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Biomedical subjects

A R Genazzani

Publications and source records attributed to A R Genazzani.

At least 37 records · Page 2Linked to original sources
PubMed2003

Hormone replacement therapy and endometrial, ovarian and colorectal cancer.

Sex-steroid-related tumours in women are represented by breast cancer and endometrial cancer, but a possible relationship may exist between sex steroids and both ovarian and colon cancer. Unopposed oestrogen therapy is known to increase the risk of endometrial cancer and is appropriate only for hysterectomized women. In women with an intact uterus, an appropriate combination of oestrogen and progestin does not appear to increase-and may even decrease-the risk of endometrial cancer. Current users of HRT seem to benefit from a reduced risk for colon cancer. As for epithelial ovarian cancer, the present data are very conflicting. The association between replacement hormones and this malignancy seems to be stronger for unopposed oestrogen than for oestrogen-progestin treatment. Data available at the moment do not allow discriminating for dose, routes of administration, bioavailability and tissue effects of different compounds so that it is inappropriate to consider all forms of HRT jointly. The future of HRT in post-menopausal women lies in the individualization of the therapy based upon personal risk factors and characteristics.

Colorectal Neoplasms↗
PubMed2003

CNS: sex steroids and SERMs.

The central nervous system (CNS) is one of the main target tissues for sex steroid hormones, which act both through genomic mechanisms, modulating synthesis, release, and metabolism of many neuropeptides and neurotransmitters, and through nongenomic mechanisms, influencing electrical excitability, synaptic function, and morphological features. The identification of the brain as a de novo source of neurosteroids modulating cerebral function, suggests that the modifications in mood and cognitive performances occurring in postmenopausal women could also be related to a modification in the levels of neurosteroids, particularly allopregnanolone and DHEA, GABA-A agonist, and antagonist, respectively. The selective estrogen receptor modulators (SERMs) are compounds that activate the estrogen receptors with different estrogenic and antiestrogenic tissue-specific effects. In addition to the effects of the classic steroid hormones on the CNS, the study of selective estrogen receptor modulators impact on the neuroendocrine system has recently provided encouraging results, indicating that raloxifene analog LY 117018 and the new generation SERM EM-652 have an estrogen-like action on beta-endorphin and on allopregnanolone in ovariectomized rats, while they exert an anti-estrogenic effect in fertile rats and in ovariectomized rats treated with estrogens. In addition, raloxifene administration in postmenopausal women plays an estrogen-like effect on circulating beta-EP and allopregnanolone levels, and it restores the response of beta-EP and allopregnanolone to neuroendocrine tests. In conclusion, the positive effects of HRT on mood and cognition in postmenopausal women occur via the modulation of neuroendocrine pathways and probably also of neurosteroidogenesis. The effects of raloxifene on mood and cognition encourage the efforts in the research of an ideal estrogen replacement therapy, showing all the positive effects of estrogens and fewer side effects.

Aged↗
PubMed2003

Effect of different hormonal replacement therapies on circulating allopregnanolone and dehydroepiandrosterone levels in postmenopausal women.

The effects of hormone replacement therapy (HRT) on the central nervous system in postmenopausal women might be mediated by changes in neurosteroid synthesis and/or release. The aim of this study was to evaluate the impact of HRT on the levels of allopregnanolone, a sedative anxiolytic GABA(A) agonist steroid, and dehydroepiandrosterone (DHEA), a GABA(A) antagonist steroid. We evaluated allopregnanolone and DHEA circulating levels after 1, 3, 6, 9 and 12 months of HRT with ten different estrogen or estrogen-progestin molecules, regimens and routes of administration in 186 postmenopausal women. Cortisol, luteinizing hormone, follicle stimulating hormone, estradiol and progesterone levels were also evaluated. Allopregnanolone levels significantly increased during follow-up with all HRT preparations. The addition of progestin molecules (except for 19-nor derivatives) to transdermal estradiol administration alone determined a higher increase in allopregnanolone levels. Transdermal HRT showed a significantly higher percentage change in allopregnanolone levels compared with oral HRT. DHEA levels showed a progressive decline starting from the 3-month follow-up, without significant differences between the transdermal and oral groups, as well as among the ten groups, independently of the presence and type of progestin molecule used. In conclusion, HRT strongly modifies circulating neurosteroid levels in postmenopausal women.

Administration, Cutaneous↗
PubMed2003

Adrenal function under long-term raloxifene administration.

