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Background In a double-blind placebo-controlled randomized trial with parallel groups, the efficacy of individually prescribed homeopathic medicines was evaluated in women with premenstrual syndrome (PMS). Methods In an outpatient department of a university clinic in Jerusalem, Israel (1996–1999), women with PMS, aged 18 to 50 years, entered a 2-month screening phase with prospective daily recording of premenstrual symptoms by the Menstrual Distress Questionnaire (MDQ). They were included after being diagnosed with PMS. A reproducible treatment protocol was used: women received a homeopathic prescription based on symptom clusters identified in a questionnaire. The symptoms were verified during a complementary, structured, interview. Only women whose symptoms matched the symptom profile of one of 14 pre-selected homeopathic medicines were included. Each participant was administered active medicine or placebo via random allocation. Primary outcome measures were differences in changes in mean daily premenstrual symptom (PM) scores by the MDQ. Analysis was by intention-to-treat. Results A total of 105 women were included: 49 were randomized to active medicine and 56 to placebo. Forty-three women in the active medicine group and 53 in the placebo group received the allocated intervention with at least one follow-up measurement and their data were analyzed. Significantly greater improvement of mean PM scores was measured in the active medicine group (0.443 [standard deviation, SD, 0.32] to 0.287 [SD, 0.20]) compared to placebo (0.426 [SD, 0.34] to 0.340 [SD, 0.39]); p = 0.043. Conclusions Individually prescribed homeopathic medicines were associated with significantly greater improvement of PM scores in women with PMS, compared to placebo. Replication, with larger sample size and other refinements, is recommended to confirm the efficacy of this treatment in other settings.

Background Low-level laser therapy (LLLT) is an emerging medical technology in which non-thermal laser irradiation is applied to treat pain. Because LLLT has been found effective in treating various pain syndromes without known side effects, we conducted a study evaluating the effect of LLLT on provoked vestibulodynia (PVD), a complex sexual pain disorder characterized by pain confined to the vulvar vestibule in response to contact or pressure. Aim To investigate the effectiveness of LLLT for PVD in a randomized, placebo-controlled, double-blinded trial. Methods Patients with PVD were randomly assigned to receive treatment with LLLT or sham treatment. Patients were treated twice weekly for 6 weeks, for a total of 12 LLLT or placebo sessions. Patients who showed improvement after LLLT were followed for 1 year by clinical pain report and Q-tip examination. Outcomes Change in pain scores obtained in response to the Q-tip test, clinical pain report, visual analog scale score, pain with tampon insertion, daily pain intensity, intercourse pain intensity, frequency of intercourse, and a battery of quality-of-life measures. Results Thirty-four patients with PVD participated, 18 received LLLT and 16 received placebo. In the clinical pain report at study completion, 14 of 18 patients (78%) receiving LLLT reported improvement compared with 7 of 16 (44%) in the placebo group (P = .042). This effect was not apparent in other outcome measurements. None of the patients reported side effects during the study. At 1-year follow-up, eight patients (57%) reported lasting improvement. Clinical Implications Larger studies with various treatment protocols are needed to define which patients can benefit from LLLT therapy. Strengths and Limitations Strengths include a placebo-controlled, double-blinded design, measurement of a large number of multidimensional end points, and a follow-up period of 1 year. Limitations include the small number of patients recruited, no improvement in measurable parameters, a high improvement rate in the placebo group, the absence of use of validated questionnaires, and the lack of evaluation of psychological and interpersonal factors that might have influenced the results. Conclusions Given the results of this pilot study, LLLT cannot currently be recommended as a treatment for PVD. Further studies with a larger population, various treatment protocols, and evaluation of LLLT in different subgroups of PVD are needed to define which patients can benefit from this therapy.

The pineal hormone Melatonin plays an important role in the regulation of the circadian sleep/wake cycle, mood, and perhaps immune functions, carcinogensis and reproduction. The human circadian rhythm of melatonin release from the pineal gland is tightly synchronized with the habitual hours of sleep. Peri- and postmenopausal women often complain of difficulties initiating and/or maintaining sleep, with frequent nocturnal and early morning awakenings. In this review we discuss the pathophysiology of melatonin function as it relates to sleep disorders in menopausal women, highlighting the potential use of exogenous melatonin during the menopausal transition and beyond.

Background Our aims were to evaluate critically the evidence from systematic reviews as well as narrative reviews of the effects of melatonin (MLT) on health and to identify the potential mechanisms of action involved. Methods An umbrella review of the evidence across systematic reviews and narrative reviews of endogenous and exogenous (supplementation) MLT was undertaken. The Oxman checklist for assessing the methodological quality of the included systematic reviews was utilised. The following databases were searched: MEDLINE, EMBASE, Web of Science, CENTRAL, PsycINFO and CINAHL. In addition, reference lists were screened. We included reviews of the effects of MLT on any type of health-related outcome measure. Results Altogether, 195 reviews met the inclusion criteria. Most were of low methodological quality (mean -4.5, standard deviation 6.7). Of those, 164 did not pool the data and were synthesised narratively (qualitatively) whereas the remaining 31 used meta-analytic techniques and were synthesised quantitatively. Seven meta-analyses were significant with P values less than 0.001 under the random-effects model. These pertained to sleep latency, pre-operative anxiety, prevention of agitation and risk of breast cancer. Conclusions There is an abundance of reviews evaluating the effects of exogenous and endogenous MLT on health. In general, MLT has been shown to be associated with a wide variety of health outcomes in clinically and methodologically heterogeneous populations. Many reviews stressed the need for more high-quality randomised clinical trials to reduce the existing uncertainties. Electronic supplementary material The online version of this article (10.1186/s12916-017-1000-8) contains supplementary material, which is available to authorized users.

