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P Kenemans

Publications and source records attributed to P Kenemans.

At least 19 recordsLinked to original sources
PubMed2006

No increase in C-reactive protein levels during intranasal compared to oral hormone therapy in healthy post-menopausal women.

BACKGROUND: Inflammation plays an important role in the development of atherosclerotic disease. Oral post-menopausal hormone therapy increases serum C-reactive protein (CRP) levels. This study compared the effects of intranasal and oral administration of 17beta-estradiol (E2) combined with norethisterone acetate (NETA) on markers of inflammation in healthy post-menopausal women. METHODS: Ninety healthy post-menopausal women (age 56.6 +/- 4.7 years) participated in this 1-year trial. After computerized block randomization, they daily received, in a double-blind fashion, either intranasal E2/NET [175 microg/275 microg (n = 47)] or oral E2/NETA [1 mg/0.5 mg (n = 43)]. Concentrations of high sensitivity CRP and adhesion molecules were measured at baseline and after 12, 24 and 52 weeks of treatment. RESULTS: CRP levels were increased (P = 0.001) in the oral but not in the intranasal group. The increase in the oral group was highest at week 12 (64.9%) and was larger (P < 0.01) compared with the non-significant increase (8.6%) found in the intranasal group. Both groups showed decreases (P < 0.001) in soluble vascular cell adhesion molecule (sVCAM), soluble intracellular adhesion molecule (sICAM) and sE-selectin. The decreases were larger (P < 0.01) in the oral than in the intranasal group. CONCLUSION: Intranasal E2/NET therapy did not significantly increase CRP levels, in contrast to the increase observed in the oral E2/NETA treatment group. Both intranasal and oral therapy lowered plasma concentrations of adhesion molecules, however, more so in the oral group.

Administration, Intranasal↗
PubMed2006

Oral, more than transdermal, oestrogen therapy lowers asymmetric dimethylarginine in healthy postmenopausal women: a randomized, placebo-controlled study.

OBJECTIVE: To compare the effects of oral and transdermal hormone therapy (HT) on asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, in postmenopausal women. DESIGN: In a multicentre, placebo-controlled, double-blind study, 152 hysterectomized healthy women were randomized to receive daily transdermal 17beta-oestradiol (tE2, n = 33), or oral micronized 17beta-oestradiol either unopposed (oE2, n = 37), or continuous combined with gestodene (oE2 + G, n = 33), or placebo (n = 49) for 13, 28-day treatment cycles. Plasma concentrations of ADMA, arginine and symmetric dimethylarginine (SDMA) were measured at baseline and in treatment cycles 4 and 13 with a high-performance liquid chromatography method. RESULTS: After 13 cycles all active treatment groups showed a significant reduction in ADMA compared with placebo: tE2, -4.0% (95% CI: -7.5 to -0.6%); oE2, -7.7% (95% CI: -10.9 to -4.4%) and oE2 + G, -7.5% (95% CI: -10.8 to -4.3%). ancova showed a significantly larger reduction in the oral groups compared with the transdermal group (tE2 vs. oE2 and tE2 vs. oE2 + G, both P < 0.01). Oral, but not transdermal treatment, significantly reduced arginine compared with placebo. All active treatments reduced SDMA; however, this was only statistically significant in the oE2 group. CONCLUSION: Reduction of ADMA was more pronounced after oral than after tE2 administration. Adding gestodene to oral 17beta-oestradiol did not alter the reduction of ADMA. The clinical implications of these findings remain uncertain; however, the decrease of ADMA by 17beta-oestradiol could be a key phenomenon in the modulation of nitric oxide synthesis by postmenopausal HT.

Administration, Cutaneous↗
PubMed2005

Practical guidelines for postmenopausal hormone therapy.

The fourth Amsterdam Menopause Symposium (2-4 October 2004) was dedicated to practical recommendations to guide clinicians after the confusion, concerns, and controversies generated by study results over the previous several years. Those recommendations are summarized in this deliberately concise and user-friendly document, always recognizing that each clinician must help women with their decision-making according to individual needs, desires, and understanding of benefits and risks.

