Menopausal hormone therapy in questions and answers - a manual for physicians of various specialties.

This manual has been prepared by the Expert Team of the Polish Menopause and Andropause Society for physicians representing various medical specialties who see patients with menopausal symptoms in their daily practice. In order to make the manual as practical as possible, the current state of knowledge on menopausal hormone therapy (MHT) is presented in the form of questions and answers. They address issues which are essential for initiating and managing MHT based on the most up-to-date treatment algorithms and, at the same time, in line with the old maxim "primum non nocere".

The value of the free androgen index depends on the phenotype of polycystic ovary syndrome - a single-centre experience.

INTRODUCTION: The free androgen index (FAI) values differ among patients with polycystic ovarian syndrome; however, the differences are not fully understood or known. The aim of the study was to evaluate FAI in women with polycystic ovary syndrome (PCOS) in regard to the phenotype of the PCOS and insulin resistance status. MATERIAL AND METHODS: Anthropometric, hormonal, and biochemical parameters were assessed in 312 recruited women with PCOS. The FAI values were calculated in the reproductive and metabolic phenotypes of PCOS in groups of insulin resistance status based on the homeostasis model assessment-insulin resistance (HOMA-IR) > 2.0 or fasting insulin (FI) > 10 mmol/L. To test the relationship between individual variables, Spearman's correlation analysis, the Kolmogorov-Smirnov test, and Student's t-test were used. RESULTS: The correlation between FAI values and HOMA-IR and FI was 0.42 and 0.47, respectively, in PCOS patients. A two fold higher FAI value was observed in metabolic PCOS phenotype when compared to the reproductive one (8.51 ± 5.56 vs. 4.40 ± 2.45 for HOMA-IR and 8.73 ± 6.09 vs. 4.31 ± 3.39 for FI, respectively; p < 0.05). CONCLUSIONS: PCOS patients are not a homogenous group in terms of FAI value. Patients with metabolic PCOS phenotype are characterised by two-fold higher FAI values compared with reproductive PCOS phenotype. Further studies on the metabolic and androgenic status of different types of PCOS phenotypes should be carried out.

Vascular effects of simvastatin are similar to hormone replacement therapy in postmenopausal women.

Aim of the study: To compare effect of six month transdermal 17 ß-estradiol supplementation with oral medroxyprogresterone acetate to oral simvastatin treatment on nitric oxide (NO), endothelin-1, ß-thromboglobulin, vascular endothelial growth factor (VEGF) and von Willebrand factor (vWF) levels during standard exercise test in post menopausal women. Patients and Methods: 32 women were included to the study. Group 1 treated with 17ß-estradiol combined with medroxyprogesterone. Group 2 treated with simvastatin, group 3 was the controls. VEGF plasma levels as well as basal and standard exercise test induced levels of vWF, NO, endothelin- 1, ß-thromboglobulin were measured at the beginning of the study, at 3rd and 6th month of the study. During standard exercise test these parameters were measured three times: at the beginning, at peak exercise and at the 15th minute of recovery. Results: 17ß-estradiol supplementation and simvastatin treatment reduced basal and exercise test induced endothelin-1 plasma level. 17ß-estradiol supplementation gradually increased NO release, whereas simvastatin initially reduced and finally increased nitric oxide release. NO/ET-1 ratio was increased at peak exercise and recovery time in group 1 whereas only at peak exercise in group 2. Basal VEGF plasma level and ß-thromboglobulin level at recovery time were reduced after 6 month of simvastatin therapy. Conclusion: Six months long oral simvastatin exerted beneficial influence on endothelial function equal to that of continuous transdermal 17ß-estradiol supplementation combined with medroxyprogesterone acetate. Simvastatin only exerted benefical effect on platelet function. The protective effect of both therapies was more pronounced during exercise and recovery time.

Evening not morning plasma cortisol level is higher in women with polycystic ovary syndrome.

