680), MTHFR c.677C>T (SNP 1801133) and ESR1 454(-351) A>G (SNP 9340799) polymorphisms to mild and moderate depressive symptoms in menopausal women. In the perimenopausal and postmenopausal women, genotype association of the MAOA c.1460 CT and c.1460 CT+TT (OR=1.83; pcorr=0.009 and OR=1.85; pcorr=0.003, resp.), and of the MTHFR c.677 TT and c.677 CT+TT (OR=3.52; pcorr=0.00009 and OR=2.06; pcorr=0.0006, resp.), as well as of the COMT c.472 GA and COMT c.472 GA+AA genotypes (OR=2.23; pcorr=0.03 and OR=2.17; pcorr=0.027, resp.) in the postmenopausal women revealed significantly higher frequencies of these variants in depressed female patients than in controls, whereas the ESR1 454(-351) AG and 454(-351) AG+GG genotypes were associated with lower risk of depression in postmenopausal women (OR=0.48; pcorr=0.012, and OR=0.52; pcorr=0.015, resp.). CONCLUSIONS Our study substantiates the involvement of the MAOA and MTHFR polymorphisms in climacteric depression and offers evidence that the COMT and ESR1 genes may also play a role in the susceptibility to depressive mood in postmenopausal women.

Disturbances of sleep continuity in women during the menopausal transition.

OBJECTIVES The objective of the study was to evaluate the prevalence of sleep continuity disorders in women during menopausal transition, to evaluate the relationship between disturbances of sleep continuity and the severity of menopausal syndrome and the occurrence of various symptoms of this syndrome, as well as to evaluate the association between the presence of sleep disturbances and serum concentrations of gonadotropins, prolactin and sex hormones. METHODS Consecutive 140 women (mean age 54.4 ± 4.7 years) searching for the treatment in the Clinic for Gynaecological Endocrinology who reported symptoms of menopausal syndrome were investigated. The type and severity of disturbances of sleep continuity were evaluated using a survey based on the sleep related questions from Hamilton Depression Rating Scale. The severity of symptoms of menopausal syndrome was assessed using the Kupperman Index. The concentration of the following hormones in blood serum was tested: FSH, LH, 17β-estradiol, PRL, total testosterone, DHEAS and SHBG. RESULTS Disturbances of sleep continuity were a prevalent complaint in the studied group of women. Difficulties in falling asleep were found in 57.8% of women, difficulties in maintaining sleep in 70%, waking up too early in 60.7%. The severity of all three types of sleep continuity disturbances was related to the severity of menopausal syndrome as measured with Kupperman Index (Spearman correlation coefficient r = 0.63, r = 0.61, r = 0.52, respectively; p < 0.001). Difficulties in maintaining sleep were negatively correlated with the concentration of FSH (r = - 0.19; p < 0.05), 17β-estradiol (r = - 0.19; p < 0.05) and SHBG (r = - 0.18; p < 0.05), difficulties in falling asleep negatively correlated with the concentration of 17β-estradiol in the blood serum (r = - 0.19; p < 0.05). CONCLUSIONS Sleep continuity disturbances are frequently reported by women during the menopausal transition. Interventions aimed at reducing the symptoms of menopausal syndrome should be considered as important action to improve sleep quality in this population of patients.

Overweight in Boys With ADHD Is Related to Candidate Genes and Not to Deficits in Cognitive Functions

Objective: The aim of the study was to assess the relationship of overweight, the polymorphisms of selected candidate genes, and deficits in the executive functions among children with ADHD. Method: We examined 109 boys with ADHD aged between 7 and 17 years. The study indicated variants of 14 polymorphisms in eight candidate genes. We applied seven neuropsychological tests to evaluate the executive functions. Overweight was diagnosed on the basis of the guidelines of the International Obesity Task Force. Results: Analyses revealed significant association between DRD4 rs1800955, SNAP25 rs363039 and rs363043, 5HTR2A rs17288723, and overweight in boys with ADHD. There were no significant differences in the level of neuropsychological test results between patients with overweight and without overweight. Conclusion: Overweight in boys with ADHD is associated with polymorphisms in three candidate genes: DRD4, SNAP25, and 5HTR2A, but not through conditioning deficits in cognitive functions.