Alzheimer Disease↗
PubMed2005

Tibolone: clinical recommendations and practical guidelines. A report of the International Tibolone Consensus Group.

An international multidisciplinary panel of experts in the management of the menopause met at the 4th Amsterdam Menopause Symposium in October 2004 to determine the specific place of tibolone, a synthetic steroid with a unique clinical profile, within the wide range of currently available postmenopausal therapy options. The consensus was that tibolone is a valuable treatment option for women with climacteric complaints. As well as relieving vasomotor symptoms, tibolone has positive effects on sexual well-being and mood, and improves vaginal atrophy and urogenital symptoms. Prevention of bone loss with tibolone is comparable to that seen with estrogen therapy (ET) and estrogen/progestogen therapy (EPT). As tibolone rarely causes endometrial proliferation, no additional progestogen is required. It also has good tolerability, being associated with a low incidence of vaginal bleeding and of breast pain. Tibolone does not increase mammographic density. Absolute numbers of women at increased risk for breast cancer are estimated to be low or absent with both tibolone and ET, and the risk with tibolone should be significantly lower than that with EPT. Tibolone might therefore be preferable to EPT in certain women who have not been hysterectomised. Based on the evidence available, the panel proposed a number of subgroups of postmenopausal women with vasomotor symptoms in whom tibolone might have added value; these included women with sexual dysfunction, mood disorders, fibroids and urogenital complaints, as well as those with breast tenderness or high mammographic breast density with EPT use.

Estrogen Receptor Modulators↗
PubMed2005

Oral estradiol decreases plasma homocysteine, vitamin B6, and albumin in postmenopausal women but does not change the whole-body homocysteine remethylation and transmethylation flux.

Estrogens, both endogenous and exogenous, lower the fasting levels of the independent risk factor for cardiovascular disease homocysteine. The mechanism behind this observation remains unclear. In a randomized, placebo-controlled, double-blind study, 25 postmenopausal women with a screening homocysteine concentration above 10 micromol/liter were included. We investigated the influence on homocysteine levels of a 3-month treatment with a daily oral dose of 4 mg 17beta-estradiol (ET) or 4 mg ET combined with 10 mg dydrogesterone (EPT); the comparison group received placebo treatment. We performed primed continuous infusions of L-[2H3-methyl-13C]methionine to assess steady-state flux rates of transmethylation, remethylation, and transsulfuration. Homocysteine concentration relationships with S-adenosylmethionine, S-adenosylhomocysteine, creatinine, albumin, vitamins B6 and B12, and folate status were determined as well. The mean change from baseline in homocysteine concentration by both treatments compared with placebo (ET, -13%; EPT, -10%) was accompanied by a decrease in the concentration of vitamin B6 (ET, -25%; EPT, -38%) and albumin (ET, -7%; EPT, -11%). No significant changes in flux rates were observed. In a .multiltivariate analysis, changes in homocysteine concentration were related to changes in albumin concentration. No relation to other variables was observed. We conclude that the ET- and EPT-induced homocysteine changes in this study were not accompanied by a significant change in methionine-homocysteine flux rates and hypothesize that an estrogen-induced lowering of homocysteine levels is primarily part of a change in albumin metabolism.

Aged↗
PubMed2004

Hormone replacement influences homocysteine levels in the methionine-loading test: a randomized placebo controlled trial in postmenopausal women.

OBJECTIVE: To investigate the mechanism by which exogenous oestrogen influences the homocysteine metabolism in postmenopausal women. STUDY DESIGN: A randomized placebo controlled trial in which a methionine-loading test was performed, in 25 healthy postmenopausal women, before and after a 12-week oral treatment with placebo or daily 4 mg 17beta-estradiol with (HRT) or without (ERT) 10 mg dydrogesterone. Fasting and post-load homocysteine as well as Vitamins B(6), B(12) and folate were determined. RESULTS: In both treatment groups a significant 12% decrease in fasting homocysteine was observed. This decrease was accompanied by a post-load homocysteine increase of more than 20%. Vitamin B(6) values were decreased by more than 25%. CONCLUSION: The hormone therapy induced lowering of fasting homocysteine and Vitamin B(6) levels and an increase in post-load homocysteine, supporting the hypothesis that homocysteine-methionine metabolism is modulated by hormone therapy in postmenopausal women.

