The influence of endogenous estrogen on transcranial direct current stimulation: A preliminary study.

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulatory technique. Responses to tDCS differ substantially between individuals. Sex hormones that modulate cortical excitability, such as estrogen, may contribute to this inter-individual variability. The influence of estrogen on tDCS after-effects has not yet been researched. This study aimed to investigate whether endogenous estrogen levels influence cortical response to tDCS. Data from 15 male and 14 female healthy adults were analyzed. Males completed one experimental session. Females completed two, one during the early follicular phase of the menstrual cycle when estrogen was low, one during the mid-luteal phase when estrogen was high. Each session comprised 15-min of anodal tDCS delivered to the left dorsolateral prefrontal cortex (DLPFC). Response to stimulation was assessed using electroencephalography with DLPFC transcranial magnetic stimulation (TMS) administered before, immediately after, and 20-min after tDCS. Changes in amplitudes of N120 and P200 components of TMS-evoked potentials over time were compared between males, women with low estrogen and women with high estrogen. Blood assays verified estrogen levels. Women with high estrogen demonstrated a significant increase in P200 amplitude at both time points and change over time was greater for the high estrogen group compared with males. No significant differences were observed between males and women with low estrogen, or between women with low and high estrogen. These preliminary results indicate that greater neuroplastic response to DLPFC tDCS is seen in highest compared with lowest estrogen states, suggesting that endogenous estrogen levels contribute to inter-individual variability of tDCS outcomes.

Prevalence and Predictors of Low Sexual Desire, Sexually Related Personal Distress, and Hypoactive Sexual Desire Dysfunction in a Community-Based Sample of Midlife Women.

BACKGROUND: Low desire is the most common sexual problem in women at midlife. Prevalence data are limited by lack of validated instruments or exclusion of un-partnered or sexually inactive women. AIM: To document the prevalence of and factors associated with low desire, sexually related personal distress, and hypoactive sexual desire dysfunction (HSDD) using validated instruments. METHODS: Cross-sectional, nationally representative, community-based sample of 2,020 Australian women 40 to 65 years old. OUTCOMES: Low desire was defined as a score no higher than 5.0 on the desire domain of the Female Sexual Function Index (FSFI); sexually related personal distress was defined as a score of at least 11.0 on the Female Sexual Distress Scale-Revised; and HSDD was defined as a combination of these scores. The Menopause Specific Quality of Life Questionnaire was used to document menopausal vasomotor symptoms. The Beck Depression Inventory-II was used to identify moderate to severe depressive symptoms (score ≥ 20). RESULTS: The prevalence of low desire was 69.3% (95% CI = 67.3-71.3), that of sexually related personal distress was 40.5% (95% CI = 38.4-42.6), and that of HSDD was 32.2% (95% CI = 30.1-34.2). Of women who were not partnered or sexually active, 32.4% (95% CI = 24.4-40.2) reported sexually related personal distress. Factors associated with HSDD in an adjusted logistic regression model included being partnered (odds ratio [OR] = 3.30, 95% CI = 2.46-4.41), consuming alcohol (OR = 1.48, 95% CI = 1.16-1.89), vaginal dryness (OR = 2.08, 95% CI = 1.66-2.61), pain during or after intercourse (OR = 1.63, 95% CI = 1.27-2.09), moderate to severe depressive symptoms (OR = 2.69, 95% CI 1.99-3.64), and use of psychotropic medication (OR = 1.42, 95% CI = 1.10-1.83). Vasomotor symptoms were not associated with low desire, sexually related personal distress, or HSDD. CLINICAL IMPLICATIONS: Given the high prevalence, clinicians should screen midlife women for HSDD. STRENGTHS AND LIMITATIONS: Strengths include the large size and representative nature of the sample and the use of validated tools. Limitations include the requirement to complete a written questionnaire in English. Questions within the FSFI limit the applicability of FSFI total scores, but not desire domain scores, in recently sexually inactive women, women without a partner, and women who do not engage in penetrative intercourse. CONCLUSIONS: Low desire, sexually related personal distress, and HSDD are common in women at midlife, including women who are un-partnered or sexually inactive. Some factors associated with HSDD, such as psychotropic medication use and vaginal dryness, are modifiable or can be treated with safe and effective therapies. Worsley R, Bell RJ, Gartoulla P, Davis SR. Prevalence and Predictors of Low Sexual Desire, Sexually Related Personal Distress, and Hypoactive Sexual Desire Dysfunction in a Community-Based Sample of Midlife Women. J Sex Med 2017;14:675-686.

Androgens and Female Sexual Function and Dysfunction--Findings From the Fourth International Consultation of Sexual Medicine.