The aim of the present study was to evaluate the effect of long-term (12 months) administration of raloxifene hydrochloride (60 mg/day) on the steroid production of the adrenal cortex and on the hypothalamic-pituitary-adrenal axis in postmenopausal women. We performed a basal evaluation, a corticotropin releasing factor (CRF) (100 microg i.v. bolus) test and a dexamethasone (DXM) (0.25 mg) suppression-adrenocorticotropic hormone (ACTH) (10 microg i.v. bolus) stimulation test in 11 postmenopausal women, before and after 3, 6 and 12 months of raloxifene treatment. Raloxifene administration significantly modified circulating levels of adrenal steroids, decreasing cortisol (-24%), dehydroepiandrosterone (DHEA) (-36%), and its sulfate (DHEAS) (-41%), and androstenedione (-29%), and increasing circulating allopregnanolone (+39%) levels. Progesterone and 17OH-progesterone levels remained unmodified, while estradiol and estrone levels showed a significant decrease (-51% for estradiol and -61% for estrone). We also observed an increase in circulating ACTH (+58%) and beta-endorphin (+120%). No modifications in the hormonal responses to CRF were observed during the treatment. DXM significantly suppressed circulating steroids at any time with a lower suppression of cortisol from the third month and a higher suppression of DHEA at 12 months. ACTH administration was associated with a significantly blunted cortisol response from the sixth month and a significantly increased response of allopregnanolone from the third month. The present data exclude a raloxifene effect on pituitary sensitivity to CRF and demonstrate a reduced adrenal sensitivity to ACTH, sustained by the opposite changes in basal cortisol and Delta5 androgens, which were reduced, and in ACTH and beta-endorphin, which were increased, as well by the reduced response of cortisol to the direct ACTH stimulus. The reduction of circulating cortisol levels and cortisol response to the ACTH challenge suggests that raloxifene protects against the neurotoxic effects of endogenous glucocorticoids. Furthermore, the progressive increase in basal allopregnanolone and its increased response to ACTH indicate that chronic raloxifene administration exerts direct effects on the pattern of adrenal enzymes, leading to specific changes in the circulating levels of this anxiolytic progesterone metabolite. The important reduction in the circulating levels of estradiol and estrone under long-term raloxifene administration may represent a further mechanism by which this molecule may exert a protective effect against breast and endometrial malignancies.

Adrenal Cortex↗
PubMed2003

The missing R.

Explore the source record for details and available documents.

Aged↗
PubMed2003

[Aerodiol: the efficacy and tolerability of intranasal estrogen administration. An overview].

UNLABELLED: Estrogen supplementation, given mainly by oral or transdermal route has been shown to decrease climacteric symptoms, bone turnover, prevent postmenopausal bone loss, and significantly reduce fracture risk in both early and late postmenopausal women. Estrogens exert their principal biological effects through the actions on 2 different intracellular estrogen receptor (ER) proteins, ERa and ERb. These receptors, are completely distinct in their action. However, regardless the type of receptor involved, the response induced through the action of ER induction can be dependent also on the total dose exposure rather than estradiol concentrations at subsaturating levels. The nasal route is an effective and well-established route of drug delivery. Nasal administration produces a pulsed profile of plasma estradiol, with plasma levels rising rapidly and returning to pre-administration levels within 12 h (fall to 10% of their peak level within approximately 2 h). As a consequence, daily intranasal administration results in a pulse-like estrogen profile, rather than the relatively sustained serum levels attained with both oral and transdermal administration. In addition, exposure obtained with a single dose is compared with the exposure obtained with the same total dose given as 2 divided doses administered 12 h apart. It's known that different route of administration exert different biological and clinical RESULTS: In the years, several clinical studies have demonstrated the efficacy and safety of intranasal estradiol in the treatment of climacteric symptoms, compared with other routes of estrogen administration. Interestingly, intranasal therapy also showed a lower tendency to stimulate endometrial proliferation than the oral route, with a high incidence of atrophic endometrium maintained during the long-term study. The reduced level of stimulation of the reproductive organs produced by Aerodiol compared with oral estradiol therapy of equivalent efficacy on climacteric symptoms may be related to the pulsed kinetic profile of estradiol exposure that occurs with the intranasal route. Improvement of climacteric symptoms observed with nasal estradiol administration is comparable to that seen with transdermal or oral estrogens. A similar reduction in Kupperman Index or in the number of hot flushes was reported over a 6-month period with results similar to those of several studies performed with transdermal patches delivering estradiol or with conjugated equine estrogen. Different routes of administration may exert different results in terms of compliance, biological and clinical effects even if long term clinical trials are needed for demonstrating it. The pulsed kinetics of Aerodiol may exert less side effects in terms of coagulation cascade activation and a favourable lipid profile with less mammary tissue stimulation. These aspects became of paramount importance since the recent publication of 2 trials, Women Health Initiative (WHI) and Heart and Estrogen/Progestin Replacement Study (HERS), regardless their important population selection bias and uncertain results, left important consequences in terms of HRT indication and use for both women and clinicians. In conclusion, Aerodiol introduces the new concept of pulsed estrogen therapy. Pulsed estrogen therapy is safe, well accepted and highly efficient in alleviating postmenopausal symptoms and prevent postmenopausal bone loss. Aerodiol therapy demonstrated also a lower stimulation of reproductive tissues (endometrium, breast) compared with the equivalent oral therapy, with important repercussion for future HRT strategies.

