bluuebunny/crossref_metadata_2025 huggingface dataset:
Seventy‐Five Microgram Desogestrel Minipill, A New Perspective in Estrogen‐Free Contraception
Authors: BENAGIANO GIUSEPPE , PRIMIERO FRANCESCO MARIA
Published: January 2004

Abstract: Progestin‐only minipills have been available for over three decades, yet their use has been limited, because of a documented lower efficacy when compared to pills that combine estrogen and progestin. The availability of a new low‐dose progestin‐only minipill containing 75 μg desogestrel (DSG) offers a new perspective, since, in a large multicenter study, this minipill gave a crude Pearl index of 0.41 and an adjusted one of 0.14, which is comparable to indicies found in clinical trials of oral contraceptives. This minipill also allows for a 12‐hour tolerance time in taking the pill. The high effectiveness of the DSG minipill is attributable to an almost constant inhibition of ovulation, as shown by the absence of elevated progesterone circulating levels and inhibition of follicular growth in the vast majority of cycles studied. Since irregular bleeding patterns are observed with all minipills, patterns experienced with DSG 75 μg have been compared to those obtained with levonogestrel 30 μg. As expected, the more pronounced ovarian inhibition produced wider bleeding variability with DSG, but also less bleeding overall. The DSG minipill is suitable for lactating women and represents a valuable addition to oral contraception.
The Levonorgestrel Intrauterine System: A Clinical Perspective from the UK
Authors: GUILLEBAUD JOHN
Published: January 2004

Abstract: The main contraceptive effects of this valuable product [the levonorgestrel intrauterine system (LNG‐IUS)] are by endometrial suppression and changes to the cervical mucus and uterotubal fluid that impair sperm migration. The blood levels of LNG are very low, so progestogenic symptoms are uncommon. Most women still ovulate and in the remainder sufficient estrogen for health is produced from the ovary, even if they become amenorrhoeic, as many do; this is primarily a local end‐organ effect and should be seen as a benefit. Although usable by selected nulliparae, it is ideal for the parous woman. It has unsurpassed efficacy, and return of fertility is rapid. Combining the best features of hormonal and intrauterine contraception, its gynecological benefits are impressive: the LNG‐IUS user can expect a dramatic reduction in the amount and, after the first few occasionally troublesome months, in the duration of blood loss. Hemoglobin levels rise and dysmenorrhea is usually greatly benefited, unlike with current uterine ablation techniques. In perimenopausal women, it can protect the endometrium from overstimulation when estrogen replacement therapy (ERT) is added, by any chosen route. It thus provides a contraceptive modality of ERT with, usually, no bleeding and few progestogenic side effects—and is applicable before final ovarian failure. In summary, adverse side effects are few and in general they are not in the “hazardous” category. Regarding the admitted inconvenience of the first weeks of light postinsertion bleeding and the early phase low incidence of steroidal side effects: good counseling is paramount, since forewarned is forearmed!
Oral Contraception Over the Age of 40
Authors: KOVÁCS LÁSZLÓ
Published: January 2004

Abstract: Scientific data from the past decade have proved that the age of 35 years is not an obligatory border at which to stop taking oral contraceptives (OCs). Combined OC formulations (COCs) are safe and effective for healthy women up to the age of the menopause. The use of OCs in women who do not smoke does not result in an increased risk of cardiovascular disease. Since the risk of thromboembolism increases with age and the level of obesity in women of 40 and over, it is wise to prescribe the lowest available dose of ethinyl‐estradiol in the COCs. Some authors prefer levonorgestrel to any third‐generation progestogen in COCs, but the excess risk of venous thromboembolism associated with the use of third‐generation products can be balanced by the reduced risk of myocardial infarction associated with the same products. When OCs are considered for perimenopausal women, it is important to take into account progestogen‐only pills. In consequence of the reduced fecundity, these have a better contraceptive efficacy in this age group than in women aged below 35 years. Their only important possible adverse effect is an unpredictable bleeding pattern; further, they do not alleviate climacteric symptoms if these are present. In such cases, progestogen‐only pills can be combined with cyclic hormone replacement therapy.
Steroid Receptors in the Uterus: Implications in Endometriosis
Authors: MOUTSATSOU P. , SEKERIS C. E.
Published: January 2004

Abstract: Receptor proteins for estrogens, progesterone, androgens, and glucocorticoids have been detected in the various cell types of the uterus. Reference is made to the genes encoding these receptors, to the structure of the receptor proteins, and their functional domains. The mode of action of steroid hormones by gene activation, through their cognate receptors, and by nongenomic effects is briefly presented. The role of the steroid receptors in uterine physiology and the significance of the use of steroid receptor knock‐out animals in delineating the in vivo action of the hormones is discussed. Recent results on the possible correlation of steroid receptor gene polymorphisms and of quantitative and qualitative changes in the receptor proteins to the etiopathology of endometriosis are reviewed.
Urokinase‐Type Plasminogen Activator and Insulin‐Like Growth Factor‐Binding Protein 3 mRNA Expression in Endometriotic Lesions and Eutopic Endometrium
Authors: LEMBESSIS PETER , MILINGOS SPYROS , MICHALAS STELIOS , MILINGOS DIMITRIS , CREATSAS GEORGE , SOURLA ANTIGONE , KOUTSILIERIS MICHAEL
Published: January 2004