INTRODUCTION: Androgens have been implicated as important for female sexual function and dysfunction. AIM: To review the role of androgens in the physiology and pathophysiology of female sexual functioning and the evidence for efficacy of androgen therapy for female sexual dysfunction (FSD). METHODS: We searched the literature using online databases for studies pertaining to androgens and female sexual function. Major reviews were included and their findings were summarized to avoid replicating their content. MAIN OUTCOME MEASURES: Quality of data published in the literature and recommendations were based on the GRADES system. RESULTS: The literature supports an important role for androgens in female sexual function. There is no blood androgen level below which women can be classified as having androgen deficiency. Clinical trials have consistently demonstrated that transdermal testosterone (T) therapy improves sexual function and sexual satisfaction in women who have been assessed as having hypoactive sexual desire disorder. The use of T therapy is limited by the lack of approved formulations for women and long-term safety data. Most studies do not support the use of systemic dehydroepiandrosterone therapy for the treatment of FSD in women with normally functioning adrenals or adrenal insufficiency. Studies evaluating the efficacy and safety of vaginal testosterone and dehydroepiandrosterone for the treatment of vulvovaginal atrophy are ongoing. CONCLUSION: Available data support an important role of androgens in female sexual function and dysfunction and efficacy of transdermal T therapy for the treatment of some women with FSD. Approved T formulations for women are generally unavailable. In consequence, the prescribing of T mostly involves off-label use of T products formulated for men and individually compounded T formulations. Long-term studies to determine the safety of T therapy for women and possible benefits beyond that of sexual function are greatly needed.

Hormones and Female Sexual Dysfunction: Beyond Estrogens and Androgens--Findings from the Fourth International Consultation on Sexual Medicine.

INTRODUCTION: In recent years, multiple hormones have been investigated in relation to female sexual function. Because consumers can easily purchase products claiming to contain these hormones, a clear statement regarding the current state of knowledge is required. AIM: To review the contribution of hormones, other than estrogens and androgens, to female sexual functioning and the evidence that specific endocrinopathies in women are associated with female sexual dysfunction (FSD) and to update the previously published International Society of Sexual Medicine Consensus on this topic. METHODS: The literature was searched using several online databases with an emphasis on studies examining the physiologic role of oxytocin, prolactin, and progesterone in female sexual function and any potential therapeutic effect of these hormones. The association between common endocrine disorders, such as polycystic ovary syndrome, pituitary disorders, and obesity, and FSD also was examined. MAIN OUTCOME MEASURES: Quality of data published in the literature and recommendations were based on the Grading of Recommendations Assessment, Development and Education system. RESULTS: There is no evidence to support the use of oxytocin or progesterone for FSD. Treating hyperprolactinemia might lessen FSD. Polycystic ovary syndrome, obesity, and metabolic syndrome could be associated with FSD, but data are limited. There is a strong association between diabetes mellitus and FSD. CONCLUSION: Further research is required; in particular, high-quality, large-scale studies of women with common endocrinopathies are needed to determine the impact of these prevalent disorders on female sexual function.

Role of Estrogens and Estrogen-Like Compounds in Female Sexual Function and Dysfunction.

INTRODUCTION: Sex steroids are important in female sexual function and dysfunction. AIM: To review the role of estrogens in the physiology and pathophysiology of female sexual functioning and the evidence for efficacy of estrogen therapy for female sexual dysfunction to update the previously published International Society of Sexual Medicine Consensus on this topic. METHODS: Panel members reviewed the published literature using online databases for studies pertaining to estrogen in female sexual function and dysfunction. Attention was specifically given to clinical trials that had reported on sexual function outcomes in women treated with estrogen. MAIN OUTCOME MEASURES: Quality of data published in the literature and recommendations were based on the GRADES system. RESULTS: Observational studies that have considered relationship factors and physical or mental health have reported that these factors contribute more to sexual functioning than menopausal status or estrogen levels. Few clinical trials have investigated estrogen therapy with sexual function as a primary outcome. The available data do not support systemic estrogen therapy for the treatment of female sexual dysfunction. Topical vaginal estrogen therapy improves sexual function in postmenopausal women with vulvovaginal atrophy (VVA) and is considered first-line treatment of VVA. Oral ospemifene, a selective estrogen receptor modulator, is effective for the treatment of VVA and might have independent systemic effects on female sexual function. CONCLUSION: For sexual problems, the treatment of VVA remains the most pertinent indication for estrogen therapy. When systemic symptoms are absent, estrogen therapy ideally can be administered by a vaginal preparation alone. Systemic estrogen therapy with combined estrogen and progestin in non-hysterectomized women is indicated for women who require treatment for vasomotor and/or other systemic estrogen deficiency symptoms. The improvement in well-being achieved by relief of vasomotor and other symptoms might improve libido in some women and abrogate further intervention.

