Suicidality in women with Premenstrual Dysphoric Disorder: a systematic literature review.

Previous research has identified how menstruation is an important factor in both attempted and completed suicides for women. The purpose of this review was to outline (a) the risk profile for suicidality in women who were identified to experience Premenstrual Dysphoric Disorder (PMDD), a condition characterized by severe physical and psychological changes that occur during the luteal menstrual phase, and (b) the implications of these findings for clinical practice. A systematic literature review was conducted using five databases to identify any peer-reviewed articles published between 1989 and 2019. Ten papers eligible for inclusion were identified: three pertaining to suicide cognitions, five to suicide attempts and two to both cognitions and attempts. Findings showed that suicidal thoughts, ideation, plans and attempts were strongly associated with experiences of PMDD and that these findings were independent of psychiatric co-morbidities. However, women with PMDD did not present with more severe risk profiles for suicide attempts (in terms of frequency, impulsivity and lethality) or make more frequent attempts during the luteal menstrual phase compared with suicide attempters without PMDD. Women with PMDD should be considered a high risk group for suicidality; thus, identifying and treating symptoms are vital in reducing suicide attempts. Implications for clinical practice are outlined in the discussion.

Women's experiences of receiving a diagnosis of premenstrual dysphoric disorder: a qualitative investigation.

BACKGROUND: Premenstrual dysphoric disorder (PMDD) is a complex and disabling condition that affects women of reproductive age, characterised by severe physical and psychological symptoms that occur cyclically and remit following the onset of menses. As the psychological nature and consequences of PMDD often seem indistinguishable from symptoms of other mental health difficulties, this condition presents distinct diagnostic challenges for healthcare professionals. Therefore, this study aimed to explore women's experiences of both having PMDD and of receiving this diagnosis. METHODS: Participant recruitment took place in the United Kingdom during 2018. Seventeen women who had been diagnosed with PMDD by a medical specialist and met the clinical criteria for PMDD on the premenstrual symptoms screening tool were interviewed. The data from these semi-structured interviews were audio-recorded, transcribed and inductively analysed using reflexive thematic analysis. RESULTS: Twelve subthemes were identified and organised around four main themes: (1) A broken woman, (2) Misdiagnosis and the lost decades, (3) A life transformed and (4) Negotiating the aftermath. CONCLUSIONS: The findings of this study highlight the critical importance of the accurate and timely detection of PMDD, with the aim of preventing women from experiencing severe and prolonged psychological distress. In order to achieve this, there needs to be a greater understanding and awareness of PMDD within both the medical and lay communities, alongside training for healthcare practitioners in PMDD assessment.

Potential strategies to avoid progestogen-induced premenstrual disorders.

Non-hormonal approaches to premenstrual syndrome (PMS) treatment such as selective serotonin reuptake inhibitors are by no means effective for all women and frequently we must resort to endocrine therapy. During many of the hormonal approaches, PMS-like symptoms can be introduced or re-introduced during the necessary cyclical or continuous progestogen component of the therapy. This is seen with combined oral contraception, progestogen only contraception, progestogen therapy for heavy menstrual bleeding and endometriosis, sequential hormone replacement therapy and any therapeutic strategy for premenstrual syndrome where it is necessary to provide endometrial protection, including estrogen suppression of ovulation or add-back during gonadotrophin releasing hormone suppression. The link to progestogen is very often missed by health professionals. When the pattern of symptoms mimics the cyclicity of PMS, it is termed progestogen-induced premenstrual disorder. The need to use progestogen to protect the endometrium from the proliferative actions of estrogen can pose insurmountable difficulties in managing premenstrual disorders. In the absence of any really useful evidence, nearly all practice in this area depends on clinician experience. We cannot afford to wait for adequate research evidence to be produced - it never will - and so we must rely on empirical findings, clinical experience, theoretical strategies and common sense.

Premenstrual syndrome (PMS): a peri-menopausal perspective.

