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Biomedical subjects

A R Genazzani

Publications and source records attributed to A R Genazzani.

At least 19 recordsLinked to original sources
PubMed2006

Progesterone and progestins: effects on brain, allopregnanolone and beta-endorphin.

The increased use of hormonal therapies over the last years has led to improve the knowledge of pharmacological, biochemical and metabolic properties of several progestins and their effects in target tissues, such as the central nervous system. Progesterone and synthetic progestational agents are able to modulate the synthesis and release of several neurotransmitters and neuropeptides in response to specific physiological and pathological stimuli. While these actions may relay on differential activation of progesterone receptor or recruitment of intracellular pathways, some of the differences found between synthetic progestins may depend on the specific conversion to neuroactive steroids, such as the 3-alpha, 5-alpha reduced metabolite, allopregnanolone. This is a potent endogenous steroid that rapidly affects the excitability of neurons and glia cells through direct modulation of the GABA-A receptors activity exerting hypnotic/sedative, anxiolytic, anaesthetic and anticonvulsive properties. Estrogens increase the CNS and serum levels of allopregnanolone and the addition of certain but not all synthetic progestins determines a further increase in allopregnanolone levels, suggesting that the metabolism into this reduced product is related to the chemical structure of progestin molecule used. In addition, depending on specific progestin molecule used, different interaction are found with the estradiol-induced beta-endorphin synthesis and release, showing that diverse progestins have specific and divergent actions on the opiatergic system. These results highlight the concept that natural and synthetic progesterone receptor agonists may systematically induce different biological actions in CNS. This may have far-reaching implications for the clinical effects and related indications of each compound.

Animals↗
PubMed2005

Placental barrier breakage in preeclampsia: ultrastructural evidence.

OBJECTIVE: It is known that the placenta acts as an immunological barrier between the mother and fetal "graft" allowing two antigenically different organisms to tolerate one another. Preeclampsia may be considered as a fetal rejection consequent to severe damage at placental endothelial and syncytiotrophoblast level. In order to verify this placental barrier damage we undertook the present study by electron microscopy. STUDY DESIGN: 14 placentae from preeclaptic women, and the same number of placentae from healthy controls were examined. RESULTS: The results showed that endothelial cells from preeclamptic placentae express various and severe alterations, consisting of swollen and bulbous cytoplasm, degenerated inter-endothelial junctions with consequent crossing of fetal blood cells outside the vessels. CONCLUSIONS: These lesions could be the ultrastructural evidence of the placental barrier breakage leading to rejective reaction we presumed to be basis of preeclampsia.

Adult↗
PubMed2005

Tibolone, transdermal estradiol or oral estrogen-progestin therapies: effects on circulating allopregnanolone, cortisol and dehydroepiandrosterone levels.

The aim of the present study was to evaluate, in healthy postmenopausal women, the impact of tibolone (2.5 mg), transdermal estradiol (50 microg) (TE) and different oral estrogen-progestin regimens, conjugated equine estrogens (0.625 mg) plus medroxyprogesterone acetate (5 mg) (CEE + MPA) and estradiol (2 mg) plus norethisterone acetate (1 mg) (E2 + NETA) on circulating estradiol, progesterone, allopregnanolone, cortisol and dehydroepiandrosterone (DHEA) levels. Blood samples were collected before and after 1, 3, 6 and 9 months of treatment in 85 postmenopausal women. Estradiol levels increased (p < 0.001) in the TE, CEE + MPA and E2 + NETA groups after 1 month of therapy, but did not change in the tibolone group during the entire follow-up period. Both E2 + NETA and tibolone treatments induced an increase in progesterone levels (p < 0.05) after 1 year of therapy. Allopregnanolone levels showed an increase in all estrogen-based groups, being significant after 3 months of treatment (p < 0.01). Patients receiving tibolone showed a significant increase in allopregnanolone levels at 3 months (p < 0.05), but lower than in the other groups. Cortisol levels decreased significantly in the TE and CEE + MPA groups after 6 months and 12 months of treatment, respectively. Neither tibolone nor E2 + NETA treatments modified circulating cortisol levels. DHEA levels significantly (p < 0.05) decreased after 6 months of TE or estrogen-progestin therapies independently of the presence or the type of progestin used. In contrast, DHEA remained stable throughout the 12 months of treatment with tibolone. The increase of allopregnanolone, a steroid with sedative and anxiolytic properties, in response to these different treatments could underlie, at least in part, the central effects that hormone replacement therapy and tibolone have on anxiety, mood and behavior. Unlike estrogen-based therapy, tibolone treatment did not reduce the DHEA milieu in the menopause, and thus did not enhance the androgen deficiency syndrome in postmenopausal women.

