Consequences of 1,4-Butanediol Misuse: A Review.

Gamma-hydroxybutyrate (GHB), along with its precursors, 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL), are potent central depressant agents widely illicitly used for their euphoric and relaxant effects. The article presents a review of the literature on the 1,4-BD misuse, the clinical picture of intoxication, development of addiction and delirium. The available evidence shows that 1,4-BD is a substance with its own psychoactive effects, a high addiction potential and potentially severe withdrawal symptoms.

Periconceptional 1,3-butanediol supplementation suppresses the superimposed preeclampsia-like phenotype in the Dahl salt-sensitive rat.

Preeclampsia is a hypertensive pregnancy disorder with no treatment beyond management of symptoms and delivery of the fetus and placenta. Chronic hypertension increases the risk of developing superimposed preeclampsia. Previous reports showed that 1,3-butanediol attenuates hypertension in rodents; however, the therapeutic potential of 1,3-butanediol for the prevention of preeclampsia has not been investigated. This study tested the hypothesis that attenuating hypertension before pregnancy and through the placentation period via 1,3-butanediol prevents the onset of preeclampsia in female Dahl salt-sensitive (SS/Jr) rats. Female Dahl SS/Jr rats were divided into two groups: 1,3-butanediol treated (20% via drinking water) and control (ad libitum water). Both groups were maintained on low-salt rodent chow (Teklad 7034, 0.3% NaCl; n = 8/group). Animals were treated with 1,3-butanediol for 7 wk (baseline), mated, and treated through day 12 of pregnancy. 1,3-Butanediol treatment increased plasma ß-hydroxybutyrate (metabolite of 1,3-butanediol) that negatively correlated with maternal body weight in late pregnancy. Mean arterial pressure was lower in the treated group at baseline, early, and mid pregnancy, but no difference was observed in late pregnancy after treatment ended. Uterine artery resistance index (UARI) was reduced in the treated dams. No adverse fetal effects were observed, and there were no differences in pup weight or length. Placentas from treated dams had decreased vascular endothelial growth factor levels as well as decreased placental basal zone thickness and increased labyrinth zone thickness. These findings support the therapeutic role of physiological ketosis via 1,3-butanediol as a potential therapeutic approach for managing chronic hypertension, thereby preventing and mitigating adverse pregnancy outcomes associated with preeclampsia.NEW & NOTEWORTHY A ketogenic diet or increased ß-hydroxybutyrate levels can reduce hypertension, but the potential of 1,3-butanediol, a ß-hydroxybutyrate precursor, for treatment of preeclampsia is unknown. We hypothesized that attenuating hypertension before and during pregnancy via 1,3-butanediol prevents preeclampsia in Dahl Salt-sensitive rats. 1,3-Butanediol significantly lowered blood pressure and improved uterine artery resistance with no observable adverse fetal effects. Physiological ketosis via 1,3-butanediol may be a potential therapeutic approach for managing hypertension and mitigating adverse pregnancy outcomes.

Tolerability and Safety of a Novel Ketogenic Ester, Bis-Hexanoyl (R)-1,3-Butanediol: A Randomized Controlled Trial in Healthy Adults.

Nutritional ketosis is a state of mildly elevated blood ketone concentrations resulting from dietary changes (e.g., fasting or reduced carbohydrate intake) or exogenous ketone consumption. In this study, we determined the tolerability and safety of a novel exogenous ketone diester, bis-hexanoyl-(R)-1,3-butanediol (BH-BD), in a 28-day, randomized, double-blind, placebo-controlled, parallel trial (NCT04707989). Healthy adults (n = 59, mean (SD), age: 42.8 (13.4) y, body mass index: 27.8 (3.9) kg/m2) were randomized to consume a beverage containing 12.5 g (Days 0-7) and 25 g (Days 7-28) of BH-BD or a taste-matched placebo daily with breakfast. Tolerability, stimulation, and sedation were assessed daily by standardized questionnaires, and blood and urine samples were collected at Days 0, 7, 14, and 28 for safety assessment. There were no differences in at-home composite systemic and gastrointestinal tolerability scores between BH-BD and placebo at any time in the study, or in acute tolerability measured 1-h post-consumption in-clinic. Weekly at-home composite tolerability scores did not change when BH-BD servings were doubled. At-home scores for stimulation and sedation did not differ between groups. BH-BD significantly increased blood ketone concentrations 1-h post-consumption. No clinically meaningful changes in safety measures including vital signs and clinical laboratory measurements were detected within or between groups. These results support the overall tolerability and safety of consumption of up to 25 g/day BH-BD.