Menstrual cycle characteristics in women with persistent schizophrenia.

OBJECTIVE: Oestradiol has been implicated in the pathogenesis of schizophrenia. Women with schizophrenia often suffer with menstrual dysfunction, usually associated with low oestradiol levels, but whether menstrual dysfunction has an effect on their psychiatric symptoms is not well researched. The aim of this study is to document the menstrual characteristics of women with chronic schizophrenia with focus upon menstrual regularity, menstrual cycle length and menstrual symptoms. To determine which patient characteristics are associated with irregular menses and whether irregular menses are associated with the severity of psychotic symptoms, menstrual symptoms or depressive symptoms. METHOD: Cross-sectional analyses using baseline data of women enrolled in a clinical trial. Inclusion criteria include Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition, Text Revision diagnosis of schizophrenia, schizoaffective or schizophreniform disorder; aged between 18 and 51 years; residual symptoms of psychosis despite treatment with a stable dose of antipsychotic medication for at least 4 weeks. Menstrual cycle characteristics including regularity, cycle length and menstrual associated symptoms were documented. Symptoms of schizophrenia were measured using Positive and Negative Syndrome Scale, cognition was measured using Repeatable Battery for the Assessment of Neuropsychological Status and depression was assessed using the Montgomery-Asberg Depression Rating Scale. Blood samples were collected at baseline for hormone assays. RESULTS: Of the 139 women, 77 (55.4%) had regular menses, 57 (41%) had irregular menses and 5 (3.6%) women had missing data on their menstrual cycle. Use of atypical antipsychotics associated with hyperprolactinaemia was positively associated with irregular menses (odds ratio = 4.4, 95% confidence interval = [1.8, 10.9], p = 0.001), while age more than 30 years was negatively associated (odds ratio = 0.3, 95% confidence interval = [0.1, 0.6], p = 0.004). Women with irregular cycles had significantly lower oestradiol levels than women with regular cycles (213.2 ± 25.0 vs 299.0 ± 27.3, p = 0.03), but there was no difference in Positive and Negative Syndrome Scale, Montgomery-Asberg Depression Rating Scale or Repeatable Battery for the Assessment of Neuropsychological Status between those with regular and irregular cycles. The most common menstrual associated symptoms were decrease in mood with the menstrual cycle (64.8%), bloating (64.8%), cramps (59.7%), back pain (37.6%) and worsening of psychosis symptoms (32.4%). CONCLUSION: Regular menses are associated with higher oestradiol levels and higher rates of cyclical mood symptoms but are not associated with Positive and Negative Syndrome Scale scores. Understanding the effect the menstrual cycle can have on psychiatric illness, such as premenstrual exacerbations, is important for the holistic care of women with schizophrenia.

Use of complementary and alternative medicines for menopausal symptoms in Australian women aged 40-65 years.

OBJECTIVE: To document the prevalence of, and factors associated with, the use of complementary and alternative medicines (CAMs) for vasomotor symptoms (VMS) and other symptoms of menopause in Australian women aged 40-65 years. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional questionnaire-based study of Australian women aged 40-65 years living independently in the community. Women able to complete a questionnaire in English were recruited by telephone between October 2013 and March 2014 from a large, representative, national, continually refreshed database derived from the electoral roll. MAIN OUTCOME MEASURES: Use of CAMs for VMS and other menopausal symptoms (eg, arthralgia, depression and sleep disturbance), assessed using the Menopause-Specific Quality of Life questionnaire. RESULTS: Of 5850 women contacted, 2911 agreed to participate, and 2020 eligible women returned completed questionnaires (response rate, 34.53%). Most of the women were postmenopausal (54.90%), resided in metropolitan areas (62.70%) and were born in Australia (80.43%). The prevalence of use of CAMs for VMS was 13.22%. Phytoestrogens were most commonly used for VMS (6.29%), followed by evening primrose oil (3.91%) and ginseng (1.73%). Compared with premenopausal women, perimenopausal women (odds ratio [OR], 2.09; 95% CI, 1.42-3.06) and early postmenopausal women (OR, 1.83, 95% CI, 1.21-2.76) were more likely to use any CAM for VMS. The prevalence of use of CAMs for other symptoms was 32.23%; being postmenopausal and older were the factors associated with this use. CONCLUSIONS: Australian women at midlife are using CAMs that are known to be ineffective for managing VMS. Health care providers need to be more involved in guiding women in the treatment of VMS and other menopausal symptoms. More judicious use of supplements such as fish oil and glucosamine, particularly by older women, is needed until their efficacy and safety profiles are better understood.