INTRODUCTION: The aim of our study was to assess the morning and evening cortisol plasma levels in women with polycystic ovary syndrome (PCOS). MATERIAL AND METHOD: 95 patients gave their informed consent to participate in the study and were divided into 2 groups. Group A consisted of 40 PCOS patients and group B consisted of 55 women without features of PCOS. Between day 5 and 8 of the menstrual cycle, morning (7 am), fasting blood samples were taken for the assessment of luteinizng hormone (LH), follicle stimulating hormone (FSH), estradiol, cortisol, prolactin, thyreotropin (TSH), testosterone and dehydroepeiandrosterone (DHEAS). Evening (5 pm) blood samples were also taken for the evaluation of plasma cortisol level RESULTS: There were no differences in mean age, body mass index (BMI), FSH, SHBG, PRL, estradiol and TSH levels between group A and group B. Mean plasma LH level was higher in group A compared to group B (10.7 ± 6.8 IU/l vs 6.6 ± 4.5 LU/l, p < 0.02). Mean plasma testosterone and DHEAS levels were also higher in PCOS patients (3.8 ± 0.6 nmol/l vs 1.63 ± 0.6 nmol/l; 427.7 ± 162.9 vs 236.6 ± 97.8 respectively, p < 0.001). Mean evening plasma cortisol level was higher in PCOS patients (11.8 ± 4.1 ug/dl vs 4.7 ± 1.3 ug/dl, p < 0.02). Mean morning plasma cortisol levels did not differ between groups. CONCLUSION: PCOS women showed the increased evening plasma cortisol level with impacted diurnal secretion rate.

[The influence of age, place of living, education and number of earlier pregnancies on attendance of pregnant women to screening tests--questionnaire study]. / Wplyw wieku, miejsca zamieszkania, wyksztalcenia i Iiczby wczesniejszych ciaz na zglaszalnosc ciezarnych do badan przesiewowych- badanie ankietowe.

UNLABELLED: The aim of this study was to assess attendance at the screening programme in pregnancy and the influence of age, number of past pregnancies, level of education and place of residence on the attendance. MATERIAL AND METHODS: Our study was performed on the basis of an anonymous questionnaire handed out 543 women aged 16-45, on the third day of their puerperal, in one of the five obstetric wards in southern Poland. The questionnaire contained questions about participation in recommended for pregnant women screening tests such as: fasting blood glucose level measurement, oral glucose tolerance test, blood type test, measurement of hepatitis B surface antigen and antibodies to VDRL, Rubella, Toxoplasma gondii, hepatitis C virus at least once during pregnancy. RESULTS: The highest attendance rate was related with blood type test, whereas the lowest was related with measurement of antibodies to hepatitis C virus (95.6% vs 22.7%, p < 0.001). A very low percentage of pregnant patients measured Rubella antibodies (29.1%). A larger proportion of the respondents checked antibodies against Toxoplasma gondii (41.6%). The attendance at fasting blood glucose level was 66.9 % and at oral glucose tolerance test was 63.7%. The attendance according as age, place of living, number of past pregnancies and level of education was described in detail. CONCLUSION: Despite current recommendations of Polish Gynecological Society and the ordinance of polish Minister of Health the percentage of women participating in screening tests during pregnancy is still insufficient. Age, place of residence and education remain strong factors influencing attendance at the screening programme in pregnancy.

Markers of insulin resistance in perimenopausal women with endometrial pathology.

OBJECTIVES: To determine and compare the prevalence of insulin resistance and carbohydrate metabolism parameters in women with endometrial pathology MATERIAL AND METHODS: 100 perimenopausal women with abnormal uterine bleeding and/or abnormal endometrium were included into the study. Hysteroscopy with biopsy was performed. The study population was divided into four groups according to histopathological results of the endometrium: non-atypical endometrial hyperplasia, endometrial polyp, endometrial cancer and controls. Fasting glucose and insulin levels and OGTT, IR indexes, occurrence of diabetes, pre-diabetic state, overweight, obesity and hypertension were assessed. RESULTS: Insulin resistance was diagnosed in 41.0% of the patients. The prevalence of markers of insulin resistance increased to 57.1% in cases with confirmed endometrial pathology compared to 31.8% in histologically normal endometrium (p<0.01). The frequency of insulin resistance was 52.6% (p=0.059) and 55.5% (p=0.04), respectively in women with non-atypical hyperplasia and patients with endometrial polyps when compared to the control group. Abnormal parameters of carbohydrate metabolism indicate little sensitivity and specificity in predicting endometrial hyperplastic lesions. The insulin levels at 120 minutes of OGTT correlate best with such changes (concentration >57 microU/ml in case of hyperplasia and >61 microU/ml in endometrial polyps). CONCLUSION: Insulin resistance and carbohydrate metabolism disturbances are common in women with endometrial pathologies. In these patients there is clinical basis for recommending lifestyle modification (change of diet, more physical activity), or for introduction of pharmaceutical insulin-sensitizing agents.

[The incidence of neoplasm in women using contraceptives]. / Czestosc nowotworów u kobiet stosujacych doustne srodki antykoncepcyjne.