Administration, Cutaneous↗
PubMed2005

Vascular endothelial growth factor and its soluble receptor in ovarian pathology.

OBJECTIVE: The soluble form of the vascular endothelial growth factor (VEGF) receptor, s-VEGFR-1, may negatively regulate the action of VEGF. Our purpose was to better understand the regulation of angiogenetic processes in ovarian cysts. METHODS: Seventy-three women, 36 with serous cystoadenoma, 30 with ovarian endometriosis and seven with cystoadenocarcinoma, were enrolled. We calculated both VEGF and s-VEGFR-1 levels in cystic fluid and a VEGF activity index by means of the ratio VEGF/s-VEGFR-1. Student's t test was used for the statistical analysis. RESULTS: We found higher VEGF concentration in both endometriotic and malignant lesions than in serous cystoadenoma (p=0.03 and 0.001, respectively). Also s-VEGFR-1 concentration was higher in endometrioma than in serous cysts (p=0.005); however, there was no statistically significant difference between cystoadenoma and the malignant lesions (p=0.15). VEGF activity index in cystoadenoma, endometriotic and malignant lesions was 0.61, 0.27 and 0.50, respectively. CONCLUSIONS: VEGF certainly has an important role in both ovarian endometriosis and for cancer progression; however, the activity index may be better to investigate the real role of VEGF in the pathology we have considered.

Cyst Fluid↗
PubMed2005

Efficacy on climacteric symptoms of a continuous combined regimen of 1 mg 17beta-estradiol and trimegestone versus two regimens combining 1 or 2 mg 17beta-estradiol and norethisterone acetate.

OBJECTIVES: To compare the efficacy of a continuous combined regimen of 1mg 17beta-estradiol (17beta-E2) and 0.125 mg trimegestone (TMG) with two continuous combined 17beta-E2/norethisterone acetate (NETA) combinations in the relief of climacteric symptoms in postmenopausal women. STUDY DESIGN: This was a randomized, double-blind, multicenter study conducted in 13 countries over a 2-year period. Healthy postmenopausal women with an intact uterus were treated with 1 mg 17beta-E2/0.125 mg TMG, 2 mg 17beta-E2/1 mg NETA or 1 mg 17beta-E2/0.5 mg NETA for up to 26 cycles, each of 28 days. RESULTS: The 1 mg 17beta-E2/0.125 mg TMG combination was effective in significantly reducing the mean daily number and severity of hot flushes and in reducing the number of night sweats from cycle 1 onward. No overall significant differences between this regimen and the comparators were detected. Other efficacy variables, including the Kupperman index, psychofunctional disorders and quality-of-life sub-scales, experienced a similar improvement from baseline with all treatments. CONCLUSION: Continuous combined 1 mg 17beta-E2/0.125 mg TMG provides relief of menopausal symptoms that is non-inferior to both 17beta-E2/NETA combinations. Furthermore, trimegestone appeared to provide a better improvement of depressive mood than 0.5 mg NETA when combined with 1 mg 17beta-estradiol.

Administration, Oral↗
PubMed2004

Clinical usefulness of endometrial screening by ultrasound in asymptomatic postmenopausal women.