PMS (premenstrual syndrome) affects 30-40% of the reproductive female population and hence creates significant impairment amongst women of working age [1]. Having such an economical and financial impact makes it an important disorder to know more about in terms of diagnosis and treatment. In this article, as well as addressing diagnosis and treatments, we focus mainly on peri-menopausal women who are equally (if not more) affected by this disorder and who are subjected to PMS via a host of widely used hormonal treatments. We describe the vicious cycle that exists between exogenous progestogen stimulating PMS-like symptoms and the progestogen that is required for endometrial protection and ways of avoiding this. The treatment should address all concerns of the individual, namely contraceptive requirements, control of PMS and menopausal symptoms. The main theory behind treatment of PMS is to suppress ovulation along the hypothalamo-pituitary-ovarian axis, however neurotransmitters are also implicated in reducing sensitivity to progesterone via receptors, and therefore selective serotonin reuptake inhibitors are also useful. Surgical methods are strongly discouraged and are a last resort. With so many pitfalls, this article aims to tackle the issues commonly encountered with diagnosis and treatment of PMS in the peri-menopause.

Collagen and calcium-binding EGF domains 1 is frequently inactivated in ovarian cancer by aberrant promoter hypermethylation and modulates cell migration and survival.

BACKGROUND: Collagen and calcium-binding EGF domains 1 (CCBE1) is an uncharacterised gene that has down-regulated expression in breast cancer. As CCBE1 maps to 18q21.32, a region frequently exhibiting loss of heterozygosity in ovarian cancer, the aim of this study was to determine the expression and function of CCBE1 in ovarian cancer. METHODS: Expression and methylation patterns of CCBE1 were determined in ovarian cancer cell lines and primary tumours. CCBE1 contains collagen repeats and an aspartic acid/asparagine hydroxylation/EGF-like domain, suggesting a function in extracellular matrix remodelling and migration, which was determined using small-interfering RNA (siRNA)-mediated knockdown and over-expression of CCBE1 in cell lines. RESULTS: CCBE1 is expressed in normal ovary, but is reduced in ovarian cancer cell lines and primary carcinomas. Pharmacological demethylation/deacetylation in ovarian cancer cell lines re-induced CCBE1 expression, indicating that epigenetic mechanisms contribute to its silencing in cancer. CCBE1 promoter hypermethylation was detected in 6/11 (55%) ovarian cancer cell lines and 38/81 (41%) ovarian carcinomas. siRNA-mediated knockdown of CCBE1 in ovarian cancer cell lines enhanced their migration; conversely, re-expression of CCBE1 reduced migration and survival. Hence, loss of CCBE1 expression may promote ovarian carcinogenesis by enhancing migration and cell survival. CONCLUSIONS: These data suggest that CCBE1 is a new candidate tumour suppressor in ovarian cancer.

Premenstrual syndrome.

Most women of reproductive age have some physical discomfort or dysphoria in the weeks before menstruation. Symptoms are often mild, but can be severe enough to substantially affect daily activities. About 5-8% of women thus suffer from severe premenstrual syndrome (PMS); most of these women also meet criteria for premenstrual dysphoric disorder (PMDD). Mood and behavioural symptoms, including irritability, tension, depressed mood, tearfulness, and mood swings, are the most distressing, but somatic complaints, such as breast tenderness and bloating, can also be problematic. We outline theories for the underlying causes of severe PMS, and describe two main methods of treating it: one targeting the hypothalamus-pituitary-ovary axis, and the other targeting brain serotonergic synapses. Fluctuations in gonadal hormone levels trigger the symptoms, and thus interventions that abolish ovarian cyclicity, including long-acting analogues of gonadotropin-releasing hormone (GnRH) or oestradiol (administered as patches or implants), effectively reduce the symptoms, as can some oral contraceptives. The effectiveness of serotonin reuptake inhibitors, taken throughout the cycle or during luteal phases only, is also well established.

The E3 ubiquitin ligase EDD is an adverse prognostic factor for serous epithelial ovarian cancer and modulates cisplatin resistance in vitro.