Contraceptive is an important issue of women's life. In the present times there are many methods to prevent unwanted pregnancy. Each of them has its advantages and disadvantages and an appropriate choice of the method determines its promotion high efficiency and comfort its application. Today there is no method of contraception, which would not be charged some risk for the application. Following the review will allow literature to analyze impact of the various methods for the development of cancer control means diseases which may constitute a serious threat to health and life women.

Clomiphene citrate challenge test and serum anti-Müllerian hormone levels in women with menstrual irregularities and/or infertility.

AIM: Evaluation of CCCT results and anti-Müllerian hormone (AMH) plasma levels in women with menstrual cycle irregularities and/or infertility. PATIENTS AND METHODS: 70 patients with menstrual cycle disturbances were recruited to the study. Clomiphene citrate challenge test (CCCT) was carried out in each patient enrolled. At day 3 of the cycle plasma basic levels of FSH, estradiol, progesterone, IGFBP-1, TSH, prolactin, DHEAS and anti-Müllerian hormone were measured. At day 10 of the cycle plasma levels of FSH and estradiol were evaluated. Plasma levels of hormones were measured by commercially available ELISA kits. RESULTS: 50 women with normal result of CCCT (group A) had higher mean plasma level of AMH compared to 20 women with abnormal result of CCCT (group B). Mean plasma FSH level at day 3 of the cycle was lower in group A compared to group B. There were no other statistically significant differences in mean values of assessed parameters between groups A and B. Taking into account all patients enrolled to the study AMH correlated significantly with patients' age and plasma levels of FSH at day 3 and day 10 of the cycle). Basic AMH plasma levels in group A correlated negatively with plasma levels of FSH at day 3 and day 10. In group B plasma levels of FSH at day 10 of the cycle also correlated with basic AMH plasma levels. Plasma levels of estradiol at day 10 of the cycle were related inversely with basic AMH plasma levels in group A, but directly in group B. CONCLUSION: It should be recommended to perform the CCCT before infertility treatment. Evaluation of the anti-Müllerian hormone plasma level reflects the results of the CCCT.

[Molecular action of insulin-sensitizing agents]. / Molekularne podstawy antynowotworowego dzialania uwrazliwiaczy na insuline.

Atypical endometrial hyperplasia has been associated with progression to endometrial cancer, the most common genital malignancy. There are multiple risk factors for endometrial cancer, such as early menarche, exogenous estrogen exposure, obesity and diabetes. Diabetics have a 3-4 fold relative risk of endometrial cancer. Also, several studies have demonstrated an association between insulin resistance and endometrial cancer. There is known the first description of atypical endometrial hyperplasia resistant to progestogen therapy, which was subsequently treated with an insulin-sensitizng agent, metformin. Metformin is a biguanide antihyperglycemic agent used in the treatment of adult-onset diabetes. Unlike the sulfonylureas, metformin does not act primarily by increasing insulin secretion. In contrast, metformin lowers the rate of gluconeogenesis in the presence of insulin. Therefore, it is considered an insulin-sensitizer. Increased insulin sensitivity may improve the metabolic effect of insulin and decrease its mitogenic effect by tissue-specific mechanisms. One explanation for tissue specific differences in insulin binding and action may be through the relative expression of the insulin receptor (IR) isoforms. The IR isoforms IR-A and IR-D differ by 12 amino acid residues, owing to the alternative splicing of exon. The IR-A is predominantly expressed in malignant tissues and may lead to mitogenic effects within the cell. The relative expressions of IR-A and IR-B in normal and malignant endometrial tissue is not known. Besides direct effects on the IR, several additional mechanisms have been proposed for the mitogenic effect of insulin in endometrial cancer. In addition to the possible direct mitogenic effects of insulin through the IR-A, insulin resistance may be associated with alterations in expression of insulin-like growth factors (IGFs) and the IGF binding proteins (IGFBPs) or may inhibit the protective effect of progestagens. Binding sites for IGF-1 and IGF-2 have been confirmed in both normal and malignant endometrium. Binding of IGF-1 is significantly higher in endometrial cancer compared to normal endometrium. In the Ishikawa human endometrial cancer cell line IGF-1 was a more potent mitogen than insulin or IGF-2. Insulin may increase mitogenicity by regulating the expression of IGFBPs. The IGFBPs are a family of proteins that have both proliferative and anti-proliferative effects. While all six high-affinity IGFBPs are expressed in the endometrium, IGFBP-1 is the best characterized. Hyperinsulinemia can decrease IGFBP-1 even in the presence of progesterone, perhaps inhibiting progesterone's protective effects. Interestingly, IGFBP-1 was undetectable or minimally expressed in endometrial cancers. Nestler discussed results of a 6-month treatment of 100 nonebese women with PCOS, which showed a somewhat greater effect of metformin than rosiglitazone and no benefit of administering both agents in combination. Long-term treatment with oral contraceptives decreases endometrial cancer, with a reduction in serum androgens and a decreases in hirsutism and acne, but may worsen insulin resistance and lead to deteriration in glucose tolerance. Insulin sensitizers, on the other hand, should decrease endometrial hyperplasia by inducing regular menses, but may not be as beneficial in improving androgen - related symptoms. Note that the Nurses Health Study (NHS) showed increased risk of diabetes in oral contraceptive users. These considerations may be related to the finding that women who used oral contraceptives have increased risk of myocardial infarction. Thus, in view of the particular increase in CVD risk among women with PCOS, one might be less likely to recommend oral contraceptives, while insulin sensitizers may be of particular benefit, decreasing androgens, improving ovulation and fertility, and reducing the risk of diabetes and CVD. Theoretically, metformin, a treatment which is now widely used to treat infertile women with PCOS, may have a role in preventing endometrial hyperstimulation by lowering insulin concentrations and restoring ovulation. However, the long-term effects of this drug in women with PCOS are not known and more studies are required before suggesting its use for preventing endometrial cancer.