OBJECTIVE: The aim of the present study was to evaluate the clinical usefulness of routine use of endometrial ultrasound in asymptomatic, bleeding-free postmenopausal women. METHODS: We retrospectively reviewed the data of 850 postmenopausal women subjected to hysteroscopy, focusing our attention on those cases (148) with an ultrasound indication of endometrial thickening. RESULTS: In 850 postmenopausal women, we identified 27 (3.2%) endometrial adenocarcinomas. In these subjects, the indication for office hysteroscopy was abnormal uterine bleeding in 24 (24/27; 88.9%) cases; pathological pap smear with abnormal endometrial cells in 2 (2/27; 7.4%) cases and thickened endometrium upon transvaginal ultrasound (tvUS) only in one (1/27; 3.7%) patient. On the other hand, 148 hysteroscopies were performed on the basis of the tvUS indication in otherwise asymptomatic (bleeding free) postmenopausal women; only 1(0.7%) of these presented an adenocarcinoma. CONCLUSION: Our findings show that the use of tvUS as a screening tool for endometrial pathology in asymptomatic postmenopausal women generates 93.2% false positive results, so that most of these women undergo this second level invasive procedure uselessly. Our data suggest that, in asymptomatic postmenopausal women, endometrial ultrasound evaluation is not worthwhile as a screening tool, such as it is considered in common clinical practice. The present results call for a larger prospective trial to further elucidate this controversial issue.

Adenocarcinoma↗
PubMed2004

A longitudinal evaluation of the effect of two doses of tibolone on bone density and metabolism in early postmenopausal women.

Tibolone, a steroid with tissue-specific activities, can reduce the bone resorption that takes place after the menopause. The present calcium-controlled, 2-year study aimed to evaluate the effect of two doses of oral tibolone, 1.25 mg and 2.5 mg, on bone loss in early postmenopausal women. The subjects were randomly allocated to one of the three groups, namely tibolone 2.5 mg (n = 30), tibolone 1.25 mg (n = 30) and a control group (n = 30). All subjects received 1000 mg of calcium per day. In the control group, vertebral and femur bone mineral density (BMD) decreased significantly (p < 0.05) after 12 and 24 months. In both tibolone groups, vertebral and femur BMD increased significantly (p < 0.05) increased after 12 and 24 months. In the control group, bone turnover markers (urinary excretion of hydroxyproline/creatinine and plasma osteocalcin levels) remained constant, while in both tibolone groups these markers showed similar significant decreases (p < 0.05) after 12 and 24 months. After 24 months, body weight increased in the control group (p < 0.05), while smaller increments were evident in the tibolone groups. Symptom scores in the control group did not show any significant modification during the study. In contrast, the administration of 2.5 mg tibolone was significantly (p < 0.05) effective in reducing hot flushes and other symptoms. The tibolone 1.25 mg group yielded similar results (even if it was proportionally less efficient) to the higher dose. It is concluded that tibolone is effective, even at lower doses, in relieving climacteric symptoms and preventing a decrease in spine and femur BMD in early postmenopausal women.

Administration, Oral↗
PubMed2004

Adrenal response to adrenocorticotropic hormone stimulation in patients with premenstrual syndrome.

Several studies have been performed during recent years to investigate the existence of a possible endocrine cause for premenstrual syndrome (PMS); the results reported are often discordant. Great interest has been raised around allopregnanolone, which could be involved in the determination of mood disorders reported by PMS patients. During the luteal phase, lower levels of this hormone have been detected in PMS patients. The aim of our study was to evaluate estradiol, progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), androstenedione, total and free testosterone, cortisol, pregnenolone and allopregnanolone levels in 20 patients suffering from PMS and to compare them with those found in 20 fertile healthy women in the follicular and the luteal phases. Adrenocorticotropic hormone (ACTH) tests after dexamethasone suppression were performed in 10 patients of each group during the follicular and the luteal phases. In the PMS group, significantly lower allopregnolone levels were found in the luteal phase, while progesterone was lower in the PMS group in both phases. In the PMS group, higher free testosterone levels were found during the luteal phase and higher DHEA levels in both the follicular and the luteal phases. The present data confirm reduced allopregnanolone levels in the luteal phase in PMS patients, together with higher levels of DHEA and free testosterone. It is possible to conclude that, in addition to the previously described reduced luteal secretion of allopregnanolone, the adrenal gland production of this steroid in PMS sufferers is also impaired in the luteal phase. Considering the specific actions of these hormones on the control of mood and behavior, this specific hormonal milieu may contribute to the cyclic occurrence of anxiety, aggressiveness and irritability reported by PMS patients.

Adolescent↗
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↗
PubMed2004

Disadaptive disorders in women: allopregnanolone, a sensitive steroid.