Despite a high initial response rate to first-line platinum/paclitaxel chemotherapy, most women with epithelial ovarian cancer relapse with recurrent disease that becomes refractory to further cytotoxic treatment. We have previously shown that the E3 ubiquitin ligase, EDD, a regulator of DNA damage responses, is amplified and overexpressed in serous ovarian carcinoma. Given that DNA damage pathways are linked to platinum resistance, the aim of this study was to determine if EDD expression was associated with disease recurrence and platinum sensitivity in serous ovarian cancer. High nuclear EDD expression, as determined by immunohistochemistry in a cohort of 151 women with serous ovarian carcinoma, was associated with an approximately two-fold increased risk of disease recurrence and death in patients who initially responded to first-line chemotherapy, independently of disease stage and suboptimal debulking. Although EDD expression was not directly correlated with relative cisplatin sensitivity of ovarian cancer cell lines, sensitivity to cisplatin was partially restored in platinum-resistant A2780-cp70 ovarian cancer cells following siRNA-mediated knockdown of EDD expression. These results identify EDD as a new independent prognostic marker for outcome in serous ovarian cancer, and suggest that pathways involving EDD, including DNA damage responses, may represent new therapeutic targets for chemoresistant ovarian cancer.

Serotonin receptor 1A C(-1019)G polymorphism associated with premenstrual dysphoric disorder.

OBJECTIVE: To assess whether the G allele of the serotonin receptor 1A C(-1019)G polymorphism is associated with premenstrual dysphoric disorder. METHODS: The study sample comprised 53 women with clinically diagnosed premenstrual dysphoric disorder (age range 27-46 years, mean 37.7 years) and 51 healthy control subjects (age range 22-48 years, mean 36.2 years). The serotonin receptor 1A C(-1019)G polymorphism was genotyped and compared between the two groups. RESULTS: In contrast to the postulated "high-risk" G/G genotype, there was a marked overrepresentation of the C/C genotype in the premenstrual dysphoric disorder group (P=.034; odds ratio 3.63, 95% confidence interval 1.22-10.78). The presence of at least one C allele was associated with a 2.5-fold increased risk of premenstrual dysphoric disorder (P=.053; odds ratio 2.46, 95% confidence interval 1.03-5.88). CONCLUSION: Our hypothesis that the high-risk G allele is associated with the occurrence of premenstrual dysphoria was not proved in this study. However, due to the increased prevalence of the C variant, we suggest that the C(-1019) allele may contribute to the risk of premenstrual dysphoria. LEVEL OF EVIDENCE: II.

Are there differential symptom profiles that improve in response to different pharmacological treatments of premenstrual syndrome/premenstrual dysphoric disorder?

Current evidence suggests that the accepted treatments for premenstrual syndrome (PMS)/premenstrual dysphoric disorder (PMDD) have similar overall efficacy. While these treatments are more effective than placebo, response rates associated with them are far from satisfactory (<60%), such that, irrespective of treatment modality, there remain a significant number of women who are unresponsive to current conventional pharmacological therapy. The available data on response rates of specific types of premenstrual symptoms to, or symptom profiles that are most amenable to, each treatment modality are limited and not well defined because most studies were not designed to assess specific symptom profiles. Those studies that have attempted to evaluate which symptom profiles respond to specific therapies have revealed variations within the individual modalities, as well as between the different modalities. It appears that suppression of ovulation ameliorates a broad range of behavioural as well as physical premenstrual symptoms. SSRIs are most effective for irritability and anxiety symptoms, with lesser efficacy for 'atypical' premenstrual symptoms. GABAergic compounds are most efficacious for anxiety and anxious/depressive symptoms, while dopamine agonists, particularly bromocriptine, are perhaps most efficacious for mastalgia. Overall treatment response rates may improve if treatments are targeted at well-defined subgroups of patients. Re-analysis of available datasets from randomised clinical trials may shed more light on the notion that targeting women with specific premenstrual symptom profiles for specific treatment modalities would improve response rates beyond the current ceiling of approximately 60%. Such information would also improve understanding of the putative pathophysiological mechanisms underlying PMS and PMDD, and may point to a more specific diagnosis of these conditions.

Repair techniques for obstetric anal sphincter injuries: a randomized controlled trial.