Genomic markers of ovarian adenocarcinoma and its relevancy to the effectiveness of chemotherapy

Ovarian cancer is the eighth most common cancer and the seventh highest cause of cancer-associated mortality in women worldwide. It is the second highest cause of mortality among female reproductive malignancies. The current standard first-line treatment for advanced ovarian cancer includes a combination of surgical debulking and standard systemic platinum-based chemotherapy with carboplatin and paclitaxel. Although a deeper understanding of this disease has been attained, relapse occurs in 70% of patients 18 months subsequent to the first-line treatment. Therefore, it is crucial to develop a novel drug that effectively affects ovarian cancer, particularly tumors that are resistant to current chemotherapy. The aim of the present study was to identify genes whose expression may be used to predict survival time or prognosis in ovarian cancer patients treated with chemotherapy. Gene or protein expression is an important issue in chemoresistance and survival prediction in ovarian cancer. In the present study, the research group consisted of patients treated at the Surgical Clinic of the Gynecology and Obstetrics Gynecological Clinical Hospital, Poznan University of Medical Sciences (Poznan, Poland) between May 2006 and November 2014. Additional eligibility criteria were a similar severity (International Federation of Gynecolgy and Obstetrics stage III) at the time of diagnosis, treatment undertaken in accordance with the same schedule, and an extremely good response to treatment or a lack of response to treatment. The performance of the OncoScan® assay was evaluated by running the assay on samples obtained from the four patients and by following the recommended protocol outlined in the OncoScan assay manual. The genomic screening using Affymetrix OncoScan Arrays resulted in the identification of large genomic rearrangements across all cancer tissues. In general, chromosome number changes were detected in all examined tissues. The OncoScan arrays enabled the identification of ~100 common somatic mutations. Chemotherapy response in ovarian cancer is extremely complex and challenging to study. The present study identified specific genetic alterations associated with ovarian cancer, but not with response for treatment.

Correlation between allopregnanolone levels and depressive symptoms during late menopausal transition and early postmenopause

Abstract Objectives: This observational, cross-sectional study included 140 women with climacteric symptoms. The aim of the study was to evaluate the correlation between the presence and severity of depressive symptoms and allopregnanolone levels in women during late menopausal transition and early postmenopause. Methods: The study group was divided into two groups: 45 women in late menopausal transition and 95 early postmenopausal women. We evaluated Kupperman index, Hamilton scale and serum follicle-stimulating hormone, luteinizing hormone, 17β-estradiol, prolactin, total testosterone, dehydroepiandrosterone sulfate and allopregnanolone levels. Results: We found that serum allopregnanolone concentration was lower in early postmenopausal women compared to women in late menopausal transition; that there was a correlation between serum allopregnanolone levels in early postmenopausal women and time since last menstruation, intensity of climacteric symptoms, and intensity of depression symptoms and that there was a correlation between serum allopregnanolone levels and several depression symptoms presence (shallow sleep and symptoms of the digestive tract in women during late menopause transition; feelings of guilt, sleep disorders and general somatic symptoms in early postmenopausal women). Conclusion: We concluded that reproductive aging is characterized by a reduction of allopregnanolone circulating levels that correlate to Hamilton depression index in early postmenopause and presence of specific depressive symptoms during late menopausal transition and early postmenopause.

Use of oral contraceptives for management of acne vulgaris and hirsutism in women of reproductive and late reproductive age

Hormonal contraception in both reproductive and late reproductive age, as well as contraceptive action, is used also for other indications like dysmenorrhoea, menstrual disorders, endometriosis, acne vulgaris, and hirsutism. Acne vulgaris and hirsutism are important signs related to hyperandrogenaemia and present a serious medical problem for the patients and a challenge for medical doctors in terms of effective treatment. The application of hormonal contraception to treat acne vulgaris and hirsutism requires knowledge of the mechanism of antiandrogenic actions and the possible contraindications and complications. These data are presented in this review.

Denosumab – a new medication in the treatment of postmenopausal osteoporosis

Osteoporosis is a chronic, systemic skeletal disorder characterised by decreased bone density. It leads to an increased risk of bone fractures – one of the major causes of disability in modern societies. Bisphosphonates are the most commonly used medications in the treatment of postmenopausal osteoporosis. Denosumab, a new approach to fracture prevention, is a fully human monoclonal antibody that targets nuclear factor-κB ligand (RANKL), an important cytokine regulating formation and function of osteoclasts. Generally, denosumab is not used as initial therapy; however, in some cases it should be considered. It concerns patients at high risk of fracture, such as older patients who have difficulty with the dosing requirements of oral bisphosphonates or who have markedly impaired renal function. Denosumab can be also considered in patients who present intolerance or unresponsiveness to other therapies. Clinical studies have shown that denosumab is highly effective in increasing bone mineral density (BMD) in postmenopausal women regardless of the site analysed, as well as reducing the risk of bone fractures. The risk of developing antiresorptive, agent-induced osteonecrosis of the jaw related to denosumab therapy is low.