Vitex agnus castus effects on hyperprolactinaemia.

Background: Vitex agnus castus (VAC), also known as chaste tree, is a plant from the Mediterranean area, Crimea, and central Asia. Its fruit has been used for more than 2500 years as phytotherapic agent. In the last century, VAC has been mostly used for the treatment of premenstrual syndrome (PMS), menstrual irregularities, fertility disorders, and symptoms of menopause. Since some degree of hyperprolactinaemia may be observed in patients with such disorders, VAC effects on hyperprolactinaemia have been assessed in a small number of studies and in some patient series or single case reports. It has been postulated that the diterpenes contained in VAC extract may interact with dopamine D2 receptors (D2R) and inhibit prolactin release via dopamine D2R activation in the anterior pituitary. Most of the published papers focus on the use of VAC for the management of PMS or infertility. However, due to its action on D2R, VAC could have a role in the treatment of mild hyperprolactinaemia, including patients with idiopathic hyperprolactinaemia, microprolactinoma, drug-induced hyperprolactinaemia, or polycystic ovary syndrome. Methods: We have reviewed and analysed the data from the literature concerning the use of VAC extracts in patients with hyperprolactinaemia. Results: Some evidence suggests a possible role of VAC for the management of hyperprolactinaemia in selected patients, though in an inhomogeneous way. However, there are not any large randomized controlled trials supporting the same and the precise pharmacological aspects of VAC extract in such a clinical setting still remain obscure. Conclusion: It appears that VAC may represent a potentially useful and safe phytotherapic option for the management of selected patients with mild hyperprolactinaemia who wish to be treated with phytotherapy. However, larger studies of high quality are needed to corroborate it.

The inconvenience due to women's monthly bleeding (ISY) survey: a study of premenstrual symptoms among 5728 women in Europe.

OBJECTIVES: The aim of the ISY study was to investigate the prevalence of menstrual-related symptoms prior to and/or during menstrual or withdrawal bleeding among women from 12 European countries. METHODS: A 15-min quantitative online survey was conducted in two waves from February to September 2015 among 5728 women aged between 18 and 45 years, with an equal distribution of women using a combined hormonal contraceptive, including regular combined oral contraceptives (COCs) (CHC group, n = 2739) and women using a non-hormonal contraceptive or no contraceptive (non-HC group, n = 2989). RESULTS: The prevalence of at least one menstrual-related symptom was high in CHC users (93%) and in non-HC users (95%) (p < .0001) and the average number of symptoms reported was 5.3 vs. 5.9, respectively, (p < .0001). Pelvic pain, bloating/swelling, irritability and mood swing were reported in more than half of the women in both groups. Although generally modest, symptom severity was higher in non-HC users, except for headache. Overall, during the last four cycles, 60-75% of women did not require a treatment for most symptoms but headaches and pelvic pain. Mood swings/irritability, water retention/weight gain, lack of energy/mood swings and lack of energy/irritability were common symptoms that frequently co-occurred. No associations were reported between symptoms and age, educational qualifications or women's desire to reduce the frequency of menstruation. CONCLUSIONS: Premenstrual and menstrual symptomatology was less frequent, less numerous and less severe (except for headache) in women using CHCs; however, it remains a common concern. Reducing the frequency of menstrual periods could reduce withdrawal-related symptoms.

The Influence of Cyclic Hormonal Contraception on Expression of Premenstrual Syndrome.

BACKGROUND: Some women who use cyclic hormonal contraception (CHC) suffer from premenstrual symptoms; whether their symptoms differ from women who do not use CHC is not clear. OBJECTIVE: To compare women who use or do not use CHC on perimenstrual symptom timing and change severity. STUDY DESIGN: We analyzed daily symptom ratings from women who requested participation in (Screened Cohort: 103 used CHC and 387 did not) or were randomized in (Randomized Cohort: 41 used CHC and 211 did not) a clinical trial for premenstrual syndrome. We used effect sizes to compute and compare change scores between cycle phases in four partially overlapping perimenstrual windows defined relative to day 1 of menses [(-6, -1), (-5, 1), (-4, 2), (-3, 3)]. Differences in magnitude of change and timing were estimated using linear mixed-effects models. RESULTS: Both cohorts showed a significant two-way interaction between CHC use and symptom change scores (p < 0.01) and a significant main effect of perimenstrual window (p < 0.0001). Overall menstrual cycle symptom change was greater for the nonhormonal contraception versus hormonal contraception group. In the Screened Cohort, change scores were greater in the nonhormonal group specifically for depression (p = 0.04); anger or irritability (p < 0.01); and physical symptoms (p < 0.01). Mean change scores increased as the window shifted forward toward menses for both cohorts with the largest effect size and greatest group difference for (-4, 2) interval. CONCLUSIONS: CHC slightly attenuates menstrual cycle symptom change. The (-4, 2) perimenstrual interval shows the largest change compared with postmenses.