OBJECTIVE: To compare one-year outcomes of primary overlap versus end-to-end repair of the external anal sphincter after acute obstetric anal sphincter injury. METHODS: Women who sustained third-degree (3b = greater than 50% external anal sphincter thickness, 3c = internal sphincter injury) or fourth-degree (including anorectal epithelium) perineal tears were randomly allocated to either immediate primary overlap or end-to-end repair. They were prospectively followed up for 12 months postrepair with serial questionnaires. The primary outcome was fecal incontinence at 12 months. Secondary outcomes were fecal urgency, flatus incontinence, perineal pain, dyspareunia, quality of life, and improvement of anal incontinence symptoms. RESULTS: Thirty-two women were randomized to each group. At 12 months, 24% (6/25) in the end-to-end and none in the overlap group reported fecal incontinence (P = .009, relative risk [RR] 0.07, 95% confidence interval [CI] 0.00-1.21, number needed to treat 4.2). Fecal urgency at 12 months was reported by 32% (8/25) in the end-to-end and 3.7% (1/27) in the overlap group (P = .02, RR 0.12, 95% CI 0.02-0.86, number needed to treat 3.6). There were no significant differences in dyspareunia and quality of life between the groups. At 12 months, 20% (5/25) reported perineal pain in the end-to-end and none in the overlap group (P = .04, RR 0.08, 95% CI 0.00-1.45, number needed to treat 5). During 12 months, 16% (4/25) in the end-to-end and none in the overlap group reported deterioration of defecatory symptoms (P = .01). CONCLUSION: Primary overlap repair of the external anal sphincter is associated with a significantly lower incidence of fecal incontinence, urgency, and perineal pain. When symptoms do develop, they appear to remain unchanged or deteriorate in the end-to-end group but improve in the overlap group. LEVEL OF EVIDENCE: I.

A distinct molecular profile associated with mucinous epithelial ovarian cancer.

Mucinous epithelial ovarian cancers (MOC) are clinically and morphologically distinct from the other histological subtypes of ovarian cancer. To determine the genetic basis of MOC and to identify potential tumour markers, gene expression profiling of 49 primary ovarian cancers of different histological subtypes was performed using a customised oligonucleotide microarray containing >59 000 probesets. The results show that MOC express a genetic profile that both differs and overlaps with other subtypes of epithelial ovarian cancer. Concordant with its histological phenotype, MOC express genes characteristic of mucinous carcinomas of varying epithelial origin, including intestinal carcinomas. Differences in gene expression between MOC and other histological subtypes of ovarian cancer were confirmed by RT-PCR and/or immunohistochemistry. In particular, galectin 4 (LGALS4) was highly and specifically expressed in MOC, but expressed at lower levels in benign mucinous cysts and borderline (atypical proliferative) tumours, supporting a malignant progression model of MOC. Hence LGALS4 may have application as an early and differential diagnostic marker of MOC.

The effectiveness of GnRHa with and without 'add-back' therapy in treating premenstrual syndrome: a meta analysis.

OBJECTIVE: To determine the effectiveness of gonadotrophin-releasing hormone analogues (GnRHa) with and without hormonal add-back therapy in the management of premenstrual syndrome. DESIGN: Randomised controlled trials were identified by searching multiple databases. SETTING: Exeter and North Devon Research and Development Support Unit and Keele University Academic Unit of Obstetrics and Gynaecology. POPULATION: Women with pre-diagnosed premenstrual syndrome and/or premenstrual dysphoric disorder. METHODS: A meta-analysis of published randomised placebo-controlled trials assessing the use of GnRHa in the management of premenstrual syndrome. The standardised mean difference for each individual study and subsequently an overall standardised mean difference were calculated after demonstrating the consistency or homogeneity of the study results. MAIN OUTCOME MEASURES: Overall improvement in premenstrual symptomatology and effectiveness of GnRHa with additional hormonal add-back therapy were the main outcome measures assessed in this analysis. A secondary analysis was performed to assess the effectiveness of GnRHa in treating physical and emotional symptoms. RESULTS: Overall standardised mean difference for all trials that assessed the efficacy of GnRHa was -1.19 (95% confidence interval [CI] -1.88 to -0.51). The equivalent odds ratio was 8.66 (95% CI 2.52 to 30.26) in favour of GnRHa. GnRHa were more efficacious for physical than behavioural symptoms, although the difference was not statistically significant. The addition of hormonal add-back therapy to GnRHa did not appear to reduce the efficacy of GnRHa alone; standardised mean difference 0.12 (95% CI -0.35 to 0.58). CONCLUSIONS: GnRHa appear to be an effective treatment in the management of premenstrual syndrome. The addition of hormonal add-back therapy to reduce side effects does not reduce efficacy.

Sequence variants of bovine papillomavirus E5 detected in equine sarcoids.