Abstract: The peritoneal fluid of women with endometriosis contains an increased insulin‐like growth factor 1 (IGF‐1) bioavailability, which is produced by limited hydrolysis of urokinase‐type plasminogen activator (uPA) on IGF‐binding protein 3 (IGFBP‐3). Recently, IGF‐1 was shown to inhibit apoptosis of endometrial‐like cells in vitro, suggesting that a microenvironment of increased IGF‐1 bioavailability can optimize the survival of endometrial cells grown ectopically. Here the expression of mRNA of IGFBP‐3 and uPA in tissue biopsies from eutopic endometrium and endometriotic lesions obtained at laparoscopy from women with endometriosis have been analyzed, and it is documented that both IGFBP‐3 and uPA mRNA expression are increased from 3‐ to 10‐fold in endometriotic lesions versus eutopic endometrium. Consequently, the necessary components (uPA and IGFBP‐3 expression) of endocrine/autocrine/paracrine enhancement of local IGF bioavailability mediated by uPA hydrolysis of the IGFBP‐3 were present in endometriotic lesions. These data possibly explain the origin of the increased content of uPA activity, IGF‐1 bioavailability, and NH2‐truncated forms of IGFBP‐3 in the peritoneal fluid of women with endometriosis.
Endometriosis: Treatment Strategies
Authors: VALLE RAFAEL F. , SCIARRA JOHN J.
Published: January 2004

Abstract: Endometriosis is often a perplexing medical condition for both the physician and the patient. Accordingly, development of treatment strategies based on the needs of the individual patient is highly desirable. Although endometriosis has been part of the clinical practice for almost a century, many questions remain relating to the relationship between endometriosis and infertility as well as endometriosis and pelvic pain. Endometriosis is a disease of reproductive‐age women, and it is now well recognized that a genetic susceptibility appears probable. The prevalence in the general population has never been clearly established. Factors to consider in management include the age and reproductive desires of the patient, the stage of the disease, and, most importantly, the symptoms. Therapeutic options include no treatment, medical therapy, surgery, or combination therapy. Oral contraceptives, androgenic agents, progestins, and gonadotropin releasing hormone (GnRH) analogs have all been used successfully, although at the present time, the latter preparations are the most popular medical therapy for endometriosis. Leuprolide acetate, goserelin acetate, and nafarelin acetate are all effective agents. Surgical therapy is appropriate, especially for advanced stages of the disease. Laparoscopy is an effective surgical approach with the goal of excision of visible endometriosis in a hemostatic fashion. Since endometriosis is a chronic condition, it is not uncommon for recurrences to occur. While endometriosis remains an enigmatic disease, the introduction of new pharmacologic agents, such as GnRH analogs and newer endoscopic methods of surgical treatment, have facilitated and improved the overall management of this disease.
Evaluation of the Role of Laser Treatment for the Treatment of Pain in Endometriosis
Authors: Shaw R. W.
Published: January 2004

Abstract: There have been few appropriately conducted trials to evaluate the effectiveness of laser destruction of endometriosis in relieving pain symptoms, yet the techniques are increasingly being used. Laser destruction has been shown to be more effective than the placebo effect of laparoscopy alone in one trial, at least at 6‐month follow‐up. Longer‐term studies suggest increasing recurrence of symptoms with time [23% at 12 months in one study, and 44% by a mean of 19.7 months (5–60) follow‐up]. These recurrence rates are similar to those seen following 6 months medical treatment. It is unknown whether laparoscopic uter‐sacral nerve ablation (LVNA) in addition to destrution of lesions will produce better results, and appropriate trials are needed in several areas to determine the role of laser therapy.
Endometriosis and Reproductive Disorders
Authors: ELSHEIKH A. , MILINGOS S. , LOUTRADIS D. , KALLIPOLITIS G. , MICHALAS S.
Published: January 2004