Transdermal testosterone improves verbal learning and memory in postmenopausal women not on oestrogen therapy.

OBJECTIVE: The aim of this study was to examine the effects of testosterone on verbal learning and memory in postmenopausal women. DESIGN: Randomized, placebo-controlled trial in which participants were randomized (1:1) to transdermal testosterone gel 300 mcg/day, or identical placebo, for 26 weeks. PATIENTS: Ninety-two postmenopausal women aged 55-65 years, on no systemic sex hormone therapy. MEASUREMENTS: The primary outcome was the score for the International Shopping List Task (ISLT) of CogState. Secondary outcomes included other CogState domains, the Psychological General Well-Being Index (PGWB) and safety variables. RESULTS: Eighty-nine women, median age 60 years, were included in the primary analysis. Testosterone treatment resulted in statistically significantly better performance for the ISLT (improved verbal learning and memory) compared with placebo, adjusted for age and baseline score (mean difference 1·57; 95%CI 0·13, 3·01) P = 0·03). There were no significant differences for other CogState domains or the PGWB scores. At 26 weeks, the median total testosterone was 1·7 nm (interquartile range (IQR) 1·1, 2·4) in the testosterone group and 0·4 nm (IQR 0·3, 0·5) in the placebo group. CONCLUSIONS: The small but statistically significant effect of testosterone treatment on verbal learning and memory in postmenopausal women provides the basis for further clinical trials.

The use of first and second-generation antipsychotic drugs and the potential to develop gestational diabetes mellitus among perinatal patients with psychosis.

There is limited knowledge about the effects of antipsychotic exposure on the development of gestational diabetes mellitus (GDM) in women with mental illness. Studies have demonstrated an association between antipsychotic medications and metabolic problems such as weight gain and diabetes mellitus in non-pregnant patients with psychiatric disorders. GDM increases the risk of adverse maternal outcomes, including pregnancy-induced hypertension, antepartum and postpartum haemorrhage, and caesarean delivery. The National Register of Antipsychotic Medication in Pregnancy (NRAMP) is a prospective Australian cohort study that observed women who took antipsychotics during pregnancy. Data from 205 women were extracted for the final analysis and included women who took first or second-generation antipsychotics (FGA,SGA) during the first trimester of pregnancy (at minimum) and had a diagnosis of a psychotic disorder (n = 180). The comparison (non-exposed) group (n = 25) were women with psychosis who chose not to take any antipsychotic during the first trimester (at minimum). The comparison groups were not matched, although groups were homogenous in terms of sex, age range, diagnosis and perinatal status. The results of logistic regression analysis revealed that women who were exposed to FGAs, SGAs were seven and five times, respectively, more likely to develop GDM compared to non-exposed groups. When adjusted for confounding variables such as BMI and family history of diabetes, the potential of developing GDM decreased for women taking SGAs. In conclusion, the risk of developing GDM is lower in women taking SGAs compared with women taking FDAs. In addition, family history of diabetes and BMI adds to the risk.

Correction: A Prospective Cohort Study of Antipsychotic Medications in Pregnancy: The First 147 Pregnancies and 100 One Year Old Babies.

[This corrects the article DOI: 10.1371/journal.pone.0094788.].

Effects of Oral Contraceptive Androgenicity on Visuospatial and Social-Emotional Cognition: A Prospective Observational Trial.

Oral contraceptives (OCs) containing estrogen and progesterone analogues are widely used amongst reproductive-aged women, but their neurocognitive impact is poorly understood. Preliminary studies suggest that OCs improve verbal memory and that OCs with greater androgenic activity may improve visuospatial ability. We sought to explore the cognitive impact of OCs by assessing performance of OC users at different stages of the OC cycle, and comparing this performance between users of different OC formulations according to known androgenic activity. We conducted a prospective, observational trial of OC users, evaluating cognitive performance with CogState software on two occasions: days 7-10 of active hormonal pill phase, and days 3-5 of the inactive pill phase (coinciding with the withdrawal bleed resembling menstruation). Thirty-five OC users (18 taking androgenic formulations, 17 taking anti-androgenic) were assessed. Analysis by androgenic activity showed superior performance by users of androgenic OCs, as compared to anti-androgenic OCs, in visuospatial ability and facial affect discrimination tasks. A growing understanding of cognitive effects of OC progestin androgenicity may have implications in choice of OC formulation for individuals and in future OC development.

The influence of endogenous estrogen on high-frequency prefrontal transcranial magnetic stimulation.