Acetoin and 2,3-butanediol from Bacillus amyloliquefaciens induce stomatal closure in Arabidopsis thaliana and Nicotiana benthamiana.

Plants live in close association with large communities of microbes, some of which are foliar pathogens that invade tissues, primarily via stomata on the leaf surface. Stomata are considered part of an integral, innate immunity system capable of efficiently preventing pathogens from entering the host plant. Although Bacillus, a typical plant growth-promoting rhizobacterium, is known to induce stomatal closure, the substances participating in this closure and the mechanism involved in its regulation remain poorly understood. Here, we screened a mutant library and conducted site-specific mutagenesis experiments in order to identify such substances. We found that acetoin and 2,3-butanediol from B. amyloliquefaciens FZB42 induced stomatal closure in Arabidopsis thaliana and Nicotiana benthamiana. These two components could function either via root absorption or volatilization to restrict stomatal apertures, but root absorption was more efficient. Both substances invoked the salicylic acid and abscisic acid signaling pathways to close the stomata and stimulated accumulation of hydrogen peroxide and nitric oxide. The results present comprehensive evidence of how soil rhizobacteria may affect plant stomata, in a way that reinforces the evolved mutualism between the two groups of organisms, and provide potential alternative avenues of research towards reducing the incidence of disease in crops.

A Comparative Study between the Efficacy and Safety of 5% Minoxidil Solution and 5% Minoxidil Milky Lotion in the Treatment of Male Androgenic Alopecia.

Background: 5% minoxidil solution is approved for the treatment of male androgenetic alopecia (AGA). However, there have been occasional reports of adverse events that were caused mostly by propylene glycol sensitivity. As an alternative treatment, Siriraj hair team developed a proprietary preparation referred to as "minoxidil milky lotion" that uses butylene glycol as a substitute for propylene glycol. Objective: To compare the efficacy and safety of 5% minoxidil solution with 5% minoxidil milky lotion in the treatment of male AGA. Materials and Method: Twenty males with AGA were recruited for this prospective randomized study. Subjects were randomly treated with 5% minoxidil solution or 5% minoxidil milky lotion. Clinical outcomes and adverse events were recorded at 8, 16, and 24 weeks. Results: The mean age of subjects was 43.5±12.5 years (range, 26-65 years). Percentage increase in hair density at 8 weeks after receiving 5% minoxidil solution and 5% minoxidil milky lotion was 8.8% and 37.4%, respectively (p = 0.01). However, there was no statistically significant difference between the two preparations at the 16 and 24 week visits. Mild irritation was reported in 1 case in the 5% minoxidil milky lotion group. Study limitation: Small sample size. Conclusion: Both formulations were found to be effective and safe in the treatment of male AGA. 5% minoxidil milky lotion may be an alternative treatment in propylene glycol-sensitive patients, with efficacy that is comparable to that of 5% minoxidil solution.

The behavioural profile of gamma-hydroxybutyrate, gamma-butyrolactone and 1,4-butanediol in humans.

Gamma-hydroxybutyrate (GHB) is a putative neurotransmitter, a drug of abuse, and a medical treatment for narcolepsy and other neuropsychiatric disorders. Its precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are endogenously converted to GHB and thereby exert their psychobehavioural effects. In humans, GHB has a wide spectrum of properties ranging from stimulation and euphoria in lower doses, to sedation, deep sleep, and coma after ingestion of high doses. However, behavioural studies in healthy volunteers remain scarce and are usually limited to psychomotor performance testing. Most available data arise from either qualitative studies with illicit users or clinical trials examining therapeutic properties of GHB (then usually termed sodium oxybate). Here, we present an overview of the behavioural effects of GHB, GBL, and 1,4-BD in these three populations. GHB and its precursors strongly influence behaviours related to core human autonomic functions such as control of food intake, sexual behaviour, and sleep-wake regulation. These effects are instrumentalised by illicit users and clinically utilised in neuropsychiatric disorders such as narcolepsy, fibromyalgia, and binge-eating syndrome. Considering the industry withdrawal from psychopharmacology development, repurposing of drugs according to their behavioural and clinical profiles has gained increasing relevance. As such, GHB seems to be an attractive candidate as an experimental therapeutic in depression.

Sensitization to reactive diluents and hardeners in epoxy resin systems. IVDK data 2002-2011. Part II: concomitant reactions.