One of the core symptoms of the menopausal transition is sleep disturbance. Peri-menopausal women often complain of difficulties initiating and/or maintaining sleep with frequent nocturnal and early morning awakenings. Factors that may play a role in this type of insomnia include vasomotor symptoms and changing reproductive hormone levels, circadian rhythm abnormalities, primary insomnia, mood disorders, coexistent medical conditions, and lifestyle. Exogenous melatonin reportedly induces drowsiness and sleep, and may ameliorate sleep disturbances, including the nocturnal awakenings associated with old age and the menopausal transition. Recently, more potent melatonin analogs with prolonged effects and slow-release melatonin preparations have been developed. The melatonergic receptor ramelteon is a selective melatonin-1 (MT1) and melatonin-2 (MT2) receptor agonist with negligible affinity for other neuronal receptors, including gamma-aminobutyric acid and benzodiazepine receptors. It was found effective in increasing total sleep time and sleep efficiency, as well as in reducing sleep latency, in insomnia patients. The melatonergic antidepressant agomelatine, displaying potent MT1 and MT2 melatonergic agonism and relatively weak serotonin 5HT2C receptor antagonism, reportedly is effective in the treatment of depression associated insomnia. This article presents the currently available evidence regarding the effects of these compounds on sleep quality and their possible use in menopause associated sleep disturbances.

Objective To assess the association between demographic and lifestyle parameters and perceived severity of the climacteric syndrome in perimenopausal women. Study design A cross-sectional study of 151 healthy women aged 45–55 years who attended the University Medical Center affiliated menopause clinics. The analysis was based on self completion of the Greene climacteric score, consisting of psychological, somatic/physical, sexual and vasomotor subscores. The Greene total score and subscores were the main outcomes of the study. Results Of all demographic, anthropometric and lifestyle parameters recorded, the correlates with reduced total Greene score were high-order maternity and regular physical exercise. Mothers of 3 or more children reported significantly lower total Greene score (18 ± 12.8 vs. 22.1 ± 8.1) (p = 0.01) as well as lower psychological subscore (8.7 ± 6.8 vs. 11.5 ± 5.4) (p = 0.01). Regular physical activity was also associated with significantly lower total Greene score (17.0 ± 11.0 vs. 22.6 ± 11.3) (p = 0.01) and specifically lower psychological subscore (9.5 ± 6.6 vs. 12.8 ± 7.7) (p = 0.03) and sexual subscore (1.1 ± 0.99 vs. 1.61 ± 1.05) (p = 0.03). Linear regression models showed that regular exercise was the lifestyle parameter most significantly correlated with a lower total Greene score (p = 0.006) independent of menopausal status. Of particular note, regular exercise was significantly correlated with lower psychological (p = 0.006) and physical subscores (p = 0.06). Moreover, the higher the frequency of exercise (both aerobic and non aerobic), the lower the severity of the climacteric symptoms reported, yet the vasomotor and sexual subscores remained unchanged. Conclusions Regular exercise of at least 3 times a week was the most significant lifestyle parameter to be associated with the severity of climacteric symptoms.

Daytime administration of exogenous melatonin (when it is not present endogenously) promotes sleep in humans and results in sleep-like brain activity patterns at specic areas such as the precuneus and hippocampus. However, existing studies on the hypnotic efcacy of melatonin have been highly heterogeneous in regard to inclusion and exclusion criteria, measures to evaluate insomnia, doses of the medication, and routes of administration. The inconsistent reports about the effectiveness of exogenous melatonin in the treatment of insomnia brought about the development of more potent melatonin analogs with prolonged effects and the design of slow-release melatonin preparations. The melatonergic receptor ramelteon is a selective melatonin-1 (MT1) and melatonin-2 (MT2) receptor agonist with negligible afnity for other neuronal receptors, including gamma-aminobutyric acid and benzodiazepine receptors. It was found effective in increasing total sleep time and sleep efciency as well as in reducing sleep latency in insomnia patients. The melatonergic antidepressant agomelatine, displaying potent MT1 and MT2 melatonergic agonism and relatively weak serotonin 5HT2C receptor antagonism, reportedly is effective in the treatment of depression-associated insomnia.

The aim of this review is to examine three questions: What are the risks and benefits of treating women with schizophrenia with hormone therapy (HT) at menopause? Should the antipsychotic regimen be changed at menopause? Do early- and late-onset women with schizophrenia respond differently to HT at menopause? MEDLINE databases for the years 1990 to 2016 were searched using the following interactive terms: schizophrenia, gender, menopause, estrogen, and hormones. The selected articles (62 out of 800 abstracts) were chosen on the basis of their applicability to the objectives of this targeted narrative review. HT during the perimenopause in women with schizophrenia ameliorates psychotic and cognitive symptoms, and may also help affective symptoms. Vasomotor, genitourinary, and sleep symptoms are also reduced. Depending on the woman's age and personal risk factors and antipsychotic side effects, the risk of breast cancer and cardiovascular disease may be increased. Antipsychotic types and doses may need to be adjusted at menopause, as may be the mode of administration. Both HT and changes in antipsychotic management should be considered for women with schizophrenia at menopause. The question about differences in response between early- and late-onset women cannot yet be answered.

Melatonin, the hormone secreted by the pineal gland, plays an important role in sleep induction and sleep maintenance. With the advancement of age, there is a decline in melatonin production, and elderly individuals often complain difficulties in sleep onset, maintenance of sleep-wake rhythm, and poor quality of sleep. Melatonin replacement therapy has been used for treating insomnias but it is not uniformly successful. With the synthesis of melatonergic agonist, ramelteon, a chronohypnotic drug with a higher affinity for MT1 and MT2 melatonergic receptors, treatment of insomnias has become easy, and many clinical studies have attested the efficacy of ramelteon in treating primary insomnia and secondary insomnias associated with neurodegenerative and neurodevelopmental disorders like autistic disorder. Melatonin has been implicated in the pathogenesis of delirium and autism spectrum disorders (ASD) and has been tried for treatment of these disorders. Although found successful in treating these disorders, melatonergic agonist ramelteon is used for treating autistic disorder and delirium where the drug has been found effective in not only alleviating the sleep disorders but also the behavioral problems. A low or abnormal level of melatonin is suggested as one of the main reasons for the lack of communication skill and socialization which are the main symptoms of ASD. Ramelteon has been used for treating rapid eye movement (REM) sleep behavior disorder (RBD) also and is found to be effective in increasing sleep efficiency and reducing the intensity of behavioral symptoms of this disorder. As a chronohypnotic drug, ramelteon ameliorated the symptoms of jet lag by improving the nighttime sleep efficiency and daytime alertness.