The equine sarcoid, one of the most common dermatological lesions in equids, is a benign, locally invasive dermal fibroblastic lesion. Previous studies have suggested an association with two bovine papilloma virus (BPV) types, BPV-1 and BPV-2. In the present study, we examined sarcoids from horses from two geographical areas, Switzerland and the UK, for the major transforming gene of BPV, E5. We detected BPV DNA for the E5 open reading frame and viral E5 RNA transcripts in most sarcoids. Sequence analysis of the E5 open reading frame of sarcoid-associated BPV detected several unique DNA sequence variants, three of which resulted in sarcoid specific amino acid sequence variations. It is unclear if these sequence variants contribute to the unique clinical presentation of the sarcoid. However, our work provides further evidence of the association between BPV and sarcoid development and the direct involvement of the virus in the pathogenesis of sarcoids.

Association of bovine papillomavirus with the equine sarcoid.

The equine sarcoid, a locally aggressive, fibroblastic skin tumour, is the most common dermatological neoplasm reported in horses; there is no consistently effective therapy. It is widely accepted that bovine papillomavirus (BPV) types 1 and 2 are associated with the pathogenesis of sarcoid disease. Most sarcoids appear to contain detectable viral DNA and RNA and are also known to express the BPV types 1 and 2 major transforming protein, E5, but appear not to produce infectious virions. While the mode of transmission of infection has not been elucidated, viral gene expression, in particular of E5, may contribute to virus persistence and disease pathogenesis by downregulating MHC class I expression. Here, the pathology and epidemiology of the sarcoid and its association with BPV is reviewed; the transforming functions of the BPV oncoproteins and their possible role in sarcoid pathogenesis are discussed; and the practical implications of BPV infection for diagnostic and therapeutic purposes are considered.

Menstrual symptometrics: a simple computer-aided method to quantify menstrual cycle disorders.

OBJECTIVE: To validate a menstrual symptometrics device that can quantify menstrual blood loss, dysmenorrhea, and the premenstrual syndrome against traditional methods of collecting data on symptoms. DESIGN: Validation study. SETTING: Academic research clinic for menstrual cycle disorders. PARTICIPANT(S): Women 18-50 years of age who presented with menstrual cycle disorders. Controls were recruited from lists of patients requesting sterilization and from hospital staff. INTERVENTION(S): Participants were asked to complete the menstrual symptometrics device and to record pain, blood loss, and premenstrual symptoms by using traditional methods (paper-based scales and the alkaline hematin method) for two cycles. MAIN OUTCOME MEASURE(S): Agreement between traditional methods of quantifying menstrual cycle disorders and data obtained from the menstrual symptometrics device, and acceptability of the latter technique to patients. RESULT(S): A high level of agreement was observed between the traditional methods and the menstrual symptometrics device in quantifying and diagnosing menorrhagia, dysmenorrhea, and the premenstrual syndrome. Most patients preferred the menstrual symptometrics device as a data collection tool. CONCLUSION(S): The menstrual symptometrics device is a rapid and accurate method of quantifying blood loss, pain, and premenstrual symptoms. It has a high level of patient acceptability and can provide instant pictorial feedback on symptoms for patients and clinicians.

Selective serotonin reuptake inhibitors for premenstrual syndrome.

BACKGROUND: Severe premenstrual syndrome affects between 3-5% of women of reproductive age. Such severe PMS is classified under the Diagnostic and Statistical Manual of Mental Disorders as premenstrual dysphoric disorder, PMDD. Selective serotonin reuptake inhibitors (SSRIs) are increasingly being used as a front-line therapy for premenstrual syndrome (PMS). A systematic review was undertaken on the efficacy of SSRIs in the management of severe PMS/PMDD, to assess the evidence for this treatment option. OBJECTIVES: The objective of this review was to evaluate the effectiveness of SSRIs in reducing premenstrual syndrome symptoms in women diagnosed with severe premenstrual syndrome. SEARCH STRATEGY: Electronic searches for relevant randomised controlled trials of the Cochrane Menstrual Disorders and Subfertility Group specialised register of controlled trials, Cochrane Controlled Trials Register, MEDLINE, EMBASE and PsychLit were undertaken. References were searched interactively to identify missed trials. Where insufficient data were presented original authors were contacted for further details. SELECTION CRITERIA: All trials were considered in which women with a prospective diagnosis of PMS/ PMDD were randomised to receive SSRIs or placebo in a double blind trial for the treatment of premenstrual syndrome. DATA COLLECTION AND ANALYSIS: 31 randomised controlled trials were identified which reported the use of SSRIs in the management of PMS. 16 trials were excluded, 15 trials were included in the systematic review, and ten trials were included in the main analyses. The reviewers extracted the data independently and standardised mean differences for continuous outcomes were estimated from the data. MAIN RESULTS: The primary analysis of reduction in overall symptomatology included data on 844 women with premenstrual syndrome. SSRIs were found to be highly effective in treating premenstrual symptoms. Secondary analysis showed that they were as effective in treating physical as well as behavioural symptoms. There was no significant difference between trials funded by pharmaceutical companies and those independently funded. Withdrawals due to side effects were 2.5 times more likely to occur in the treatment group, particularly at higher doses. REVIEWER'S CONCLUSIONS: There is now very good evidence to support the use of selective serotonin reuptake inhibitors in the management of severe premenstrual syndrome.