17beta-estradiol regulation of human growth hormone (hGH), insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) axis in hypoestrogenic, hypergonadotropic women.

OBJECTIVE: Ovarian hormonal function may be as important contributing factor to hGH-IGF-I-IGFBP-3 axis as age. AIM: To examine plasma hGH, IGF-1 and IGFBP-3 levels in women with premature ovarian failure compared to healthy normal controls and postmenopausal ones. PATIENTS: Group A-15 women with premature ovarian failure (POF) (mean: age 38.9+/-5.2 years, FSH 101.4+/-29.0 IU/l; 17beta-estradiol 22.5+/-14.6 ng/l). Group B consisted of 15 menopausal women (mean: age 54.7+/-2.7 years; FSH 81.9+/-32.1 IU/l; 17beta-estradiol 17.1+/- 8.0 ng/l). Group C - controls - 15 normally menstruating women (mean: age 37.1+/-9.0 years; FSH 6.2+/-1.0 IU/l; 17beta-estradiol 144.8+/-117.1 ng/l). METHODS: Body mass and BMI were measured. Basic fasting plasma hGH, IGF-I, IGFBP-3, insulin, testosterone and LH as well as prolactin (PRL), FSH and estradiol were assessed by RIA kits. Statistical analysis. Shapiro-Wilk test, Mann-Whitney u-test, Spearman rang correlation coefficient, stepwise multiple regression. RESULTS: Mean serum IGF-I level was the lowest (p<0.005) in group B (172.0+/-54.6 microg/l) and the highest in group C (273.6+/-109.0 microg/l). The mean plasma IGF-I level in group A was similar (NS) (208.3+/-66.5 microg/l) to that found in group B and lower (p<0.02) compared with that in group C. The lowest (p<0.005) serum IGFBP-3 level was found in group B (3.1+/-0.7 microg/l) compared to group C (4.4+/-0.3 microg/l). The mean plasma IGFBP-3 level (3.1+/-1.0 microg/l) in group A was lower than in group C (p<0.005) but identical as in group B. No statistically significant differences between groups were observed in mean hGH levels. Women in group A and C were younger (p<0.001) than those in group B. The lowest mean estradiol level was found in groups A and B. The highest was in group C (p<0.001). Mean plasma LH and FSH levels were higher (p<0.001) in groups A and B vs group C. In group C there were links between IGF-I and age (r=-0.60; p=0.014) The IGF-I/age relation disappeared in the groups A and B (rA=-0.26; rB=0.10; NS). The same regards IGFBP-3/ age link (rA=-0.44, NS; rB=0,31;NS). Estradiol level was related to hGH levels in group C (r=-0.54; p<0.05). In none of groups hGH/IGF-1 as well as IGFBP-3/hGH relations were found. Prolactin accounted for 69% of the variance in IGF-I level in the group B (p=0.003) and for 24% in group A (NS). Testosterone accounted for 88% (p=0.004) of the variance in IGF-I level in group B and IGFBP-3 was responsible for 86% (p=0.038) of the variance in IGF-I level in group C. Again IGFBP-3 was responsible for 47% (p=0.023) in group A and for 49% (p=0.04) in group B of the hGH variance. CONCLUSIONS: 17b-estradiol may be as important contributor to insulin-like growth factor-I (IGF-I) plasma level as age in hypoestrogenic, hypogonadotropic women.