Effect on quality of life of switching to combined oral contraception based on natural estrogen: an observational, multicentre, prospective phase IV study (ZOCAL Study).

OBJECTIVES: This observational, multicentre, prospective phase IV study examined change in health-related quality of life (QOL) from baseline to 6 months in women initiating combined oral contraception (COC) based on natural estrogen. METHODS: Eligible women attending a baseline and 6-month gynaecology appointment belonged to one of three groups: group 1 used barrier contraception (condoms) and elected to continue this method; group 2 used condoms and elected to switch to COC based on natural estrogen; group 3 used COC based on ethinylestradiol and elected to switch to COC based on natural estrogen. The Spanish Society of Contraception (SEC)-QOL scale assessed health-related QOL. Secondary outcomes included symptoms of premenstrual syndrome, intermenstrual bleeding, duration and intensity of menstrual bleeding, contraception continuation rate, and tolerability. RESULTS: A total of 857 women were enrolled and 785 completed the study. Group 2 (n = 224 completed) had significantly lower SEC-QOL global and dimension scores at baseline and significantly greater increases in SEC-QOL from baseline to 6 months compared with groups 1 (n = 72) and 3 (n = 489). Group 3 reported a similar SEC-QOL score to that of group 1 at baseline but showed significantly greater improvement in SEC-QOL global and psychological scores from baseline to 6 months. Among women receiving COC based on natural estrogen, the contraception continuation rate was 713/780 (91.4%); treatment-related adverse events were reported by 13/780 (1.7%). CONCLUSIONS: Improved SEC-QOL after 6 months was found in women who were dissatisfied with their current contraception at baseline and chose to switch to COC based on natural estrogen.

Frovatriptan vs. other triptans for the acute treatment of oral contraceptive-induced menstrual migraine: pooled analysis of three double-blind, randomized, crossover, multicenter studies.

Oral contraceptive-induced menstrual migraine (OCMM) is a particularly severe form of migraine triggered by the cyclic hormone withdrawal. To review the efficacy of frovatriptan vs. other triptans, in the acute treatment of OCMM through a pooled analysis of three individual randomized Italian studies. With or without aura migraineurs were randomized to frovatriptan 2.5 mg or rizatriptan 10 mg (study 1), frovatriptan 2.5 mg or zolmitriptan 2.5 mg (study 2), frovatriptan 2.5 mg or almotriptan 12.5 mg (study 3). All studies had a multicenter, randomized, double-blind, crossover design. After treating 1-3 episodes of migraine in 3 months with the first treatment, patients switched to the other treatment for the next 3 months. In this analysis, the subset of 35 of the 280 women of the intention-to-treat population taking combined oral contraceptives and experiencing a migraine attack during the withdrawal phase, were analyzed. The proportion of pain free and pain relief at 2 h were 25 and 51 % with frovatriptan and 28 and 48 % with comparators (p = NS). At 24 h, 71 and 83 % of frovatriptan-treated patients and 60 and 76 % of comparator-treated patients were pain free (p < 0.05 between treatments) and had pain relief (p = NS), respectively. Relapse at 24 and 48 h was significantly (p < 0.05) lower with frovatriptan (17 and 21 %) than with the comparators (27 and 31 %). Our results suggest that, due to its sustained antimigraine effect, frovatriptan may be particularly suitable for the management of OCMM than other triptans.

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.

Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons.