Abstract: The classic concept of endometriosis as a cause of infertility is challenged. Traditionally, both surgical and medical therapy have focused on alleviation of symptoms, prevention of disease progression, and promotion of fertility. In spite of significant developments in medical and surgical approaches, the optimal therapy for treating endometriosis‐associated infertility has yet to be established. The relationship between prevalence of fecundity and stage of the disease was studied according to the type of management. Of 151 women who were consecutively proved by laparoscopy to have endometriosis stage I and II, operative laparoscopy was performed in 49, medical treatment in 59, and expectant management in 43 cases. During a 24‐month period, the cumulative pregnancy rates were 36.7%, 30.5%, and 20.9%, respectively. Survival analysis over the 20 weeks of pregnancy showed that the probability of carrying the pregnancy beyond this week was 30.6%, 25.4%, and 16.2%, respectively. Of 64 patients with advanced disease, 34 (53%) became pregnant during the 2‐year follow‐up period. A significantly increased pregnancy rate was found for the first year as compared to the second (76% vs. 24%). The existence of adhesions affected adversely the outcome of the treatment when early achievement of pregnancy is considered. Diagnosis and treatment of endometriosis was beneficial for the infertile women. Laparoscopic surgery seems to be the best treatment in these cases, as it increases the fecundity and involves minimal risk.
Pelvic Adhesions: Laparoscopic Approach
Authors: METTLER L.
Published: January 2004

Abstract: A retrospective study using the American Fertility Society's Adhesion Scoring Method and the MCASM (More Comprehensive Adhesion Scoring Method) and a prospective, randomized, controlled, multicenter trial (Canadian Task Force Classification I) were conducted. Of 2124 cases operated by laparoscopy, 465 patients had adhesions. Fifty‐one female patients underwent open or laparoscopic myomectomy procedures with vs. without application of SprayGel adhesion barrier prevention, followed by second‐look laparoscopy to evaluate postoperative adhesions. Details of the 465 cases of adhesiolysis are given. In subgroup 1 (n= 34) there were no preexisting adhesions. All 34 patients were assessed at a second‐look laparoscopy for adhesion occurrence after 6–8 weeks; 29.4% were found to have no adhesions and 70.6% of patients had significant or mild adhesions. In subgroup 2, 21 patients who had undergone previous surgery for adhesiolysis were operated upon again, and 24% revealed an increased adhesion score, 57% the same adhesion score, and 19% a reduced adhesion score at second‐look laparoscopy. Out of 51 patients enrolled, 45 were randomized to either treatment (n= 24) or control (n= 21). Three to sixteen weeks following surgery, 18 of 24 treatment patients (75%) and 13 of 21 controls (61.9%) had second‐look laparoscopies (SLL). SLL showed 5 of 18 treatment patients (27.8%) were adhesion free vs. 1 in 13 of controls (7.7%). Patients randomized to SprayGel treatment were 3.6 times more likely to be adhesion free than patients randomized to control. Compared to the initial surgery, the severity score showed a 22% reduction in the treated group vs. a 39% increase in the control group, and a 12% reduction of adhesion area in the treated group vs. a 37% increase in the control group at SLL. New data confirmed previous knowledge: To avoid adhesions you must avoid surgery. If surgery has to be performed, laparoscopic surgery causes fewer adhesions than laparotomy. SprayGel was shown to be effective in reducing postoperative adhesions after laparoscopic and open myomectomy. Application of this adhesion barrier prevention system is fast, easy, and safe. Further studies are needed to confirm the promising results of this interim analysis.
Laparoscopic Management of Patients with Endometriosis and Chronic Pelvic Pain
Authors: MILINGOS SPYROS , PROTOPAPAS ATHANASIOS , DRAKAKIS PETER , LIAPI ANTHOULA , LOUTRADIS DIMITRIOS , KALLIPOLITIS GEORGE , MILINGOS DIMITRIOS , MICHALAS STYLIANOS
Published: January 2004

Abstract: Endometriosis has been traditionally included among the most important causes of chronic pelvic pain (CPP) in women of reproductive age. The main clinical manifestations of endometriosis are dysmenorrhea, dyspareunia, and chronic nonmenstrual pain. Despite the high prevalence of endometriosis in women suffering from CPP, controversy still exists regarding the true association between the stage and extent of this peculiar disease and the severity of pain. Over the last decade, advances in endoscopic technology have enabled gynecologic surgeons to recognize many atypical appearances of the endometriotic implants not known to exist before, thus allowing their complete excision or destruction. Laparoscopic surgery may offer considerable relief in patients with endometriosis and CPP. Although cases with advanced endometriosis seem to benefit the most, we also support surgical treatment in patients with early endometriosis diagnosed using laparoscopy, as many will experience improvement in their symptoms.
Laparoscopic Management of Peritoneal Endometriosis, Endometriotic Cysts, and Rectovaginal Adenomyosis
Authors: DONNEZ JACQUES , SMETS MIREILLE , JADOUL PASCALE , PIRARD CÉLINE , SQUIFFLET JEAN
Published: January 2004

Abstract: Peritoneal endometriosis is probably caused by the implantation of regurgitated menstrual cells. The ovarian endometrioma is the consequence of non‐hormone‐regulated bleeding from intraovarian epithelial inclusions after they have undergone metaplasia into endometrial‐like tissue. Rectovaginal adenomyosis is, in fact, an adenomyotic lesion and can develop from Müllerian rests. In conclusion, peritoneal endometriosis, ovarian endometriosis, and rectovaginal adenomyotic nodules must be considered as three separate entities with different pathogeneses that require a different therapeutic approach.
Laparoscopy and Oncology: Where Do We Stand Today?
Authors: THEODORIDIS THEODOROS D. , BONTIS JOHN N.
Published: January 2004