Insomnia is common among elderly people and nearly 30 to 40% of the adult population also suffer from insomnia. Pharmacological treatment of insomnia include the use of benzodiazepine and non-benzodiazepine drugs like zolpidem, zaleplon, Zopiclone. Although these drugs improve sleep, their usage is also associated with number of adverse effects, Melatonin, the hormone secreted by the pineal gland of all animals and human beings has been used for treatment of insomnias, since the timing of its secretion in humans as well as in most of the animals coincides with the increase of nocturnal sleep propensity. Because of its short half life, melatonin slow release preparations were introduced for treatment of insomnia. Recently ramelteon, a selective MT1, MT2 receptor agonist with greater efficacy of action in treating insomnia has been used clinically and has been found effective in improving sleep quality, sleep efficacy and also in reducing the sleep onset time when compared to melatonin or slow melatonin preparations. The mechanism of action of ramelteon in improving sleep is discussed in the paper. Another melatonergic drug agomelatine besides acting on MT1/MT2 receptors also displays 5-HT2c antagonism and this drug has been found effective as a novel antidepressant for treating major depressive disorders. Agomelatine besides causing remission of depressive symptoms also improves sleep quality and efficiency. Other antidepressants depressants that are in clinical use today do not improve sleep. There are other melatonergic drugs like tasimelteon, 6-chloromelatonin. But ramelteon and agomelatine deserve special attention for treatment of insomnia and sleep disturbances associated with depressive disorders and have promising role for treatment of sleep disorders.

Benzodiazepine sedative-hypnotic drugs are widely used for the treatment of insomnia. Nevertheless, their adverse effects, such as next-day hangover, dependence and impairment of memory, make them unsuitable for long-term treatment. Melatonin has been used for improving sleep in patients with insomnia mainly because it does not cause hangover or show any addictive potential. However, there is a lack of consistency on its therapeutic value (partly because of its short half-life and the small quantities of melatonin employed). Thus, attention has been focused either on the development of more potent melatonin analogs with prolonged effects or on the design of slow release melatonin preparations. The MT(1) and MT(2) melatonergic receptor ramelteon was effective in increasing total sleep time and sleep efficiency, as well as in reducing sleep latency, in insomnia patients. The melatonergic antidepressant agomelatine, displaying potent MT(1) and MT(2) melatonergic agonism and relatively weak serotonin 5HT(2C) receptor antagonism, was found effective in the treatment of depressed patients. However, long-term safety studies are lacking for both melatonin agonists, particularly considering the pharmacological activity of their metabolites. In view of the higher binding affinities, longest half-life and relative higher potencies of the different melatonin agonists, studies using 2 or 3mg/day of melatonin are probably unsuitable to give appropriate comparison of the effects of the natural compound. Hence, clinical trials employing melatonin doses in the range of 50-100mg/day are warranted before the relative merits of the melatonin analogs versus melatonin can be settled.

Fil: Srinivasan, Venkataramanujan. Sri Sathya Sai Medical Educational and Research Foundation Prasanthi Nilayam; India Fil: Srinivasan, Venkataramanujan. Universidad de Karpagam. Facultad de Medicina; Departamento de Fisiología; India Fil: Pandi Perumal, Seithikurippu R. Somnogen Inc; Canadá Fil: Brzezinski, Amnon. The Hebrew University. Hadassah Medical Center. Department of Obstetrics and Gynecology; Israel Fil: Bhatnagar, Kunwar P. University of Louisville. Department of Anatomical Sciences and Neurobiology; Estados Unidos Fil: Cardinali, Daniel P. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Departamento de Docencia e Investigación; Argentina Abstract: Melatonin is a natural substance ubiquitous in distribution and present in almost all species ranging from unicellular organisms to humans. In mammals, melatonin is synthesized not only in the pineal gland but also in many other parts of the body, including the eyes, bone marrow, gastrointestinal tract, skin and lymphocytes. Melatonin influences almost every cell and can be traced in membrane, cytoplasmic, mitochondrial and nuclear compartments of the cell. The decline in the production of melatonin with age has been suggested as one of the major contributors to immunosenescence and development of neoplastic diseases. Melatonin is a natural antioxidant with immunoenhancing properties. T‐helper cells play an important role for protection against malignancy and melatonin has been shown to enhance T‐helper cell response by releasing interleukin‐2, interleukin‐10 and interferon‐γ. Melatonin is effective in suppressing neoplastic growth in a variety of tumors like melanoma, breast cancer and ovarian and colorectal cancer. As an adjuvant therapy, melatonin can be beneficial in treating patients suffering from breast cancer, hepatocellular carcinoma or melanoma.

Melatonin, N-acetyl-5-methoxytryptamine, is a molecule with diverse physiological functions. This neuro-hormone affects reproductive performance in a wide variety of species. In most animals, but not exclusively all, melatonin has an antigonadotrophic effect. The seasonal changes in the number of hours per day that melatonin is secreted mediate the temporal coupling of reproductive activity to seasonal changes in day-length. These observations stimulated a search for a role for the pineal gland and melatonin in human reproduction. Clinical experience related to this issue has yielded inconclusive and sometimes conflicting results. This article reviews the current available evidence concerning the effects of melatonin on human reproductive processes (e.g., puberty, ovulation, pregnancy, and fertility). Possible reasons for the vagueness and elusiveness of the clinical effects are discussed.