Some women have negative mood symptoms, caused by progestagens in hormonal contraceptives or sequential hormone therapy or by progesterone in the luteal phase of the menstrual cycle, which may be attributed to metabolites acting on the GABA-A receptor. The GABA system is the major inhibitory system in the adult CNS and most positive modulators of the GABA-A receptor (benzodiazepines, barbiturates, alcohol, GABA steroids), induce inhibitory (e.g. anesthetic, sedative, anticonvulsant, anxiolytic) effects. However, some individuals have adverse effects (seizures, increased pain, anxiety, irritability, aggression) upon exposure. Positive GABA-A receptor modulators induce strong paradoxical effects including negative mood in 3%-8% of those exposed, while up to 25% have moderate symptoms. The effect is biphasic: low concentrations induce an adverse anxiogenic effect while higher concentrations decrease this effect and show inhibitory, calming properties. The prevalence of premenstrual dysphoric disorder (PMDD) is also 3%-8% among women in fertile ages, and up to 25% have more moderate symptoms of premenstrual syndrome (PMS). Patients with PMDD have severe luteal phase-related symptoms and show changes in GABA-A receptor sensitivity and GABA concentrations. Findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA-A receptor, which may be explained by one or more of three hypotheses regarding the paradoxical effect of GABA steroids on behavior: (1) under certain conditions, such as puberty, the relative fraction of certain GABA-A receptor subtypes may be altered, and at those subtypes the GABA steroids may act as negative modulators in contrast to their usual role as positive modulators; (2) in certain brain areas of vulnerable women the transmembrane Cl(-) gradient may be altered by factors such as estrogens that favor excitability; (3) inhibition of inhibitory neurons may promote disinhibition, and hence excitability. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

A Canadian multicentre prospective study on the effects of an oral contraceptive containing 3 mg drospirenone and 30 microg ethinyl oestradiol on somatic and psychological symptoms related to water retention and on body weight.

OBJECTIVES: To evaluate the effects of an oral contraceptive containing 3 mg drospirenone (DRSP) and 30 microg ethinyl oestradiol (EE) on somatic and psychological symptoms related to water retention, and on body weight. METHODS: This prospective study was performed in 26 centres in Canada over six treatment cycles. The first primary efficacy variable was the individual change in the water retention score of the Moos Menstrual Distress Questionnaire (MDQ) from baseline to the final examination in women with significant somatic symptoms related to water retention (n = 43). The second primary target variable was the change in body weight (n = 305). RESULTS: Forty-three women met the criteria for the first primary target variable. In the premenstrual phase, the score decreased from 6.49 (SEM 0.45) at baseline to 3.19 (SEM 0.54) at the final examination (p = 0.0001). The data for the menstrual phase were 4.70 (SEM 0.30) at baseline and 2.35 (SEM 0.32) at the final examination (p < 0.0001). Baseline data from 299 women were assessed for the second primary target variable. Body weight did not change significantly, having increased only by 0.14 kg (SEM 0.13) at the final visit (p = 0.3082). CONCLUSION: An oral contraceptive containing 3 mg DRSP and 30 microg EE significantly reduced the clinical symptoms of water retention. Body weight did not change.

Hormonally regulated alpha(4)beta(2)delta GABA(A) receptors are a target for alcohol.

Here we report that low concentrations of alcohol (1-3 mM) increased Cl(-) currents gated by a recombinant GABA(A) receptor, alpha(4)beta(2)delta, by 40-50% in Xenopus laevis oocytes. We also found greater hippocampal expression of receptors containing alpha(4) and delta subunits, using a rat model of premenstrual syndrome (PMS) in which 1-3 mM alcohol preferentially enhanced GABA-gated currents, and low doses of alcohol attenuated anxiety and behavioral reactivity. The alcohol sensitivity of delta-containing receptors may underlie the reinforcing effects of alcohol during PMS, when eye saccade responses to low doses of alcohol are increased.

Nitromusk compounds in women with gynecological and endocrine dysfunction.

Musk xylene (MX), musk ketone (MK), musk ambrette, musk moskene, and musk tibetene are synthetic fragrances. Between 1994 and 1996 these five nitromusk compounds (NMCs) were tested in the blood of 152 women who consulted the Endocrinological Department of the University Hospital of Obstetrics and Gynecology, Heidelberg, Germany, because of gynecological problems. The testing was conducted by gas chromotography with mass-specific detector and mass spectrometry in a retrospective cross-sectional study. MX was detected in 95% and MK in 85% of the blood samples (>20 ng per liter whole blood). The median concentration of MX was 65.5 ng/L and the maximum level of MX was 1183 ng/L; the corresponding values for MK were respectively 55.5 and 518 ng/L. The other three NMCs were found in only a few patients or not at all. Significant associations between MX and MK concentrations were found in blood and different clinical parameters of the endocrine system. MX and MK may act centrally as a disrupter of the (supra-) hypothalamic-ovarian axis, which may result in a mild ovarian insufficiency. On the basis of our data, a reproductive toxicity and an endocrine effect of NMCs in women cannot be ruled out. Further experimental and clinical studies should be conducted.