Abstract: The clinical application of laparoscopic surgery has grown rapidly over the last few years. Since the first documentations of laparoscopic lymphadenectomy, many reports highlight the use of modern laparoscopy in the field of gynecologic oncology. Laparoscopic treatment of early‐stage cervical and endometrial cancer, and laparoscopic evaluation and staging of cervical, ovarian, and endometrial carcinomas, are feasible procedures. The place of minimal‐access surgery in the arsenal of gynecologic oncological surgery has been established, especially after the recent developments and practical application of video laparoscopy, novel instrumentation, and advanced surgical techniques. Although operative laparoscopy in gynecologic oncology is still in its infancy the potentiality of the procedure is underscored. Many patients may benefit from the treatment or staging of gynecologic malignancies with laparoscopic means. Literature reports highlight that laparoscopy may be an effective procedure with lower morbidity and complication rates than traditional abdominal surgery. The short hospital stay and recovery time have a positive impact in a cancer patient's quality of life, as they return to normal activities rapidly. Many risks, though, may arise from the application of minimal‐access surgery in cancer patients, and many questions regarding safety and efficacy need answers, based on prospective clinical trials. We must emphasize that such studies with large patient numbers and long‐term follow‐up are lacking. Until results from these trials are available, laparoscopic oncologic procedures should be performed only in an investigational setting by expert teams.
Androgens and Antiandrogens
Authors: Schneider H. P. G.
Published: January 2004

Abstract: The role of androgens in women's health has been generally neglected. Currently available assays are lacking in sensitivity and reliability at the lower ranges. Circulating androgens as prohormones for other steroids (e.g., androgens) have an ubiquitous role on diverse physiological and behavioral systems. Clinical assessment of both androgen production and androgen availability can be achieved by measurement of two or three essential values. These include either total T and sex‐hormone binding globulin (SHBG), free T and SHBG, or free T and total T. The free testosterone index (total T/SHBG) correlates well with free or bioavailable T and can be used as a substitute. DHEA‐S is the most useful measure of adrenal androgen production in women. Androgen insufficiency in women is not a specific consequence of natural menopause, but may occur secondarily to the age‐related decline in both adrenal and ovarian androgen production. Since estrogen effects are also strongly linked to mood, psychological well‐being, and sexual function in women, the diagnosis of androgen insufficiency should only be made in women who are adequately estrogenized. Before initiating a trial of androgen replacement therapy, a comprehensive clinical assessment should be performed in all cases. Approved androgen replacement therapy is not yet available in most countries for treatment of female sexual dysfunction. This would include T supplements or DHEA. Several new progestins have been synthesized in the last decade. Dienogest is a hybrid progestin that is derived from both the pregnane and the estrane groups with a 17α‐cyanomethyl radical; drospirenone is derived from spirolactone. Somehow, the molecules available have demonstrated antiandrogenic properties. Cyproterone acetate (CPA) is the most potent antiandrogenic progestin, followed by dienogest, drosperinone, and chlormadinone acetate. Nomegestrol acetate and medrogestone also exert some antiandrogenic properties and are similar to chlormadinone acetate in antiandrogenic potency. While androgens act positively on libido in women, antiandrogenic properties in doses used in HRT do not appear to have a negative effect. Progestins used in HRT have varying pharmacological properties that are associated with different adverse effects. The new progestins with antiandrogenic properties avoid many of the androgenic side effects related to testosterone‐derived progestins. They also have the potential of not counteracting beneficial estrogen effects, for example, on the cardiovascular system or mental tone.
The Management of Polycystic Ovary Syndrome
Authors: BRUNI VINCENZA , DEI METELLA , PONTELLO VALENTINA , VANGELISTI PAOLO
Published: January 2004

Abstract: It is well known that subjects with polycystic ovary syndrome (PCOS) show very variable clinical and biochemical aspects. Considering long‐term repercussions, two main disturbances, not always strictly related, need to be countered: hyperandrogenism and insulin resistance, with compensatory hyperinsulinemia. The aim of this review is to summarize therapeutic perspectives for PCOS, starting from basic approach, such as weight reduction and changes in lifestyle. The benefits of long‐term use of oral contrceptives and the criteria of choice of the estro‐progestin combinations are discussed. With severe hyperandogenism, a pure antiandrogen should be added. The experiences with insulin‐sensitizing drugs, especially metformin, are reviewed; while their beneficial role as an adjuvant to treatment of ovulatory infertility has been well established, the effects of a long‐term treatment, especially in very young patients, are still under debate. Current studies are testing the results of combinations of different treatments at low dosage; randomized comparative trials on the long‐term efficacy of these approaches have yet to be scheduled.
Conservative Management of Gynecologic Diseases
Authors: DIAMANTI‐KANDARAKIS EVANTHIA , KANDARAKIS HELEN A.
Published: January 2004