The most effective strategy for prevention of ovarian and breast cancer in high-risk women is bilateral salpingo-oophorectomy. The inevitable consequence of the procedure is early menopause with the associated climacteric symptoms. Little is known about the nature of the symptoms in women who undergo risk-reducing bilateral salpingo-oophorectomy.To compare the nature, frequency, severity, duration, and overall effects of climacteric symptoms in a group of women who underwent preventive bilateral salpingo-oophorectomy as compared to women who experienced natural menopause.Forty-eight women at high risk for ovarian cancer who had risk-reducing bilateral salpingo-oophorectomy were compared to 60 postmenopausal women who had natural menopause. The participants were interviewed about their climacteric complaints, thoughts and feelings regarding the surgical procedure and their general well-being. The climacteric symptoms were evaluated by a modified Greene Climacteric Scale.Surgical menopause, as compared to natural menopause, was associated with more severe psychological, vasomotor and somatic climacteric symptoms (total score 17.36 vs. 8.65, respectively, p0.001) and more significant sexual dysfunction (1.848 vs. 0.900, respectively, p0.01). On a 0-10 scale, the satisfaction rate from the surgical procedure was 8.23 +/- 2.21. The surgery did not affect the perceived quality of life (p = 0.347) and decreased the score of anxiety and cancer fear (from 7.75 +/- 3.31 preoperatively to 2.94 +/- 3.08 postoperatively, p0.001).Risk-reducing bilateral salpingo-oophorectomy as compared to natural menopause is associated with more severe climacteric symptoms. However, the procedure does not interfere with the overall perceived quality of life and improves the perception of cancer risk.

One of the core symptoms of the menopausal transition is sleep disturbance. Peri-menopausal women often complain of difficulties initiating and/or maintaining sleep with frequent nocturnal and early morning awakenings. Factors that may play a role in this type of insomnia include vasomotor symptoms, changing reproductive hormone levels, circadian rhythm abnormalities, mood disorders, coexistent medical conditions, and lifestyle. Other common sleep problems in this age group, such as obstructive sleep apnea and restless leg syndrome, can also worsen the sleep quality. Exogenous melatonin use reportedly induces drowsiness and sleep and may ameliorate sleep disturbances, including the nocturnal awakenings associated with old age and the menopausal transition. Recently, more potent melatonin analogs (selective melatonin-1 (MT1) and melatonin-2 (MT2) receptor agonists) with prolonged effects and slow-release melatonin preparations have been developed. They were found effective in increasing total sleep time and sleep efficiency as well as in reducing sleep latency in insomnia patients. The purpose of this review is to give an overview on the changes in hormonal status to sleep problems among menopausal and postmenopausal women.

We use a 1993 policy change in Israel's public healthcare system that lowered the eligibility age for amniocentesis to 35 to study the effects of financing of screening tests. Financing is found to have increased amniocentesis testing by about 35%. At ages above the eligibility threshold, utilization rates rose to roughly 33%, reflection nearly full takeup among prospective users of amniocentesis. Additionally, whereas below the age-35 threshold amniocentesis utilization rates increase with maternal age, this relation is muted above this age. Finally, no evidence is found that financing affects outcomes such as pregnancy terminations and births of children with Down syndrome. These results support the view that women above the eligibility threshold tend to refrain from acquiring inexpensive information about their degree of risk that absent the financing they would acquire, and instead, undergo the accurate and costly test regardless of additional information that noninvasive screening would provide.

BACKGROUND: Predictive factors of women who are unable to quit prolonged hormonal therapy (HT) are largely unknown. We sought to identify predictors for the resumption of HT after the discontinuation of treatment. METHODS: A cohort prospective study was conducted allocating menopausal women treated with HT for over 3 years. Menopausal symptoms were monitored periodically after HT cessation by the Greene climacteric scale. RESULTS: Eighty-two women participated in the study. Age, the age of menopause, BMI, HT duration, the type of regimen, reasons cited to discontinue HT and the method of discontinuation did not differ between the subjects who successfully discontinued HT and those who failed to quit HT. Only the prevalence of vasomotor symptoms when HT was first prescribed significantly differed between the groups (P = 0.03). Comparable maximal Greene score was recorded in both groups. Over time, the subjects who returned to HT had higher Greene score [Hazard ratio 1.25, confidence interval (CI) 95% (1-1.07)] and significantly higher vasomotor score [Hazard score 1.22, CI 95% (1.02-1.46)]. CONCLUSIONS: The history of hot flashes and the duration of menopausal symptoms upon HT discontinuation predict the resumption of HT. Thus, the return to HT is expected in individuals who are intolerant of prolonged climacteric syndrome.

Pharmacokinetic studies of soybean isoflavones have shown that following oral ingestion, the two major isoflavones, daidzin and genistin, are hydrolyzed in the intestine, rapidly absorbed into the peripheral circulation, and eliminated from the body with a terminal half-life of 7-8 h. These characteristics make maintenance of steady-state plasma isoflavone concentrations difficult to attain unless there is repeated daily ingestion of foods or supplements containing isoflavones. In an attempt to sustain more constant plasma isoflavone concentrations, a new slow-release formulation of a soybean isoflavone extract was prepared by microencapsulation with a mixture of hydroxypropylcellulose and ethylcellulose to alter its dissolution characteristics. In vitro experiments confirmed slow aqueous dissolution of isoflavones from this formulation when compared with the conventional isoflavone extract. The pharmacokinetics of this slow-release isoflavone extract was studied in 10 healthy postmenopausal women after oral administration of a single capsule containing the equivalent of 22.3 mg of genistein and 7.47 mg of daidzein expressed as aglycons. A comparison of the key pharmacokinetic parameters obtained in this study with those established in extensive studies performed previously in this laboratory indicated that the mean residence time of genistein and daidzein increased 2-fold with microencapsulation. These findings are indicative of a decreased rate of absorption, consistent with the observed slow in vitro dissolution rate. These findings show that it is feasible to employ polymer matrices that slow the aqueous dissolution for preparing sustained-release formulations of soy isoflavones. Further studies to optimize such formulations are warranted.