Administration, Intranasal↗
PubMed2003

Is pretreatment hemoglobin level a predictor of complete response to salvage chemotherapy for recurrent platinum-pretreated ovarian carcinoma?

PURPOSE OF INVESTIGATION: The aim of this retrospective study was to correlate some patient characteristics at relapse, including also baseline hemoglobin levels, with complete response rate and survival following second-line chemotherapy for recurrent platinum-pretreated ovarian carcinoma. METHODS: The investigation was conducted on 63 patients who received salvage chemotherapy with different agents for clinically detectable recurrent ovarian carcinoma following initial surgery and first-line platinum-based chemotherapy. Some patient characteristics at relapse (patient age, serum CA 125 level, baseline hemoglobin level, number of recurrence sites, ascites, platinum-free interval, and treatment-free interval) were related to complete response rate to salvage chemotherapy and survival after recurrence. Median baseline hemoglobin level was 11.6 g/dl (range, 7.5-15.0 g/dl). RESULTS: Second-line chemotherapy obtained a complete response in 17 (27.0%) patients and a partial response in 11 (17.5%), whereas stable disease and progressive disease were detected in 19 (30.1%) and 16 (25.4%) patients, respectively. By univariate analysis, complete response rate was related to baseline hemoglobin level (p = 0.0019), platinum-free interval (p = 0.0012) and treatment-free interval (p = 0.0048). Multiple logistic regression showed that platinum-free interval (p = 0.0107) and baseline hemoglobin level (0.0312) were independent predictors of complete response. Patients with baseline hemoglobin levels >11.6 g/dl had a 5.338 higher chance of obtaining a complete response when compared to those with lower hemoglobin values. The platinum-free interval was the only independent prognostic variable for survival after recurrence (p = 0.0141), whereas baseline hemoglobin level was not related to survival at univariate nor at multivariate analysis. CONCLUSIONS: Baseline hemoglobin level is an independent predictor of complete response to salvage chemotherapy in patients with recurrent platinum-pretreated ovarian carcinoma. Attention must be paid to anemia correction in these patients, with the aim of improving both the chance of response to salvage treatment and the quality of life.

Adult↗
PubMed2002

Assessment of the QoL in Italian menopausal women: comparison between HRT users and non-users.

OBJECTIVES: The aim of this cross-sectional study was to describe QoL in a large sample of women attending menopause centres and compare untreated postmenopausal women and matched HRT users by employing the Women's Health Questionnaire (WHQ) and two generic instruments, the SF-36 and the EQ-5D. METHODS: Overall, 2906 women were recruited by 64 menopause centres throughout Italy, of whom 2160 filled in the questionnaire (1093 on HRT and 1067 not on HRT; response rate: 74%). RESULTS: HRT users tended to be younger, healthier and with shorter menopause duration as opposed to non users, while no major socio-economic differences were present. At multivariate analysis, the presence of chronic diseases, low socio-economic status and living in Southern Italy represented the most important predictors of poor QoL. Furthermore, HRT users showed a lower probability of reporting problems in usual activities and pain/discomfort (EQ-5D), role limitations due to emotional problems (SF-36) and anxiety/fears (WHQ). HRT users also showed highly significant better outcomes in those areas that are more directly attributable to hormonal changes of mid age, namely vasomotor symptoms and sexual problems. CONCLUSIONS: Although QoL is mainly influenced by socio-economic and cultural factors, HRT has the potential for improving not only symptoms, but also more general aspects of physical and psychological well-being of symptomatic postmenopausal women.

Estrogen Replacement Therapy↗
PubMed2002

Vascular endothelial growth factor, interleukin-6 and interleukin-2 in serum and follicular fluid of patients with ovarian hyperstimulation syndrome.