Abstract: A contemporary “Pandora's box” could be the polycystic ovary syndrome (PCOS), containing several negative features for a woman: compromised looks, compromised fertility; increased metabolic risk factors; and compromised general health. During the past decate, the central importance of insulin resistance (IR) in the pathogenesis of this syndrome has been established. Several in vivo and in vitro studies have demonstrated this phenomenon, initially by the hyperinsulinemic response to oral glucose in obese and lean women with PCOS compared with weight‐matched normal women, and subsequently with more sensitive techniques like euglycemic hyperinsulinemic clamp. In vitro studies have corroborated these findings, showing molecular defects at the postreceptor level of insulin action, such as increased serine phosphorylation and decreased phospoinositol 3‐kinase action. Insulin sensitizers are the group of therapeutic agents that hold some promise of helping women with polycystic ovary syndrome (PCOS), since the role of insulin resistance and hyperinsulinemia appear to be major contributors to the pathophysiology of the syndrome. The therapeutic approach with insulin sensitizers appears to have benefitial effects on the metabolic as well as on the reproductive abnormalities in women affected by PCOS. Finally, insulin sensitizers should be considered by all subspecialists who aim at a comprehensive management of patients with PCOS.
Premenstrual Syndrome and the Use of Alternative Therapies
Authors: DOMONEY C. L. , VASHISHT A. , STUDD J. W. W.
Published: January 2004

Abstract: Premenstrual syndrome is a collection of symptoms that may be encountered by up to 95% of the population, although it is estimated to affect 5% of women severely. The use of complementary and alternative therapies is high among this group, but does not seem to compromise conventional treatment. It has been established that complementary therapies are used by a large proportion of the developed world, but their efficacy and safety are not always proven. This is partly due to the difficulty of studying alternative practices and the cost, but also with respect to premenstrual syndrome, problems with defining the condition and specifying end points are encountered. The difficulties in evaluating unorthodox therapies are elucidated and the evidence base for nonprescribed treatments for premenstrual syndrome is presented. Overall these women are a neglected group for whom the evidence for conventional therapy is sparse and controversial. Since the majority of women self‐diagnose and self‐medicate, it is important that physicians have an understanding of the variety of interventions tried and their worth.
Breast Cancer and Hormonal Replacement Therapy
Authors: VASSILOPOULOU‐SELLIN RENA
Published: January 2004

Abstract: Understanding the association between hormone replacement therapy (HRT), the diagnosis of breast cancer, and the clinical outcome of women who develop breast cancer in the setting of HRT continue to present important challenges for health professionals and the public. The general impression in the medical community is that breast cancer is diagnosed more frequently after prolonged HRT; however, whether a causative relationship exists between HRT and breast cancer remains uncertain. Despite the increase in breast cancer diagnosis, clinical outcome of the disease appears favorable for women who develop breast cancer after HRT; HRT users tend to present with more localized tumors that exhibit favorable histology, and overall death from breast cancer appears reduced. The history of breast cancer constitutes a contraindication for HRT as a general rule, based on the concern that HRT may activate dormant cancer cells. Direct evidence for this practice is very limited; available studies are small and mostly retrospective, but do not indicate an adverse effect of HRT on breast cancer recurrence. In reaching a clinical decision regarding HRT, the expected benefits (largely improvement of menopausal symptoms) must be weighed against the potential risks of HRT (especially breast cancer) for each individual woman.
Hormone Replacement Therapy and Cardioprotection
Authors: ROSANO GIUSEPPE M.C. , VITALE CRISTIANA , SILVESTRI ANTONELLO , FINI MASSIMO
Published: January 2004

Abstract: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in women after the age of 50 years in most developed countries. Estrogen deficiency plays a key role in causing CVD in women. Apart from the direct effect of ovarian hormones on the vessel wall, cessation of ovarian function and the consequent reduction of sex steroid hormone levels have important metabolic and pathological implications that negatively influence the cardiovascular system. Therefore, the increased incidence of CVD observed in women after menopause should be considered on a multifactorial basis. Data available for the effects of ERT and HRT in the primary prevention of CVD are mainly observational. However, despite limitations related to this kind of study, it must be noted that their results consistently show a reduction in cardiovascular events in hormone users. Meta‐analysis of epidemiological studies found that women who had ever used estrogens had a 34% overall reduction in the relatrive risk of cardiovascular events compared to those who had never used hormones. Most of the early epidemiological studies were conducted using unopposed estrogen replacement therapy. The number of studies evaluating the effects of estrogen‐progestin replacement therapy is limited. Recently, the estrogen‐progestin arm of the Women's Health Initiative (WHI) study has been stopped because of an increased incidence of breast cancer, and too early on to give any insight into possible cardiovascular effects. Comments on the cardiovascular effects of HRT from the results of the WHI study are therefore not warranted, as the study did not continue for a duration long enough to enable a calculation of cardiovascular end points. The WHI study included only one single type of estrogen‐progestin association; whether different estrogen‐progestin combinations, more commonly used outside the United States, may have a different effect is still a matter of speculation. A major difference between observational and randomized studies on the effect of ovarian hormones on cardiovascular function is the time of HRT initiation since menopause, which is significantly shorter in obersvational studies. In conclusion, the average 35–50% risk reduction in CVD with HRT in primary prevention in postmenopausal women is based on nonrandomized observational data.
HRT and Cardiovascular Disease
Authors: SAMSIOE GORAN
Published: January 2004