Can one induce premenstrual symptomatology in women with prior hysterectomy and bilateral oophorectomy?

Nine women who had undergone hysterectomy and oophorectomy and who previously suffered from severe premenstrual syndrome (PMS) were given estrogen and progesterone in a naturalistic single-blind paradigm. The 13-item Beck Depression Inventory, Spielberger State Anxiety Inventory, Menstrual Distress Questionnaire and the Daily Ratings Form of the Premenstrual Assessment Form were all given daily. Estradiol and progesterone concentrations were estimated. When results from all subjects were considered together, these measures were not correlated with hormonal status. However, individual subjects showed correlations between some symptom scores and serum progesterone concentrations. We conclude that women diagnosed as having PMS do not respond in a uniform fashion to ovarian hormones. Further quantitative studies are needed to relate these individual differences to the syndrome of PMS.

Tasmanian survey of pill symptoms.

OBJECTIVE: To investigate young women who were currently using oral contraceptives with respect to their satisfaction, side effects, understanding of long term benefits and anxieties. METHOD: The survey was completed by 227 attendees at Family Planning Tasmania who completed a survey questionnaire during their visit. RESULTS: Seventy-eight per cent of respondents were 'very happy' or 'happy' with oral contraceptives. Overall the group reported shorter, lighter and less painful periods when compared prior to pill use, with slight increase in breast swelling and tenderness as well as fluid retention. Overall there was weight gain more often than weight loss during pill use. There was very poor understanding of the long term benefits of pill use. DISCUSSION: Although oral contraceptives are the most effective form of contraceptive, many women discontinue their use because of side effects. If women are warned about these possible effects, they may be more prepared to tolerate them. However, there is very little objective data available on the incidence of various effects on Australian women. This study shows that the single most important side effect reported was weight gain, and that we recommend that women be counselled about diet when commencing the pill. There also needs to be education about the numerous beneficial long term effects of oral contraceptive use.

Do women with premenstrual symptoms self-medicate with caffeine?

Recent investigations have suggested that caffeine consumption is related to the occurrence and severity of premenstrual symptoms. Phillis has proposed that not only the total amount of caffeine consumed but also the pattern of consumption over the menstrual cycle may be important. This study explored whether women who experience moderate or severe premenstrual symptoms differ from other women in their pattern of caffeine intake throughout the menstrual cycle. Analysis of data for 96 complete menstrual cycles from 47 women demonstrated that caffeine intake during the menstrual cycle differed between women who experience moderate or severe premenstrual symptoms and other women. Furthermore, the monthly pattern of caffeine consumption for women with moderate or severe premenstrual symptoms, but not for other women, differed substantially from Phillis's proposed beneficial pattern. Women with premenstrual symptoms may self-mediate with caffeine in response to premenstrual symptoms, thereby exacerbating their symptoms.

Caffeine-containing beverages, total fluid consumption, and premenstrual syndrome.

The main objective of this study was to evaluate whether daily consumption of caffeine-containing beverages is related to the prevalence and severity of premenstrual syndrome apart from any effects of daily total fluid consumption. A secondary objective was to determine whether daily total fluid consumption itself is related to premenstrual syndrome. The study is based on 841 responses to a questionnaire probing menstrual and premenstrual health, and daily fluid consumption, which was mailed to female university students in Oregon. Analysis of the data revealed that consumption of caffeine-containing beverages was strongly related to the prevalence of premenstrual syndrome. Among women with more severe symptoms, the relation between consumption of caffeine-containing beverages and premenstrual syndrome was dose-dependent, with prevalence odds ratios equal to 1.3 for consumers of one cup of a caffeine-containing beverage per day and increasing steadily to 7.0 for consumers of eight to 10 cups per day. The effects were apparent among both caffeine-containing tea/coffee consumers and caffeine-containing soda consumers. The observed effects were only slightly reduced when daily total fluid consumption was controlled. Daily total fluid consumption also was related to the prevalence of premenstrual symptoms although the effects were large only for consumers of 13-19 cups of fluid per day (the largest amount studied).