BACKGROUND: The pathogenesis of ovarian hyperstimulation syndrome (OHSS) is not completely understood. OBJECTIVE: To investigate the presence of VEGF, IL-6 and IL-2, in serum and follicular fluid, in patients developing severe OHSS. STUDY DESIGN: We enrolled 101 women undergoing in vitro fertilization. Eight patients developing severe OHSS were compared with 43 high risk patients and 50 controls. We analyzed VEGF and IL-6 in serum collected before hCG administration, and in both serum and follicular fluid on the day of oocyte retrieval. RESULTS: OHSS patients presented follicular fluid IL-6 levels higher than both the patients at risk and controls (P<0.05). On the day of the oocyte retrieval the patients developing OHSS showed serum and follicular VEGF values higher than the ones of the patients at risk (P<0.05). Serum and follicular fluid IL-2 levels showed no differences between the examined groups. IL-2, IL-6 and VEGF values were not correlated with each other. CONCLUSIONS: Angiogenesis and inflammation processes are both present in severe OHSS.

Adult↗
PubMed2002

Validation of Italian version of the Women's Health Questionnaire: assessment of quality of life of women from the general population and those attending menopause centers.

OBJECTIVES: The Women's Health Questionnaire has been developed and validated in Anglo-Saxon and Swedish populations. The purpose of this study was to evaluate the Italian version of the questionnaire to determine whether cross-cultural differences exist in the perception of quality of life, and to use it to compare the quality of life in women attending menopause centers with that of women in the general population. METHODS: An Italian version of the Women's Health Questionnaire (WHQ) was produced, using the forward-backward translation method to ensure conceptual equivalence, and approved by the originator. Women were recruited by random selection from the general population and from menopause centers, those taking hormone replacement therapy being ineligible. The questionnaire was completed anonymously at home and mailed to the co-ordinating center. Psychometric evaluation included tests of item convergent and discriminant validity, internal-consistency reliability, test-retest reliability, construct validity and the discriminative properties of the questionnaire. RESULTS: The completeness of the data was good, with missing-value rates consistently low for most items. Item-scale correlations, used to evaluate internal consistency, were also good and the scaling success rate, used to measure item discriminant validity, was high for all scales. Scale scores were reliable for seven out of nine scales and test-retest reliability was excellent. There were few significant differences between the two populations of women in most of the WHQ areas. A comparison of Italian data with published data on English women showed great similarity. CONCLUSION: The Italian version of the WHO is valid and reproducible. The subjective perception of the menopause and its related problems is similar in geographically and culturally different populations.

Affect↗
PubMed2002

Low-dose hormone replacement therapy: effects on bone.

Hormone replacement therapy (HRT) is considered the mainstay for postmenopausal osteoporosis prevention. However, at the standard doses, HRT preparations can induce bothersome hormone-related side-effects, in both sequential and continuous combined regimens. Lower-dose HRT schedules are reported to be highly effective in the relief of climacteric symptoms, inducing minimal endometrial stimulation with very low rates of unscheduled bleeding. Moreover, low-dose HRT associated with an adequate calcium supplement can spare bone by preventing the increase in bone turnover and the resultant bone loss in postmenopausal women. Low-dose regimens may be considered as a starting dose not only in elderly subjects, but also in early postmenopausal women to allow for adjustment to HRT. In older women, these may minimize the occurrence of side-effects and improve compliance, while preventing the long-term consequences of estrogen deprivation.

Drug Administration Schedule↗
PubMed2002

Indication of hysteroscopy in tamoxifen treated breast cancer patients.

The aim of this study was to indicate the patients treated with tamoxifen for breast cancer in which hysteroscopy with biopsy should be considered mandatory. 414 breast cancer patients who underwent hysteroscopy with bioptic evaluation were enrolled in the study. 334 subjects were treated with 20 mg of tamoxifen daily as adjuvant therapy for six up to a hundred months. Of the remaining 80 control patients, which had not received tamoxifen, 30 were in premenopause (Group IA) and 50, in postmenopause (Group IIA). The tamoxifen-treated patients were subdivided in premenopausal (Group IB = 72 patients) and in postmenopausal (Group IIB = 262 patients) groups. All patients were further classified in asymptomatic or symptomatic groups considering whether uterine bleeding was absent or present. The evaluation of the endometrial mucosa was performed by office hysteroscopy. In group IIB patients presenting uterine bleeding, malignant lesions were found in 7.8% of the cases. The incidence of premalignant and malignant lesions in IIB patients treated for longer than 3 years (11.7%) was higher than that observed in IIB patients treated for less than 3 years (1.3%). There was a significant difference in terms of endometrial pathology between Group IIB (32.8%) and Group IIA (8%) (p < 0.001); and between Group IIB (32.8%) and Group IB (13.9%) women (p = 0.003). Among IA and IIA patients there were no cases of endometrial hyperplasia or cancer; on the contrary, in IB and IIB women, 2 and 22 cases of atypical hyperplasia were observed, respectively. All cases of endometrial cancer were observed in Group IIB and had a diagnosis of poor prognosis. In conclusion the hysteroscopy with biopsy should be considered the first diagnostic procedure to perform in tamoxifen-treated postmenopausal patients presenting uterine bleeding and in postmenopausal women treated for longer than 3 years. In premenopause, hysteroscopy should be proposed to women with ultrasonographic abnormalities and/or with uterine bleeding to patients at high risk for endometrial cancer.