Abstract: Recent randomized controlled clinical trials failed to confirm a perceived beneficial effect on cardiovascular disease by hormone therapy. Given the huge amount of observational data, as well as experimental data both in humans and various animal species, there is reason to belive that female sex steroids, in particular estrogen, possess cardiovascular benefits. The type, dose, and mode of administration of exogenous sex steroids may modify and even negate the beneficial effects. The results of the randomized trials, especially the WHI, should encourage the scientific community to try to define a target population in which benefits outweigh harm, as it must be regarded as proven that any hormone therapy regimen given to any population will not reach that goal. The recent finding that transdermal estrogens, in contrast to oral preparations, do not seem to be associated with an increased risk of venous thrombosis is challenging. It would seem appropriate to conclude that estrogens prevent arteriosclerosis. On a long‐term basis, however, other more rapid effects on the cardiovascular system could be negative. Such an assumption contributes to the explanation of the discordant results from cohort studies versus randomized trials. Admittedly the current picture is complex, but far from definitive, and should challenge us all to continue research in this area.
CNS: Sex Steroids and SERMs
Authors: BERNARDI F. , PLUCHINO N. , STOMATI M. , PIERI M. , GENAZZANI A. R.
Published: January 2004

Abstract: 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 β‐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 β‐EP and allopregnanolone levels, and it restores the response of β‐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.
Synaptic Plasticity and AMPA Receptor Trafficking
Authors: MALENKA ROBERT C.
Published: January 2004

Abstract: Alterations in neuronal activity can elicit long‐lasting changes in the strength of synaptic transmission at excitatory synapses and, as a consequence, may underlie many forms of experience‐dependent plasticity, including learning and memory. The best‐characterized forms of such synaptic plasticity are the long‐term depression (LTD) and long‐term potentiation (LTP) observed at excitatory synapses in the CA1 region of the hippocampus. It is now well accepted that the trafficking of AMPA receptors to and away from the synaptic plasma membrane plays an essential role in both LTP and LTD, respectively. Here we review current models of AMPA receptor trafficking and how this trafficking may be regulated at the molecular level in order to produce the observed changes in synaptic strength. We also review recent work from our lab suggesting that synaptic plasticity in the mesolimbic dopamine system may contribute importantly to the neural adaptations elicited by drugs of abuse.
Physiological Roles and Therapeutic Potential of Metabotropic Glutamate Receptors
Authors: CONN P. JEFFREY
Published: January 2004

Abstract: Discovery of mGlu receptors has dramatically influenced our understanding of glutamatergic neurotransmission in the central nervous system. This receptor family provides a mechanism by which activation by glutamate can regulate a number of important neuronal and glial functions that are not typically modulated by ligand‐gated ion channels. This includes modulation of neuronal excitability, synaptic transmission, and various metabolic functions. Because of the ubiquitous distribution of glutamatergic synapses, discovery of the mGlu receptors immediately raised the likelihood that mGlu receptors would participate in most, if not all, major functions of the CNS. In addition, the wide diversity and heterogeneous distribution of mGlu receptor subtypes could provide an opportunity for development of pharmacological agents that selectively target specific CNS systems to achieve a therapeutic effect. Over the past decade, an increasing number of agonists and antagonists selective for specific mGlu receptor subtypes have been developed. Use of these pharmacological tools along with genetic approaches has led to major advances in our understanding of the roles of mGlu receptors in regulating CNS systems and animal behavior. These studies suggest that drugs active at mGlu receptors may be useful in treatment of a wide variety of neurological and psychiatric disorders.
Genomics and Variation of Ionotropic Glutamate Receptors
Authors: LIPSKY ROBERT H. , GOLDMAN DAVID
Published: January 2004