Age, insulin, SHBG and sex steroids exert secondary influence on plasma leptin level in women.

AIM: As the link between body fat and leptin is well known, the aim of the study was to seek for secondary regulators of plasma leptin level. PATIENTS: 86 women (mean: age 47.0+/-14.3 years; estradiol 50.0+/-60.6 ng/l; FSH 52.4+/-42.9 IU/l; BMI 26.9+/-5.9) divided into three groups according to their BMI. Group A: 39 normal weight women (mean: age 44.4+/-16.0 years; estradiol 69.6+/-79.8 ng/l; FSH 50.4+/-47.7 IU/l; BMI 22.9+/-1.3). Group B: 27 overweighted women (mean: age 55.0+/-6.4 years; estradiol 25.1+/-17.2 ng/l; FSH 75.6+/-26.3 IU/l; BMI 27.7+/-1.6). Group C: 21 obese women with mean: age 48.7+/-12.2 years; estradiol 36.9+/-44.0 ng/l; FSH 42.3+/-36.6 IU/l and BMI 34.6+/-4.9. METHODS: Standard clinical evaluation and hormone evaluation (LH, FSH, prolactin, estradiol, leptin, insulin-like growth factor-I (IGF-I), human growth hormone (hGH), insulin-like growth factor binding protein-3 (IGFBP-3), insulin, dihydroepiandrosterone sulphate (DHEAS), sex hormone binding globin (SHBG) and testosterone were done in basic condition which levels of were measured by RIA kits. Statistical analysis. Shapiro-Wilk test, Mann-Whitney-Wilcoxon u test, Spearman rank correlation coefficient and stepwise multiple regression: p values of 0.05 or less were considered as significant. RESULTS: Taking all women into account (n=86) the plasma leptin level correlated directly with age (r=0.32; p<0.02), body mass (r=0.60; p<0.001), BMI (r=0.71; p<0.001) as well as inversely with estradiol (r=-0.21; p<0.05), IGF-I (r=-0.24; p<0.05), SHBG (r=-0.34; p<0.01) and DHEAS (r=-0.30; p<0.01). However only in the group B leptin/age relation remained (r=0.40; p<0.05) after the division according to BMI. In the group B the leptin /DHEAS (r=-0.40; p<0.05) and leptin/PRL (r=0.51; p<0.05) links were also present. In the group C the leptin/SHGB relation (r=-0.56; p<0.02) only remained and an association between insulin and leptin was found (r=0.48; p<0.05). The body mass and BMI relation to age were again present only in all 86 women (r=0.30; p<0.002: r=0.36; p<0.001 resp.). Having split the women into groups, these links either disappeared or became inverse (rC=-0.39; p<0.05). Taking into consideration age/leptin relation in all women, the division according to the menopausal status revealed the direct relation in premenopausal women (n=29; r=0.43; p<0.02) and a reverse one in postmenopausal women (n=38; r=-0.32; p<0.05). The plasma leptin level was the highest (p<0.001) in group C (23.2+/-10.4 microg/l) and the lowest was found in the group A (8.9+/-4.1 microg/l). That corresponded with the differences in mean body mass index and mean body mass. The stepwise multiple regression revealed that body mass index accounted for 31% (p<0.001) and plasma SHBG level accounted for 17.7% (p<0.02) of plasma leptin variance in all women. In the group A body mass and age together accounted for 61% (p<0.01) and estradiol alone accounted for 44% (p<0.02) of plasma leptin variance. In the group B insulin alone accounted for 39% (p<0.05) and together with testosterone accounted for 46% (p<0.05) of plasma leptin variance. Finally in obese women none of the evaluated parameters significantly accounted for leptin variance. CONCLUSION: The results presented in this paper confirmed the strong influence of body fat mass on serum leptin concentration. However insulin, SHBG, sex steroids as well as age may also exert secondary influence on plasma leptin level in certain groups of women.

[The principles and the routes of progestagenes' administration in PCOS]. / Podstawy stosowania i drogi podazy progestagenów w zespole policystycznych jajników.

One of the chief findings in polycystic ovaries syndrome may be the defective luteal phase of the menstrual cycle. There is a growing list of publications indicating a defective progesterone production by granulosa cells of ovarian follicles. In consequence, women with polycystic ovaries often require both the luteal phase and early pregnancy supplementation. From different routes of progesterone administration during the menstrual cycle, as the most clinically reliable in the early pregnancy either intramuscular or intravaginal route has been recommended.