Antineoplastic Agents, Hormonal↗
PubMed2002

Molecular mechanisms of apoptosis and chemosensitivity to platinum and paclitaxel in ovarian cancer: biological data and clinical implications.

Apoptosis is a genetically regulated biological process that plays a major role in chemotherapy-induced tumor cell killing. It may be triggered by two major intracellular signaling cascades, the mitochondrial pathway and the death receptor pathway, both leading to caspase activation and cleavage of specific cellular substrates. The p53 gene is involved in the regulation of apoptosis. Caspase activation following wild-type p53 induction is associated with the release of the apoptogenic factors cytochrome c and Smac/DIABLO from the mitochondria, that is in turn controlled by the pro-apoptotic and anti-apoptotic Bcl-2 family proteins. In ovarian cancer p53 status is a strong predictor of response to platinum-based chemotherapy. Patients whose tumors have p53 mutations experience a lower chance of achieving a complete response following platinum-based regimens when compared to patients without p53 mutations. Conversely, experimental and clinical data seem to show that paclitaxel enhances apoptosis through a p53-independent pathway, that probably involves the Bax gene. Whereas patients with wild-type p53 tumors have a good chance to respond to platinum, patients with mutant p53 tumors may have a clinical benefit from the addition of paclitaxel to platinum-based chemotherapy. Therefore determining p53 status can be useful in predicting therapeutic response to specific drugs. Moreover the understanding of cellular mechanisms regulating apoptosis might offer a strong rationale for the combination of chemotherapy with other biological treatments.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Estrogen effects on neuroendocrine function: the new challenge of pulsed therapy.

A growing body of evidence shows a beneficial effect of hormone replacement therapy (HRT) on climacteric symptoms, well-being, and prevention of long-term consequences of estrogen deprivation. Nevertheless, only a relatively small number of women are users, and the mean duration of treatment is only about 18-24 months. This evident reluctance to prescribe and use HRT, so-called poor compliance, is without doubt not only due to a misunderstanding of the beneficial effects of HRT but also (and mainly) due to a discordance between expectations and treatment available. In order to improve compliance and to meet the expectations of physicians and patients, there is a need for a new treatment. This new treatment has to be effective, better tolerated, reassuring for physicians and women, convenient, easy to prescribe, easy to use and also feminine. 17beta-Estradiol remains the only natural estrogen available. It is almost identical to that secreted by the ovaries, is effective on all the consequences of estrogen deprivation, and is obviously the one to choose. Research on the intimate intracellular mode of action of estrogen is progressing on a daily basis. Today, we know that there are different estrogen receptor isoforms, that the distribution of these receptors is not uniform among the tissues, and that there are different mechanisms of action: genomic and non-genomic, with rapid (seconds or minutes) or delayed (hours or days) effects. Natural hormonal stimulation of target tissues is not a continuous event over the day. Up to now, all available forms of estrogen stimulate target cells in a continuous fashion over the day and might lead to unsatisfactory reactions. Aerodiol, the first-ever pulsed estrogen therapy with its specific mode of action, a brief stimulation of estrogen receptors made possible by its unique pharmacokinetic profile and its innovative route of administration, represents a new approach in the field of HRT. Aerodiol is not only a new route of administration but really a new way to treat hormone deficiency. Data collected during phase-3 studies provide evidence that Aerodiol is at least as effective as continuous therapy such as with oral and transdermal estrogens, is better tolerated gynecologically, and may be safer. If we consider that improvement in compliance is the key issue of HRT, we have to consider women as decision-makers in this process and we have to provide them with something that meets their expectations. With two out of three women (66%) choosing Aerodiol to continue their treatment for 1 year and 85% of women continuing their treatment after 1 year, Aerodiol goes at least some way to meeting these.

Administration, Cutaneous↗