Abstract: Sequencing of the human, mouse, and rat genomes has enabled a comprehensive informatics approach to gene families. This approach is informative for identification of new members of gene families, for cross‐species sequence conservation related to functional conservation, for within‐species diversity related to functional variation, and for historical effects of selection. This genome informatics approach also focuses our attention on genes whose genomic locations coincide with linkages to phenotypes. We are identifying ionotropic glutamate receptor (IGR) sequence variation by resequencing technologies, including denaturing high‐performance liquid chromoatography (dHPLC), for screening and direct sequencing, and by information mining of public (e.g., dbSNP and ENSEMBL) and private (i.e., Celera Discovery System) sequence databases. Each of the 16 known IGRs is represented in these databases, their positions on a canonical physical map (for example, the Celera map) are established, and comparison to mouse and rat sequences has been performed, revealing substantial conservation of these genes, which are located on different chromosomes but found within syntenic groups of genes. A collection of 38 missense variants were identified by the informatics and resequencing approaches in several of these receptor genes, including GRIN2B, GRIN3B, GRIA2, GRIA3, and GRIK1. This represents only a fraction of the sequence variation across these genes, but, in fact, these may constitute a large fraction of the common polymorphisms at these genes, and these polymorphisms are a starting point for understanding the role of these receptors in neurogenetic variation. Genetically influenced human neurobehavioral phenotypes that are likely to be linked to IGR genetic variants include addictions, anxiety/dysphoria disorders, post‐brain injury behavioral disorders, schizophrenia, epilepsy, pain perception, learning, and cognition. Thus, the effects of glutamate receptor variation may be protean, and the task of relating variation to behavior difficult. However, functional variants of (1) catechol‐O‐methyltransferase, (2) serotonin transporter, and (3) brain‐derived neurotrophic factor have recently been linked both to behavioral differences and to intermediate phenotypes, suggesting a pathway by which functional variation at IGRs can be tied to an etiologically complex phenotype.
Molecular Abnormalities of the Glutamate Synapse in the Thalamus in Schizophrenia
Authors: MEADOR‐WOODRUFF JAMES H. , CLINTON SARAH M. , BENEYTO MONICA , McCULLUMSMITH ROBERT E.
Published: January 2004

Abstract: Schizophrenia has been associated with dysfunction of glutamatergic neurotransmission. Synaptic glutamate activates pre‐ and postsynaptic ionotropic NMDA, AMPA, and kainate and metabotropic receptors, is removed from the synapse via five cell surface‐expressed transporters, and is packaged for release by three vesicular transporters. In addition, there is a family of intracellular molecules enriched in the postsynaptic density (PSD) that target glutamate receptors to the synaptic membrane, modulate receptor activity, and coordinate glutamate receptor‐related signal transduction. Each family of PSD proteins is selective for a given glutamate receptor subtype, the most well characterized being the NMDA receptor binding proteins PSD93, PSD95, NF‐L, and SAP102. Besides binding glutamate receptors, many of these proteins also interact with cell surface proteins like cell adhesion molecules, ion channels, cytoskeletal elements, and signal transduction molecules. Given the complexity of the glutamate neurotransmitter system, there are many locations where disruption of normal signaling could occur and give rise to abnormal glutamatergic neurotransmission in schizophrenia. Using multiple cohorts of postmortem tissue, we have examined these synaptic molecules in schizophrenic thalamus. The expression of NR1 and NR2C subunit transcripts is decreased in the thalamus in schizophrenia. Interestingly, three intracellular PSD molecules that link the NMDA receptor to signal transduction pathways are also abnormally expressed. Additionally, several of the cell surface and vesicular transporters are abnormal in the schizophrenic thalamus. While occasional findings of abnormal receptor expression are made, the most dramatic and consistent alterations that we have found in the thalamus in schizophrenia involve the family of intracellular signaling/scaffolding molecules. We propose that schizophrenia has a glutamatergic component that involves alterations in the intracellular machinery that is coupled to glutamate receptors, in addition to abnormalities of the receptors themselves. Our data suggest that schizophrenia is associated with abnormal glutamate receptor‐related intracellular signaling in the thalamus, and point to novel targets for innovative drug discovery.
Altered Cortical Glutamate Neurotransmission in Schizophrenia
Authors: LEWIS DAVID A. , GLANTZ LEISA A. , PIERRI JOSEPH N. , SWEET ROBERT A.
Published: January 2004

Abstract: Multiple lines of evidence from pharmacological, neuroimaging, and postmortem studies implicate disturbances in cortical glutamate neurotransmission in the pathophysiology of schizophrenia. Given that pyramidal neurons are the principal source of cortical glutamate neurotransmission, as well as the targets of the majority of cortical glutamate‐containing axon terminals, understanding the nature of altered glutamate neurotransmission in schizophrenia requires an appreciation of both the types of pyramidal cell abnormalities and the specific class(es) of pyramidal cells that are affected in the illness. In this chapter, we review evidence indicating that a subpopulation of pyramidal neurons in the dorsolateral prefrontal cortex exhibits reductions in dendritic spine density, a marker of the number of excitatory inputs, and in somal volume, a measure correlated with a neuron's dendritic and axonal architecture. Specifically, pyramidal neurons located in deep layer 3 of the dorsolateral prefrontal cortex and that lack immunoreactivity for nonphosphorylated neurofilament protein may be particularly involved in the pathophysiology of schizophrenia. The presence of similar changes in pyramidal neurons located in deep layer 3 of auditory association cortex suggests that a shared property, which remains to be determined, confers cell type‐specific vulnerability to a subpopulation of cortical glutamatergic neurons in schizophrenia.
The NMDA Receptor Hypofunction Model of Psychosis
Authors: FARBER NURI B.
Published: January 2004