Allopregnanolone, a neurosteroid acting as a potent anxiolytic agonist of the gamma-aminobutyric acid A receptor, has been shown in animal models to modify its concentrations at central and peripheral levels according to the estrous cycle. Moreover, it modulates behavioral and biochemical responses to acute and chronic stress, anxiety, depression, aggressiveness, convulsions, anesthesia, sleep, memory, pain and feeding. These observations suggest that fluctuations of allopregnanolone might be involved in the development, course and prognosis of some mental disorders in humans. This has been hypothesized for depressive disorders, premenstrual dysphoria, anorexia and bulimia nervosa and Alzheimer's disease, where increased, decreased or dysregulated secretion of the main neurosteroids and their metabolites has been observed. Women show a marked gender-related sensitivity to disadaptive disorders. In addition to the well-studied role of sex steroids in modulating mood and behavior, a putative involvement of neurosteroid fluctuations, and in particular of allopregnanolone, has recently been hypothesized. In fact, several paraphysiological events and various disadaptive disorders in women are associated with modifications of circulating levels of this neurosteroid that might associated with a certain vulnerability to an altered adaptation to stressful life events.

Affect↗
PubMed2004

Long-term low-dose dehydroepiandrosterone replacement therapy in aging males with partial androgen deficiency.

Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) age-related withdrawal is very likely to be involved in the aging process and the onset of age-related diseases, giving rise to the question of whether preventing or compensating the decline of these steroids may have endocrine and clinical benefits. The aim of the present trial was to evaluate the endocrine, neuroendocrine and clinical consequences of a long-term (1 year), low-dose (25 mg/day) replacement therapy in a group of aging men who presented the clinical characteristics of partial androgen deficiency (PADAM). Circulating DHEA, DHEAS, androstenedione, total testosterone and free testosterone, dihydrotestosterone (DHT), progesterone, 17-hydroxyprogesterone, allopregnanolone, estrone, estradiol, sex hormone binding globulin (SHBG), cortisol, follicle stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels were evaluated monthly to assess the endocrine effects of the therapy, while beta-endorphin values were used as a marker of the neuroendocrine effects. A Kupperman questionnaire was performed to evaluate the subjective symptoms before and after treatment. The results showed a great modification of the endocrine profile; with the exception of cortisol levels, which remained unchanged, DHEA, DHEAS, androstenedione, total and free testosterone, DHT, progesterone, 17-hydroxyprogesterone, estrone, estradiol, GH, IGF-1 and beta-endorphin levels increased significantly with respect to baseline values, while FSH, LH and SHBG levels showed a significant decrease. The Kupperman score indicated a progressive improvement in mood, fatigue and joint pain. In conclusion, the present study demonstrates that 25 mg/day of DHEA is able to cause significant changes in the hormonal profile and clinical symptoms and can counteract the age-related decline of endocrine and neuroendocrine functions. Restoring DHEA levels to young adult values seems to benefit the age-related decline in physiological functions but, however promising, placebo-controlled trials are required to confirm these preliminary results.

Aged↗
PubMed2003

HLA-DR in couples associated with preeclampsia: background and updating by DNA sequencing.

The placenta acts as an immunological barrier between the mother and the fetal "graft", allowing two antigenically different organisms to tolerate one another. In placentae from preeclamptic women, we have demonstrated, by an ultrastructural assessment and an immunohistochemical study, a placental barrier breakage leading to the mixing of maternal and fetal antigenically different blood. This condition could be responsible for the triggering of a maternal rejection reaction that we presume to be at the basis of the preeclamptic syndrome. Thus, we have investigated the Human Leukocyte class II DR antigens (HLA-DR), whose role in self and non-self recognition is well known, in women with preeclampsia, their partners and in control couples using the serological Terasaki tecnique. The results showed a statistically significant increase of HLA-DR homozygosity and a reduced antigenic variety in the preeclamptic women and their partners with respect to controls. In this update, we have examined the 2nd exon of the human gene, HLA-DRB1, on the short arm of the chromosome 6 using DNA sequence-based typing (S-BT) PCR in 56 preeclamptic couples and 64 control couples. The results have confirmed the significant excess of HLA-DR homozygosity in couples associated with preeclampsia versus controls. From our results, it emerges that HLA-DR homozygosity and the reduced antigenic variety seem to be associated to a major risk for preeclampsia, which further appears to be a "couple's disease".

DNA↗