Genistein is a phytoestrogen with in vitro anticancerogenic activity. We examined in vitro the effects of genistein alone, or in combination with estradiol and tamoxifen, on the growth of human dysplastic and malignant epithelial breast cell lines.Dysplastic breast cell lines (MCF-10A(1), MCF-ANeoT, MCF-T(6)3B) and cell lines of breast cancer (MCF-7, MDA-231, MDA-435) were cultured as monolayers in RPMI 1640 medium supplemented with 10% fetal bovine serum, and L-glutamine. After preincubation of 20 h, genistein (1, 2.5, 5, 7.5 and 10 microg/ml) alone or in combination with estrogen or tamoxifen was added to the cultured cells. The cells were treated continuously for 72 h and then the growth rate was assessed colorimetrically. Stepwise multiple linear regression analysis was used to evaluate the effect of genistein, tamoxifen, and estradiol on cell proliferation.Genistein had a significant (dose-dependent) inhibitory effect on the proliferation of both dysplastic (P0.0001) and malignant (P0.0001) cells. The growth inhibition was significantly higher P0.0001 in dysplastic cells compared to the cancer cells. Addition of tamoxifen to genistein further inhibited the proliferation of both cell types, reflecting a synergistic antiproliferative effect on dysplastic cells P0.0001 and an additive growth inhibition effect P0.0003 on malignant cells. Estradiol significantly (P=0.005) stimulated the growth of dysplastic cell lines while a significant (P=0.003) antiproliferative effect on growth of the malignant cells was observed. The concentration of estrogen receptor (ER) had no significant effect on growth rates and did not modulate the effects of genistein or tamoxifen.Genistein (1-10 microg/ml) inhibits the growth of dysplastic and malignant epithelial breast cancer cells in vitro and the addition of tamoxifen (10(-6), 10(-7)M) has a synergistic/additive inhibitory effect. These effects are not modulated by the presence of ER.

UNLABELLED: Breast cancer is the most common cancer among women and the leading cause of death in women, 40 to 55 years of age. The lifetime odds of developing breast cancer are apparently up to 1 in 8 women in North America and 1 in 12 in Western Europe. According to the American Cancer Society, some 200,000 women (and 1,500 men) will be diagnosed with breast cancer this year. Although the incidence of breast cancer in women has been rising since the mid-1940s, the mortality has dropped modestly over the past decade, probably due to earlier and improved diagnosis and treatment. Evidence from both epidemiological and experimental studies points to an important role of reproductive variables in the development and promotion of human breast neoplasia. Hormonal manipulations, in the form of contraceptives, hormone replacement therapy, or antiestrogens, affect the incidence and course of breast cancer and may be useful in prevention and treatment of the tumor. In this review we summarize the current status of the use of hormones and antihormones in regard to breast cancer and outline possible areas of additional development and investigation. TARGET AUDIENCE: Obstetricians and Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader will be able to summarize the effects of estrogen and progestogens on the breast and to list the effects of other hormonal modulators on the breast.

Melatonin And Melatonergic Drugs In Clinical Practice - Libros de Medicina - Neurologia general - 139,99

Periurethral injection of substrates that compress, support, or narrow the bladder neck for the treatment of stress incontinence is not new. Several injectable compounds have been used in a small number of patients during the 1940s and through the 1960s; however, the results were not very successful and often led to significant complications. More recently, two major materials have been developed that seem to be useful in treating stress incontinence by periurethral injection: Polytef paste and GAX collagen. Other injectables include autologous fat tissue and silicone microimplants. The most suitable patients for periurethral injection are elderly women, patients who constitute high operative risk, and those with stress incontinence due to intrinsic sphincter failure. Patients with stress incontinence due to a combination of urethral hypermobility and intrinsic sphincter deficiency with failure of suspension procedure may also benefit from the procedure. The reported long-term (more than 24 months) success rates according to the various substances are as follows: Teflon (Polytef) (E.I.du Pont de Nemours and Co, Wilmington, DE): 30 to 38 percent cured or improved; repeated injections usually do not improve the outcome; mostly minor complications with case reports of more serious side effects such as periurethral granuloma formation and bladder outlet obstruction. GAX collagen: 69 to 77 percent subjectively cured or improved after 24 months; 54 to 57 percent objectively cured or improved, the reported morbidity in these procedures is minimal; repeated injections can improve the outcome. The experience with autologous fat and silicone microimplants is insufficient, with an overall success rate of 70 percent (1-40 months follow-up; mean 12 months) and 58 to 70 percent (17-36 months), respectively. Most of the procedures are performed as outpatient cases, and some under local anesthesia. These procedures are minimally invasive, usually safe and well tolerated, require shorter hospitalization, and are cost effective. In conclusion, in carefully selected patients, periurethral injection seems to be a reasonable option in the modern treatment of female stress incontinence.

Experimental and epidemiologic evidence support the hypothesis that phytoestrogens have both estrogenic and antiestrogenic effects in humans. The authors investigated the effects of short-term (12 weeks) dietary intervention with phytoestrogen-rich diet on menopausal symptoms and serum level

The efficacy of melatonin in promoting and maintaining sleep has been demonstrated in most of the clinical studies. However, because of its short half-life, its sustained effect in improving sleep quality could not be demonstrated uniformly in all the studies that have been undertaken so far. The development of slow-release melatonin preparation Circadin has been found effective in reducing sleep onset time and also for improving sleep quality. This was followed by the introduction of another melatonergic drug ramelteon a melatonin receptor agonist that has high selectivity for MT1 receptors than MT2 receptors and therefore targets sleep onset more specifically than melatonin. Clinical trials undertaken in different countries of European region and Japan have conclusively demonstrated that ramelteon in various doses (from 4 to 32 mg/day) reduced sleep onset latency, increased total sleep time, and sleep efficiency and quality in patients suffering from chronic insomnia. Besides acting as a sedative-hypnotic drug, ramelteon also demonstrated its ability as a drug with chronobiotic properties and has been found useful in resetting the disturbed circadian rhythms. The action of ramelteon in improving sleep efficiency is dose independent and hence acts differently from melatonin. It has a promising value in treating patients with chronic insomnia as it does not have any of the adverse effects like next-day hangover and dependence associated with the usage of other conventional hypnotic drugs.