Analysis of Variance↗
PubMed2004

Oncogenic pathways in hereditary and sporadic breast cancer.

Cancer is a genetic disease. Breast cancer tumorigenesis can be described as a multi-step process in which each step is thought to correlate with one or more distinct mutations in major regulatory genes. The question addressed is how far a multi-step progression model for sporadic breast cancer would differ from that for hereditary breast cancer. Hereditary breast cancer is characterized by an inherited susceptibility to breast cancer on basis of an identified germline mutation in one allele of a high penetrance susceptibility gene (such as BRCA1, BRCA2, CHEK 2, TP53 or PTEN). Inactivation of the second allele of these tumour suppressor genes would be an early event in this oncogenic pathway (Knudson's "two-hit" model). Sporadic breast cancers result from a serial stepwise accumulation of acquired and uncorrected mutations in somatic genes, without any germline mutation playing a role. Mutational activation of oncogenes, often coupled with non-mutational inactivation of tumour suppressor genes, is probably an early event in sporadic tumours, followed by more, independent mutations in at least four or five other genes, the chronological order of which is likely less important. Oncogenes that have been reported to play an early role in sporadic breast cancer are MYC, CCND1 (Cyclin D1) and ERBB2 (HER2/neu). In sporadic breast cancer, mutational inactivation of BRCA1/2 is rare, as inactivation requires both gene copies to be mutated or totally deleted. However, non-mutational functional suppression could result from various mechanisms, such as hypermethylation of the BRCA1 promoter or binding of BRCA2 by EMSY. In sporadic breast tumorigenesis, at least three different pathway-specific mechanisms of tumour progression are recognizable, with breast carcinogenesis being different in ductal versus lobular carcinoma, and in well differentiated versus poorly differentiated ductal cancers. Thus, different breast cancer pathways emerge early in the process of carcinogenesis, ultimately leading to clinically different tumour types. As mutations acquired early during tumorigenesis will be present in all later stages, large-scale gene expression profiling using DNA microarray analysis techniques can help to classify breast cancers into clinically relevant subtypes.

Breast Neoplasms↗
PubMed2004

The Million Women Study: a licence to kill other investigations?

The Million Women Study (MWS), published in the summer of 2003, has suggested unexpected high risks for invasive breast cancer in women using postmenopausal hormone therapy (PHT). Recent reports from randomised controlled trials (RCTs) have demonstrated that long-term combined PHT is associated with a small risk increase for invasive breast cancer, but not for death due to breast cancer. The observational design of the MWS has made this study subject to several biases, that can easily explain the discrepancy with the observations done in RCTs and several other large observational studies. It is concluded that the hormone fear that was caused by the MWS, and augmented by some professionals and the media, was unjustifiable.

Breast Neoplasms↗
PubMed2004

Pulsed estrogen exposure selectively modulates tissue response: a hypothesis.

All postmenopausal hormone replacement therapies (HTs) aim to provide a steady mid-follicular serum concentration of estrogen, with the exception of pulsed estrogen therapy, which concentrates hormone exposure in the few hours following administration. This alteration in the kinetics of estradiol exposure does not change the beneficial effect of HT on climacteric symptoms or bone loss, but does reduce the stimulation of the breast and uterus leading to less mastalgia and bleeding. The following hypothesis provides a plausible pharmacological explanation as to how estradiol kinetics can selectively modify tissue response. Pulsed estradiol exposure influences the relative abundance of estrogen receptors (ERs) alpha and beta, via a tissue-dependent non-genomic signaling pathway, resulting in selective upregulation and activation of ERbeta in breast and endometrium, but not in bone. In addition, pulsed estrogen exposure also increases local concentration of 2-methoxyestradiol, a specific estradiol metabolite with proven anti-tumor properties.