Emergency medicine and public health: new steps in old directions.

Emergency medicine and public health have opportunities to interact in at least 4 areas: surveillance of diseases, injuries, and health risks; monitoring health care access; delivering clinical preventive services; and developing policies to protect and improve the public's health. Recent, cross-cutting initiatives and innovations in these 4 areas follow pathways first explored more than a generation ago and provide an important impetus for future work. An analysis of recent contributions also points to various obstacles and challenges that must be addressed to take full advantage of existing and rapidly developing ties between emergency medicine and public health. The connections between these 2 fields will continue to create important partnership opportunities and the strong possibility of achieving new benefits for patients, the public, and the professionals who serve them.

Determination of total menstrual blood loss.

OBJECTIVE: To develop and validate a simple method of measuring total menstrual blood loss using a pictorial representation of blood loss, the menstrual pictogram. DESIGN: A prospective evaluation of total menstrual blood loss measurement by the menstrual pictogram compared to the alkaline hematin technique. SETTING: Academic menorrhagia research clinic. PATIENT(S): One hundred twenty-one women; 62 women complaining of heavy menstrual blood loss, 59 women who considered their menstrual blood loss to be normal. INTERVENTION(S): Participants were asked to complete the menstrual pictogram through the period and collect their feminine hygiene products for an alkaline hematin assessment. MAIN OUTCOME MEASURE(S): Percentage agreement between blood loss measured by the gold standard alkaline hematin method and the menstrual pictogram. Extraneous blood loss was measured using a semiquantitative pictorial method. RESULT(S): The menstrual pictogram had a high level of agreement for blood collected on feminine hygiene products compared with the alkaline hematin method. Some women also lose a significantly large amount of extraneous blood, which is not proportional to the alkaline hematin blood loss assessment. CONCLUSION(S): The menstrual pictogram provides a simple means of measuring menstrual blood loss. It is no longer appropriate to ignore extraneous blood loss, particularly as there is no correlation between extraneous blood loss and that measured on feminine hygiene products.

Matrix metalloproteinase inhibition attenuates left ventricular remodeling and dysfunction in a rat model of progressive heart failure.

BACKGROUND: Matrix metalloproteinase (MMP) activation contributes to tissue remodeling in several disease states, and increased MMP activity has been observed in left ventricular (LV) failure. The present study tested the hypothesis that MMP inhibition would influence LV remodeling and function in developing LV failure. METHODS AND RESULTS: LV size and function were measured in 5 groups of rats: (1) obese male spontaneously hypertensive heart failure rats (SHHF) at 9 months (n=10), (2) SHHF at 13 months (n=12), (3) SHHF rats treated with an MMP inhibitor during months 9 to 13 (PD166793 5 mg. kg(-1). d(-1) PO; n=14), (4) normotensive Wistar-Furth rats (WF) at 9 months (n=12), and (5) WF at 13 months (n=12). Plasma concentrations of the MMP inhibitor (116+/-11 micromol/L) reduced in vitro LV myocardial MMP-2 activity by approximately 100%. LV function and geometry were similar in WF rats at 9 and 13 months. LV peak +dP/dt was unchanged at 9 months in SHHF but by 13 months was reduced in the SHHF group compared with WF (3578+/-477 versus 5983+/-109 mm Hg/s, P