Jet lag comprises a constellation of symptoms that occurs as a result of disruptions of entrainment associated with time zone transitions. The jet lag symptoms include daytime fatigue, impaired alertness, insomnia, loss of appetite, poor psychomotor coordination, reduced cognitive skills, and depressed mood. The severity of jet lag symptoms depends on the number of time zones crossed as well as the direction of travel. Eastbound travel tends to cause difficulties in falling asleep, whereas westbound travel interferes with sleep maintenance. Clinical studies also indicate that jet lag can exacerbate existing affective disorders. It has been suggested that dysregulation of melatonin secretion and occurrence of circadian rhythm disturbances may be the common links which underlie jet lag and affective disorders. Melatonin has proven to be highly effective for treating the range of symptoms that accompany transmeridian air travel largely because of its regulatory effects on the circadian system. The therapeutic values of melatonin and its agonists such as ramelteon in reducing the jet lag symptoms and use of the melatonergic antidepressant, agomelatine, for jet lag-associated depressive disorders are discussed in this chapter.

Exogenous melatonin reportedly induces drowsiness and sleep and may ameliorate sleep disturbances, including the nocturnal awakenings associated with old age. Daytime administration of exogenous melatonin (when it is not present endogenously) promotes sleep in humans and results in sleeplike brain activity patterns at specific areas such as the precuneus and hippocampus. However, existing studies on the hypnotic efficacy of melatonin have been highly heterogeneous in regard to inclusion and exclusion criteria, measures to evaluate insomnia, doses of the medication, and routes of administration.

Management and control of pain sensation is a matter of great clinical interest. Drugs like aspirin and nonsteroidal anti-inflammatory drugs (NSAIDS) exert their antinociceptive effects by inhibiting cyclooxygenases (COX), but their side effects such as gastrointestinal bleeding and ulceration make them unsafe for long-term clinical use. Thus, there is a need to find a safer antinociception. Melatonin’s antinociceptive effects have been demonstrated in a number of experimental models of nociception. Its clinical roles in inflammatory pain, neuropathic pain, fibromyalgia, irritable bowel syndrome, and cluster headache are discussed in this chapter. The mechanism of melatonin’s antinociceptive effects via its interaction with a number receptor sites including opioidergic, benzodiazepinergic, muscarinic, nicotinic, serotonergic, α1-adrenergic, α2-adrenergic, and, most importantly, MT1/MT2 melatonergic receptors present in the dorsal horn of the spinal cord as well in the central nervous system is also highlighted in this chapter.

Melatonin, N-acetyl-5-methhoxytryptamine, is a molecule with diverse physiological function. It affects reproductive functions in a wide variety of species. This chapter describes the roles of melatonin on various reproductive parameters. Melatonin has an inhibitory influence on hypothalamic GnRH secretion. Melatonin acts as antioxidant and reduces oxidative stress-induced testicular dysfunctions and poor oocytes quality in many experimental animals. During fetal life, melatonin regulates circadian rhythm and has been suggested to play a role in the regulation of fetal REM and NREM sleep. In adults, melatonin regulates the time of parturition in both humans and nonhuman primates. Many studies have suggested that melatonin could be an effective treatment for preeclampsia, due to its antioxidant properties as well as its antihypertensive and anticonvulsive actions.

The objective was to study the pathophysiology of the dyslipidaemia hi polycystic ovarian syndrome (PCOS) patients, and to determine how it is related to hyperinsulinaemia, hyperandrogenism and dehydroepiandrosterone sulphate (DHEA-S) concentrations. The lipoprotein lipid profile, anthropometric measurements, endocrine profile and the presence of insulin resistance were evaluated hi 31 PCOS patients and 20 age-matched healthy women, who served as controls. PCOS patients had higher fasting insulin concentrations, higher body mass indexes (BMI) and were hyperlipidaemic, with higher total cholesterol, low density lipoprotein (LDL) and triglyceride (TG) concentrations. There were no relationships between plasma lipids and anthropometric variables hi the patient group as a whole. Insulin-resistant (IR) and non-ER (NIR) PCOS patients were then evaluated separately. Obesity with marked hyperandrogenism were the predominant features hi patients with IR. NIR patients were not obese and had significantly less hyperandrogenism. The adrenal androgen DHEA-S was at the upper limit of its normal range in both groups. However, both PCOS subgroups exhibited similar significant abnormalities hi terms of then- lipid parameters. Insulin and DHEA-S concentrations were positively correlated with total cholesterol, LDL and TG, and negatively correlated with high density lipoprotein, hi IR patients. In NIR subjects, insulin was not correlated with any of the lipids and DHEA-S was negatively related to cholesterol and LDL. Anthropometric variables were related to lipids hi only the NIR patients. Thus PCOS subjects as a group exhibit dyslipidaemia, characterized by increased total cholesterol, LDL and TG concentration s. When divided into IR and NIR subjects, there were no differences hi the degree of lipid abnormalities, despite significant variations hi the BMI and androgen status. Thus, hi PCOS subjects, dyslipidaemia may occur irrespective of insulin resistance. Insulin and DHEA-S concentrations were positively correlated with an atherogenic lipid profile hi the IR group only. As distinct from syndrome X when IR was present, dyslipidaemia was not related to body weight or the waist:hip ratio. In the NTR group there was no relationship 1848 between lipids and insulin; DHEA-S, on the other hand, was negatively related to cholesterol and LDL concentrations. Thus, dyslipidaemia hi PCOS patients may occur irrespective of insulin resistance, and may have different metabolic aetiologies depending on DHEA-S metabolism. It remains to be seen whether the two types of PCOS are associated with different risks for ischaemic heart disease.