2-Methoxyestradiol↗
PubMed2003

A randomized placebo-controlled study of the effect of transdermal vs. oral estradiol with or without gestodene on homocysteine levels.

OBJECTIVE: To assess the effect of transdermal vs. oral administration of E2 on plasma homocysteine levels and to evaluate the impact of adding a progestogen to these regimens. DESIGN: Prospective, double-blind, double-dummy, placebo-controlled study. SETTING: Outpatient clinics in two university hospitals and two teaching hospitals in The Netherlands. PATIENT(S): One hundred fifty-two healthy hysterectomized postmenopausal women. INTERVENTION(S): Thirteen 28-day treatment cycles with placebo (n = 49); transdermal 17beta-E2, 50 microg (n = 33), oral E2, 1 mg (n = 37), or oral E2, 1 mg, plus gestodene, 25 microg (n = 33), followed by four cycles of placebo in each group. MAIN OUTCOME MEASURE(S): Fasting plasma total homocysteine concentrations at baseline and cycle 4, 13, and 17. RESULT(S): Mean (+/-SD) homocysteine concentrations in the oral E2 group decreased from baseline to cycle 4 (9.0 +/- 2.5 micromol/L vs. 8.2 +/- 2.0 micromol/L; mean change, -7.6%). Homocystine values in the oral E2 plus gestodene group did not change substantially from baseline to cycle 4 (8.9 +/- 1.6 micromol/L vs. 8.6 +/- 2.0 micromol/L; mean change, -4.4%). No significant changes were observed in the transdermal E2 group. After four washout cycles, the homocysteine concentration had returned to baseline values in all groups. CONCLUSION(S): Oral E2 therapy reduced the homocysteine concentration more than did therapy with transdermal E2 or oral E2 plus gestodene. This finding may indicate a role of liver metabolism and suggests that gestodene has a negative effect on these changes.

Administration, Cutaneous↗
PubMed2003

Breast cancer and post-menopausal hormone therapy.

From the introduction of post-menopausal hormone replacement therapy (HRT) there has been great concern that HRT could possibly increase the risk of breast cancer. Prolonged exposure to endogenous oestrogens undeniably increases the risk of breast cancer. Questions that are important and until now only partly answered, are the following. Are oestrogens tumour promoters, as they induce mitosis, lead to proliferation and, therefore, accelerated growth of clinically occult pre-existing tumours? In addition to this, are they genotoxic mutagenic carcinogens, or could they initiate tumours by way of accumulation of incessant DNA-replication damage mechanism? Opinions vary as to the effect of the addition of a progestogen. There is a multitude of different progestogens which could bind with differing affinity to progesterone receptor PR-A or PR-B, and which have different physiological functions via differential gene regulation. The action of a progestogen on the oestrogen-induced cellular mitotic activity could be synergistic or antagonistic (by different pathways: oestrogen receptor downregulation, activating of metabolic pathways within the breast or stimulation of apoptosis)? Over 60 observational studies and two randomized trials provide evidence that the small but significant increase in risk appears with long-term current post-menopausal hormone use. The addition of a progestogen does not decrease the risk as seen with oestrogens alone and might increase the risk further. It is not clear whether there is a difference in risk with sequentially combined versus continuously combined HRT. Many questions nevertheless still remain. Is the risk increase limited to lean women only? What about risk-modifying factors such as alcohol use and a positive family history for breast cancer? Are tumours detected under HRT less aggressive, is there a better prognosis and is the mortality not increased while morbidity is? And is HRT contraindicated for women with a positive family history for breast cancer or in those women who have been treated for breast cancer? And finally, are there alternative options for these women?

Breast Neoplasms↗
PubMed2003

Expression of differentiation and proliferation related proteins in epithelium of prophylactically removed ovaries from women with a hereditary female adnexal cancer predisposition.