Abstract: Antagonists of the NMDA glutamate receptor, including phencyclidine (PCP), ketamine, and CGS‐19755, produce cognitive and behavioral changes in humans. In rodents these agents produce a myriad of histopathological and neurochemical changes. Several lines of evidence suggest that a large number of these drug‐induced effects are dose‐dependent manifestations of the same general disinhibition process in which NMDA antagonists abolish GABAergic inhibition, resulting in the simultaneous excessive release of acetylcholine and glutamate. Progressive increases in the severity of NMDA receptor hypofunction (NRHypo) within the brain produce an increasing range of effects on brain function. Underexcitation of NMDA receptors, induced by even relatively low doses of NMDA antagonist drugs, can produce specific forms of memory dysfunction without clinically evident psychosis. More severe NRHypo can produce a clinical syndrome very similar to a psychotic schizophrenic exacerbation. Finally, sustained and severe NRHypo in the adult brain is associated with a form of neurotoxicity with well‐characterized neuropathological features. In this paper several of these effects of NMDA antagonists and a likely mechanism responsible for producing them will be reviewed. In addition the possible role of NRHypo in the pathophysiology of idiopathic psychotic disorders will be considered.
Short‐ and Long‐Term Modulation of Synaptic Inputs to Brain Reward Areas by Nicotine
Authors: FAGEN ZARA M. , MANSVELDER HUIBERT D. , KEATH J. RUSSEL , McGEHEE DANIEL S.
Published: January 2004

Abstract: Dopamine signaling in brain reward areas is a key element in the development of drug abuse and dependence. Recent anatomical and electrophysiological research has begun to elucidate both complexity and specificity in synaptic connections between ventral tegmental neurons and their inputs. Specifically, the activity of dopamine neurons in the ventral tegmental area relies on the combination of both excitatory and inhibitory inputs. Controlling endogenous neurotransmission to dopamine neurons is one mechanism by which drugs of abuse affect both transient and long‐term changes in synaptic activity. Here, we review recent findings concerning glutamatergic, GABAergic, and cholinergic inputs to dopamine neurons, and their roles in the reinforcement associated with drug abuse. Importantly, several studies support that a single drug exposure can lead to changes in synaptic strength that are associated with learning and memory. Ultimately, these cellular changes could underlie the long‐lasting effects of drugs. Furthermore, nicotinic acetylcholine receptors in the ventral tegmental area emerge as a possible common target for the behavioral and cellular actions not only of nicotine, but also of several other drugs of abuse. Finally, we explore age‐related differences in nicotine sensitivity in order to understand both human epidemiological data, and laboratory animal behavioral findings that suggest adolescents are more susceptible to developing nicotine dependence.
Exogenous and Endogenous Cannabinoids Control Synaptic Transmission in Mice Nucleus Accumbens
Authors: ROBBE DAVID , ALONSO GÉRARD , MANZONI OLIVIER J.
Published: January 2004

Abstract: Addictive drugs are thought to alter normal brain function and cause the remodeling of synaptic functions in areas important to memory and reward. Excitatory transmission to the nucleus accumbens (NAc) is involved in the actions of most drugs of abuse, including cannabis. We have explored the functions of the endocannabinoid system at the prefrontal cortex‐NAc synapses. Immunocytochemistry showed cannabinoid receptor (CB1) expression on axonal terminals making contacts with NAc neurons. In NAc slices, synthetic cannabinoids inhibit spontaneous and evoked glutamate‐mediated transmission through presynaptic activation of presynaptic K+ channels and GABA‐mediated transmission most likely via a direct presynaptic action on the vesicular release machinery. How does synaptic activity lead to the production of endogenous cannabinoids (eCBs) in the NAc? More generally, do eCBs participate in long‐term synaptic plasticity in the brain? We found that tetanic stimulation (mimicking naturally occurring frequencies) of prelimbic glutamatergic afferents induced a presynaptic LTD dependent on eCB and CB1 receptors (eCB‐LTD). Induction of eCB‐LTD required postsynaptic activation of mGlu5 receptors and a rise in postsynaptic Ca2+ from ryanodine‐sensitive intracellular Ca2+ stores. This retrograde signaling cascade involved postsynaptic eCB release and activation of presynaptic CB1 receptors. In the NAc, eCB‐LTD might be part of a negative feedback loop, reducing glutamatergic synaptic strength during sustained cortical activity. The fact that this new form of LTD was occluded by an exogenous cannabinoid suggested that cannabis derivatives, such as marijuana, may alter normal eCB‐mediated synaptic plasticity. These data suggest a major role of the eCB system in long‐term synaptic plasticity and give insights into how cannabis derivatives, such as marijuana, alter normal eCB functions in the brain reward system.