We studied the clinical and endocrine features of 35 patients with polycystic ovary syndrome (PCOS) who are either insulin resistant or non-insulin resistant. The occurrence of insulin resistance was determined by measuring insulin and glucose concentrations following a standard 75 g oral glucose load. All patients were evaluated by anthropometric measurements: body mass index (BMI), percentage of body fat (BCF) and waist-to-hip ratio (W/H), degree of hirsutism (Ferriman-Gallwey method) and endocrine profile. Fourteen patients had insulin resistance of unknown origin whereas four were due to a type A insulin receptor mutation, and 17 were non-insulin resistant. The insulin resistant patients were significantly more obese (higher BMI P < 0.0001, BCF P < 0.002 and W/H ratio P < 0.005) and were more hirsute (P < 0.002) than the non-insulin resistant patients. Testosterone concentrations were significantly higher in the insulin resistant group than in the non-insulin resistant group (2.65 versus 1.37 nmol/l; P < 0.027), whereas sex hormone-binding globulin was lower in insulin resistant patients (30.61 versus 19.48 nmol/l; P < 0.02). Non-insulin resistant patients showed a high luteinizing hormone to follicle stimulating hormone ratio, while a normal ratio was found in the insulin resistant subpopulation (2.94 versus 1.34; P < 0.0001). We concluded that PCOS comprises two subpopulations, one with insulin resistance of different aetiologies and the other which has no insulin resistance. These two groups differ in their anthropometric and endocrine features. The diagnosis of insulin resistance in PCOS can be easily determined by the insulin response to an oral glucose tolerance test.

Objective To determine prospectively whether the use of low-dose estrogen oral contraceptives (OC) is associated with changes in weight, body composition, or fat distribution. Design Anthropometric measurements were performed in 49 healthy young (16 to 21 years old) women before commencement of OC use (30 μg ethinyl estradiol [EE 2 ] plus 75 μg gestodene) and after three and six treatment cycles. Thirty one age- and weight-matched women who were not using OC served as controls. Setting Outpatient gynecological clinic of Hadassah Medical Center, a tertiary level hospital, and the "Shilo" voluntary service for the prevention of unwanted pregnancy. Main Outcome Measures Anthropometric measurements included body mass index (BMI), waist-to-hip girth ratio, and body composition (the percentage of body fat and water), estimated by mean of infrared interactance. Results In the group of OC users, baseline BMI, percent fat, percent water, and waist-to-hip girth ratio were 21.1±0.32 (kg/m 2 ), 23.8%±0.63%, 57.4%±0.39%, and 0.73±0.01, respectively, and did not change significantly after six cycles (20.6±0.41 [kg/m 2 ], 23.9%±0.57%, 58.1%±0. 49%, and 0.72±0.03, respectively). These measurements were not significantly different when compared with the nonusers. Fifteen OC users (30.6%) gained weight (>0.5 kg). Weight gain was due to a significant accumulation of fat (from 22.5%±1.1% to 25.6%±0.74%), whereas the percentage of body water remained stable. The waist-to-hip girth ratio also was not changed significantly. Similarly, 11 nonusers (35.4%) gained weight because of similar nonabdominal fat accumulation. Ten OC users (20.4%) lost weight (57kg±1.51 to 55.4±1.47 [mean±SEM]) and 6 nonusers (19.3%) also lost weight (59kg±1.42 to 57.3±1.92). In both groups the loss of weight was not associated with significant change in body composition. Conclusions The use of low-dose OC (EE 2 plus gestodene) was not associated with overall impact on weight, body composition, or fat distribution. However, when weight gain did occur during OC use, it was due to increase in body fat and not in volume of body water, and it was not associated with changes in fat distribution.

Disturbances of circadian rhythms and sleep play an important role in various types of mood disorders like major depressive disorder (MDD), bipolar depressive disorder (BPD) and seasonal affective disorder (SAD). Malfunctioning of the SCN-pineal-melatonin link has been suggested as the main cause for these disorders. As a rhythm-regulating factor and as a hormone involved in the regulation of sleep, melatonin is essential for the control of mood and behavior.Melatonin's involvement in various mood disorders is reviewed based on studies undertaken in patients with MDD, BPD and SAD. The chemistry and metabolism of the newly introduced antidepressant, agomelatine, a MT1/MT2 melatonin receptor agonist and 5-HT2c antagonist in brain areas involved in mood regulation are also discussed. Its clinical role in mood regulation, agomelatine's efficacy, safety and tolerability are also reviewed.Agomelatine, a melatonergic antidepressant with a rapid onset of action, has been shown effective in various types of mood disorders (e.g., MDD, BPD, SAD). Some studies find it superior to other common antidepressants (SSRIs, SNRIs) that are in clinical use today. Agomelatine's efficacy, good tolerability and safety profile suggest that it may become a preferred antidepressant in the near future.

The results of both epidemiologic and experimental studies suggest that endogenous (and apparently exogenous) sex hormones and other reproductive variables have an important role in the development of human breast neoplasia. Nevertheless, no controlled study has ever addressed the possible effects of ovarian stimulation on the incidence and course of human breast cancer. Over the past decade the number of women undergoing follicular stimulation, especially during assisted reproductive technology procedures, has grown rapidly. Here we present 16 cases of young women who were treated by induction of ovulation, and subsequently were diagnosed with breast cancer. These women were drawn out of 950 cases of infertile women who underwent induction of ovulation at our fertility clinic over a 10-year period. The possible association between ovarian stimulation and promotion of breast cancer is discussed and the need for a controlled study is emphasized.