AIMS: To investigate the occurrence of preinvasive neoplastic lesions in ovarian surface epithelium and ovarian inclusion cyst epithelium of women with a hereditary predisposition to the development of female adnexal (ovarian and fallopian tube) carcinoma and to assess the expression of differentiation and proliferation related proteins within putative sites of origin of serous ovarian carcinoma, the ovarian surface epithelium and ovarian inclusion cyst epithelium. METHODS: Twenty-one ovaries, prophylactically removed from 11 women predisposed to the development of female adnexal cancer (cases) were compared with 22 ovaries from 11 women without such predisposition (controls). Archival histological specimens were screened for hyperplastic and dysplastic epithelial lesions. In both the ovarian surface and inclusion cyst epithelia, the percentage of cells was determined that stained positively for Ki67, p21, p27, p53, cyclin A, cyclin D1, bcl-2 and the presence of HER-2/neu, oestrogen (ER-alpha) and progesterone receptors (PR). RESULTS: No preinvasive neoplastic lesions were detected. However, hyperplastic areas were found in three cases and in four controls (NS). ER-alpha (P = 0.013), PR (P < 0.001), bcl-2 (P = 0.008), p21 (P = 0.046) and p27 (P = 0.008) were expressed in a significantly higher percentage of cells in inclusion cyst epithelium than in ovarian surface epithelium (both groups). The latter showed higher bcl-2 expression in cases (P = 0.05) compared with controls. The inclusion cyst epithelium of cases showed higher expression of bcl-2 (P = 0.006) and PR (P = 0.039) compared with controls. Proliferation was low in both cases and controls as reflected by low Ki67 expression. Over-expression of p53, cyclin D1 and HER-2/neu was not detected. CONCLUSIONS: Premalignant changes are not a common feature of ovaries removed prophylactically from women predisposed to the development of female adnexal carcinoma. Increased expression of p21, p27, and ER-alpha is seen in inclusion cyst compared with ovarian surface epithelium of women with and without an inherited risk of adnexal carcinoma. This is most probably caused by the different intraovarian hormonal milieu of inclusion cyst epithelium. However, the increased expression of bcl-2 and PR in the inclusion cyst epithelium of patients with a hereditary predisposition may reflect early disruption of hormonal balance and growth control.

Adnexal Diseases↗
PubMed2003

Estrogens, homocysteine, vasodilatation and menopause: basic mechanisms, interactions and clinical implications.

Estrogens influence the independent cardiovascular risk factor homocysteine as well as vasodilatation. Homocysteine alone also influences vasodilatation, indicating a relational triangle that seems important in interpreting the isolated effects of estrogens on homocysteine metabolism and vasoreactivity. This paper gives an overview of the current understanding regarding vasoreactivity, homocysteine metabolism and the role of estrogens. This is placed against the background of the clinical trials on the effect of postmenopausal hormone replacement therapy on homocysteine levels and addresses the importance of the interaction between homocysteine, estrogens and vasoreactivity.

Cardiovascular Diseases↗
PubMed2002

Effects of hormone replacement therapy on blood platelets.

BACKGROUND: Hormone replacement therapy (HRT) increases the risk of cardiovascular morbidity in postmenopausal women under certain circumstances. Part of this effect may be the result of the influence of HRT on blood platelets. We studied the effect of short-term oral hormone replacement therapy (unopposed oestradiol or sequentially combined oestradiol and trimegestone or dydrogesterone) on platelet activation parameters in healthy postmenopausal women. DESIGN: We designed a prospective, randomised, placebo-controlled 12-week study. Sixty healthy, normotensive, nonhysterectomised, postmenopausal women received daily micronised oestradiol (E2) 2 mg (n = 16), or 2 mg E2 daily sequentially combined with either trimegestone 0.5 mg daily (n = 14) or dydrogesterone 10 mg daily (n = 14), or placebo (n = 16). Data on platelet activation were collected at baseline and after 12 weeks of treatment using flow cytometry. RESULTS: Twelve weeks of treatment with combined HRT was associated with an increase in platelet activation parameters P-selectin and glycoprotein 53 (by 17% and 14%, respectively, P = 0.04 vs. the placebo group for both comparisons), suggesting alpha granule and lysosome degranulation. E2 replacement therapy was associated with an increase in P-selectin labelling by 22% (P = 0.04 vs. the placebo group). CONCLUSION: Short-term treatment with oestradiol or combined HRT increases the amount of circulating activated platelets as measured by flow cytometry. This could be a mechanism by which short-term HRT might increase the risk of thrombosis.