BACKGROUND: The use of repetitive transcranial magnetic stimulation (rTMS) as both therapeutic and experimental tools has grown enormously over the past decade. However, variability in response to rTMS is one challenge that remains to be solved. Estrogen can impact neural plasticity and may also affect plastic changes following rTMS. The present study investigated whether estrogen levels influence the neurophysiological effects of high-frequency (HF) rTMS in the left dorsolateral prefrontal cortex (DLPFC). HYPOTHESIS: It was hypothesised that individuals with higher endogenous estrogen would demonstrate greater rTMS-induced changes in cortical reactivity. METHODS: 29 healthy adults (15M/14F) received HF-rTMS over left DLPFC. Females attended two sessions, one during a high-estrogen (HE) phase of the menstrual cycle, another during a low-estrogen (LE) phase. Males attended one session. Estrogen level was verified via blood assay. TMS-EEG was used to probe changes in cortical plasticity and comparisons were made using cluster-based permutation statistics and Bayesian analysis. RESULTS: In females, a significant increase in TMS-evoked P60 amplitude, and decrease in N45, N100 and P180 amplitudes was observed during HE. A less pervasive pattern of change was observed during LE. No significant changes in TEPs were seen in males. Between-condition comparisons revealed higher likelihood of the change in N100 and/or P180 being larger in females during HE compared to both females during LE and males. CONCLUSIONS: These preliminary findings indicate that a greater neuroplastic response to prefrontal HF-rTMS is seen in women when estrogen is at its highest compared to men, suggesting that endogenous estrogen levels contribute to variability in response to HF-rTMS.

Moderate to severe vasomotor and sexual symptoms remain problematic for women aged 60 to 65 years.

OBJECTIVE: This study aims to determine the prevalence and severity of menopausal symptoms in older postmenopausal women and, hence, the need for treatment options for women of this age. METHODS: This is a cross-sectional questionnaire-based study conducted between October 2013 and March 2014 among 2,020 women aged 40 to 65 years and living independently across Australia. The main outcome measures were the prevalence of moderate to severe vasomotor symptoms (VMS), as measured by the Menopause-Specific Quality of Life Questionnaire, and the current use of prescription therapy for menopausal symptoms. RESULTS: The prevalence of moderate to severe VMS was as follows: 2.8% in premenopausal women, 17.1% in perimenopausal women, 28.5% in postmenopausal women younger than 55 years, 15.1% in postmenopausal women aged 55 to 59 years, and 6.5% in postmenopausal women aged 60 to 65 years. Prescription therapy for menopausal symptoms was used by 135 women: 120 (5.9%) women using hormone therapy and 15 (0.7%) women using nonhormonal medication. The factors positively associated with moderate to severe VMS were smoking (odds ratio, 1.6; 95% CI, 1.1-2.3; P < 0.05) and a body mass index of 25 to 29.9 kg/m (odds ratio, 1.7; 95% CI, 1.1-2.5; P < 0.05); education beyond high school was inversely associated (odds ratio, 0.7; 95% CI, 0.5-0.9; P < 0.05). CONCLUSIONS: In this large, representative, community-based sample of women, there is a high prevalence of untreated moderate to severe VMS even in women aged 60 to 65 years. The use of vaginal estrogen and nonhormonal prescription therapy with proven efficacy for treatment of menopausal symptoms is strikingly low, suggesting that menopause remains an undertreated condition.

Development and validation of a new rating scale for perimenopausal depression-the Meno-D.

The menopause transition is a time when women experience an increased risk for new onset depression, as well as relapse of depression. While there are overlapping symptoms between major depression and depression during menopause, differences suggest 'perimenopausal depression' may be a unique subtype of depression associated with characteristic symptoms. There is currently no validated scale designed to measure perimenopausal depression. The aim of the current study was to develop and validate the 'Meno-D', a self-reporting or clinician rated questionnaire, designed to rate the severity of symptoms of perimenopausal depression. The development phase of the Meno-D involved literature review, clinical observation, and focus groups. A 12-item questionnaire was developed and clinically reviewed for face validity for content. The Meno-D was administered to women experiencing symptoms of perimenopausal depression as part of a larger baseline assessment battery. Validation involved confirmatory factor analysis (CFA). The development of the Meno-D resulted in 12 items. A total of 93 participants with perimenopausal depression were involved in the baseline assessments, 82 completed the Meno-D. Factor analysis identified five sub-scales of the Meno-D "somatic; cognitive; self; sleep; sexual" with high-internal consistency; discriminant validity and a good construct and convergent validity. The Meno-D provides a unique tool for clinicians and researchers to measure the presence of perimenopausal depression.