Benzodiazepine sedative-hypnotic drugs are widely used for the treatment of insomnia. Nevertheless, their adverse effects, such as next-day hangover, dependence and impairment of memory, make them unsuitable for long-term treatment. Melatonin has been used for improving sleep in patients with insomnia mainly because it does not cause hangover or show any addictive potential. However, there is a lack of consistency on its therapeutic value (partly because of its short half-life and the small quantities of melatonin employed). Thus, attention has been focused either on the development of more potent melatonin analogs with prolonged effects or on the design of slow release melatonin preparations. The MT(1) and MT(2) melatonergic receptor ramelteon was effective in increasing total sleep time and sleep efficiency, as well as in reducing sleep latency, in insomnia patients. The melatonergic antidepressant agomelatine, displaying potent MT(1) and MT(2) melatonergic agonism and relatively weak serotonin 5HT(2C) receptor antagonism, was found effective in the treatment of depressed patients. However, long-term safety studies are lacking for both melatonin agonists, particularly considering the pharmacological activity of their metabolites. In view of the higher binding affinities, longest half-life and relative higher potencies of the different melatonin agonists, studies using 2 or 3mg/day of melatonin are probably unsuitable to give appropriate comparison of the effects of the natural compound. Hence, clinical trials employing melatonin doses in the range of 50-100mg/day are warranted before the relative merits of the melatonin analogs versus melatonin can be settled.

The aim of this study was to assess the impact of menopause, age, and women's symptoms and characteristics on quality of midlife.This was a cross-sectional study of 151 healthy women aged 45 to 55 years attending university-affiliated menopause clinics. To obtain the data, a questionnaire designed by the investigators and based on the Greene Climacteric Scale and the Utian Menopause-Specific Quality of Life scale was self-completed by the participants.A significant gradual increase in the total Greene Climacteric Scale score was observed from premenopausal to perimenopausal and postmenopausal women (P = 0.02), specifically in the vasomotor and sexual subscores (P0.0001 and P = 0.001, respectively). In contrast, the total quality-of-life score remained stable in every specific aspect (occupation, health, emotion, and sex) throughout the menopausal transition (P = 0.8). A significant correlation was found between the psychological, somatic, and sexual Greene Climacteric Scale subscores and the Utian quality-of-life score (r = -0.46, P0.001; r = -0.29, P0.05; r = -0.28, P0.05, respectively), whereas the vasomotor subscore had no impact on midlife quality. The number of children was the only demographic factor that had a significant impact on the Utian score (P0.05) and to a higher extent than the climacteric syndrome. Hormone therapy equalizes the climacteric symptom profile of users to that of nonusers, yet both users and nonusers reported similar scores of midlife quality.Menopause-specific quality of life may be affected by both demographic and climacteric parameters. Menopausal symptoms, but not vasomotor symptoms, have a negative impact on midlife quality, yet to a lesser degree than does the number of children.

Fil: Srinivasan, Venkataramanujan. Sri Sathya Sai Medical Educational and Research Foundation; India Fil: Brzezinski, Amnon. The Hebrew University. Haddassah Medical Center. Department of Obstetrics and Gynecology; Israel Fil: Pandi Perumal, Seithikurippu R. Somnogen Inc; Estados Unidos Fil: Spence, David Warren. Canadian Sleep Institute; Canadá Fil: Cardinali, Daniel Pedro. Pontificia Universidad Católica Argentina. Facultad de Medicina. Departamento de Docencia e Investigación; Argentina Fil: Brown, Gregory M. Centre for Addiction and Mental Health; Canadá Abstract: Current pharmacological treatment of insomnia involves the use of sedative-hypnotic benzodiazepine and non-benzodiazepine drugs. Although benzodiazepines improve sleep, their multiple adverse effects hamper their application. Adverse effects include impairment of memory and cognitive functions, nextday hangover and dependence. Non-benzodiazepines are effective for initiating sleep but are not as effective as benzodiazepines for improving sleep quality or efficiency. Furthermore, their prolonged use produces adverse effects similar to those observed with benzodiazepines. Inasmuch as insomnia may be associated with decreased nocturnal melatonin, administration of melatonin is a strategy that has been increasingly used for treating insomnia. Melatonin can be effective for improving sleep quality without the adverse effects associated with hypnotic-sedatives. Ramelteon, a synthetic analog of melatonin which has a longer half life and a stronger affinity for MT1 and MT2 melatonergic receptors, has been reportedly effective for initiating and improving sleep in both adult and elderly insomniacs without showing hangover, dependence, or cognitive impairment. Insomnia is also a major complaint among patients suffering from depressive disorders and is often aggravated by conventional antidepressants especially the specific serotonin reuptake inhibitors. The novel antidepressant agomelatine, a dual action agent with affinity for melatonin MT1 and MT2 receptors and 5-HT2c antagonistic properties, constitutes a new approach to the treatment of major depressive disorders. Agomelatine ameliorates the symptoms of depression and improves the quality and efficiency of sleep. Taken together, the evidence indicates that MT1 / MT2 receptor agonists like ramelteon or agomelatine may be valuable pharmacological tools for insomnia and for depression-associated insomnia.

A seasonal distribution in human natural conception and birth rates has been consistently demonstrated by epidemiological studies in several geographical areas. Possible hypotheses abound to explain this seasonality. Though a seasonal effect on reproduction is well-documented and has been extensively investigated in mammals, information concerning the influence of seasonal variation and its mechanism on human and primate reproduction is scarce. Recent evidence suggests that deterioration in sperm quality during the host summer in sub-equatorial areas, may result in lower conception rates leading to a reduction in the birth rate in spring. In northern countries, however, in regions where a strong seasonal contrast in luminosity exists, activity of the anterior pituitary-ovarian axis and the conception rate are decreased during the dark winter months. In these areas, inversely, a peak in conception rate during summer leading to a maximum in birth rate in spring has been observed. It is believed that seasonality in the ovulation rate may cause this variability. However, changes in the quality of the ovum or in endometrial receptivity which may lead to a greater waste of ovulated eggs and peri-implantation conceptuses at specific times of the year, have also been suggested. These phenomena might have important implications for in-vitro fertilization and gamete intra-Fallopian transfer as well as infertility in general. The seasonal effects, which may influence primate and human fertility and reproduction and its possible mediators, are critically reviewed.