Antigens, CD↗
PubMed2002

Oral oestradiol/trimegestone replacement reduces procarboxypeptidase U (TAFI): a randomized, placebo- controlled, 12-week study in early postmenopausal women.

OBJECTIVE: To investigate the effects of short-term postmenopausal oral hormone administration on plasma levels of procarboxypeptidase U (proCPU, thrombin-activatable fibrinolysis inhibitor, EC 3.4.17.20), an inhibitor of fibrinolysis, in healthy early postmenopausal women. DESIGN: A prospective, randomized, placebo-controlled study. SETTING: Outpatient clinic of the Department of Obstetrics and Gynaecology. SUBJECTS: Seventy-seven healthy early postmenopausal women were screened of whom 65 were randomized. Analyses were based on 60 participants. INTERVENTIONS: The women received oral micronized oestradiol 2 mg either alone (E2 group, n=16), or sequentially combined with dydrogesterone 10 mg (E2 + D group, n=14) or trimegestone 0.5 mg (E2 + T, n=14), or placebo (n=16) for 12 weeks. MAIN OUTCOME MEASURE: ProCPU concentrations at baseline, and at 4 and 12 weeks of treatment. RESULTS: Four weeks of E2 + T was associated with a significant decrease in the fasting proCPU concentration, which was sustained after 12 weeks [t=0: 636 +/- 57 U L(-1) (mean +/- SD); t=4: 583 +/- 63UL-1; t=12: 589 +/- 48 U L(-1); ANCOVA versus placebo: P=0.011]. The percentage change from baseline versus placebo in this group was -8.4% [95% confidence interval (CI) -15.7 to -1.1] after 4 weeks and -5.9% (95% CI -11.7 to -0.1) after 12 weeks. There were no significant changes versus placebo in the E2 group nor in the E2 + D group. CONCLUSION: Short-term treatment with E2 + T, but not E2 alone or E2 + D, lowers proCPU concentration. These findings add to accumulating evidence suggesting that different progestagens added to oestrogen replacement may differentially affect the risk of arterial and venous disease.

Carboxypeptidase B2↗
PubMed2002

Histopathologic features of genetically determined ovarian cancer.

Inheritance of germline mutations of BRCA1 or BRCA2 genes account for approximately 10% of ovarian carcinomas, but the characterization of these genetically determined cancers is incomplete. The objective of our study was to characterize the histologic features of ovarian carcinomas associated with germline mutations of BRCA1 and BRCA2. Thirty-two ovarian carcinomas associated with germline BRCA1 or BRCA2 mutations and 40 ovarian carcinomas from patients screened as negative for germline mutations were obtained from three centers. A gynecologic pathologist, blinded to mutation status, reviewed each case, with documentation of the histologic type, Gynecologic Oncology Group (GOG) grade, architectural and nuclear grade, Silverberg grade, and mitotic activity. All BRCA1 and BRCA2 mutation-associated cases were invasive serous carcinomas, and of these 50% were GOG grade 3, 41% had an architectural grade of 3 (predominant solid architecture), 84% a nuclear grade of 3, 72% a mitotic score of 3 (>25 mitoses per 10 HPF), and 75% a Silverberg grade of 3. The differences in histologic type (p = 0.001) and Silverberg grade (p = 0.002) between these tumors and the control group were statistically significant and remained so when comparisons between BRCA carriers and noncarriers were restricted to carcinomas of serous histology alone. Ovarian carcinomas associated with germline mutations of BRCA1/BRCA2 are, in this study, invasive serous carcinomas, with a statistically significant higher histologic grade than ovarian carcinomas without BRCA mutations when using the recently proposed Silverberg grading system.

Female↗