BACKGROUND: Beside the basic resins, reactive diluents and hardeners are important sensitizers in epoxy resin systems (ERSs). Because of chemical similarities, immunological cross-reactivity may occur. OBJECTIVES: To analyse concomitant reactivity among reactive diluents and hardeners in the patients concerned, as one integral part of a research project on the sensitizing capacity of ERSs (FP-0324). METHODS: A retrospective analysis of data from the Information Network of Departments of Dermatology (IVDK), 2002-2011, was performed. RESULTS: There was close concomitant reactivity to 1,6-hexanediol diglycidyl ether and 1,4-butanediol diglycidyl ether (1,4-BDDGE), and to phenyl glycidyl ether (PGE) and cresyl glycidyl ether (CGE), whereas reactions to p-tert-butylphenyl glycidyl ether occurred more independently from those to PGE and CGE. Concomitant reactions to butyl glycidyl ether and 1,4-BDDGE may point to a common allergenic compound derived from the metabolism of 1,4-BDDGE. Among the structurally more diverse group of hardeners, there was no evidence of immunological cross-reactions. CONCLUSIONS: More detailed knowledge of cross-reactivity among ERS components facilitates the interpretation of patch test results and will allow safer ERSs to be composed in the future.

Sensitization to reactive diluents and hardeners in epoxy resin systems. IVDK data 2002-2011. Part I: reaction frequencies.

BACKGROUND: Epoxy resin systems (ERSs), consisting of resins, reactive diluents, and hardeners, are indispensable in many branches of industry. In order to develop less sensitizing ERS formulations, knowledge of the sensitizing properties of single components is mandatory. OBJECTIVES: To analyse the frequency of sensitization in the patients concerned, as one integral part of a research project on the sensitizing potency of epoxy resin compounds (FP-0324). METHODS: A retrospective analysis of data from the Information Network of Departments of Dermatology (IVDK), 2002-2011, and a comparison of reaction frequencies with (surrogate) exposure data, were performed. RESULTS: Almost half of the patients sensitized to epoxy resin were additionally sensitized to reactive diluents or hardeners. Among the reactive diluents, 1,6-hexanediol diglycidyl ether was the most frequent allergen, followed by 1,4-butanediol diglycidyl ether, phenyl glycidyl ether, and p-tert-butylphenyl glycidyl ether. Among the hardeners, m-xylylene diamine (MXDA) and isophorone diamine (IPDA) were the most frequent allergens. According to the calculated exposure-related frequency of sensitization, MXDA seems to be a far more important sensitizer than IPDA. Up to 60% of the patients sensitized to hardeners and 15-20% of those sensitized to reactive diluents do not react to epoxy resin. CONCLUSIONS: In cases of suspected contact allergy to an ERS, a complete epoxy resin series must be patch tested from the start.

Gamma hydroxybutyrate (GHB), gamma butyrolactone (GBL) and 1,4-butanediol (1,4-BD; BDO): A literature review with a focus on UK fatalities related to non-medical use.

Misuse of gamma hydroxybutrate (GHB) and gamma butyrolactone (GBL) has increased greatly since the early 1990s, being implicated in a rising number of deaths. This paper reviews knowledge on GHB and derivatives, and explores the largest series of deaths associated with their non-medical use. Descriptive analyses of cases associated with GHB/GBL and 1,4-butanediol (1,4-BD) use extracted from the UK's National Programme on Substance Abuse Deaths database. From 1995 to September 2013, 159 GHB/GBL-associated fatalities were reported. Typical victims: White (92%); young (mean age 32 years); male (82%); with a drug misuse history (70%). Most deaths (79%) were accidental or related to drug use, the remainder (potential) suicides. GHB/GBL alone was implicated in 37%; alcohol 14%; other drugs 28%; other drugs and alcohol 15%. Its endogenous nature and rapid elimination limit toxicological detection. Post-mortem blood levels: mean 482 (range 0-6500; SD 758)mg/L. Results suggest significant caution is needed when ingesting GHB/GBL, particularly with alcohol, benzodiazepines, opiates, stimulants, and ketamine. More awareness is needed about risks associated with consumption.

Comparative pharmacokinetics of purified flaxseed and associated mammalian lignans in male Wistar rats.

Consumption of flaxseed lignans is associated with various health benefits; however, little is known about the bioavailability of purified lignans in flaxseed. Data on their bioavailability and hence pharmacokinetics (PK) are necessary to better understand their role in putative health benefits. In the present study, we conducted a comparative PK analysis of the principal lignan of flaxseed, secoisolariciresinol diglucoside (SDG), and its primary metabolites, secoisolariciresinol (SECO), enterodiol (ED) and enterolactone (EL) in rats. Purified lignans were intravenously or orally administered to each male Wistar rat. SDG and its primary metabolites SECO, ED and EL were administered orally at doses of 40, 40, 10 and 10 mg/kg, respectively, and intravenously at doses of 20, 20, 5 and 1 mg/kg, respectively. Blood samples were collected at 0 (pre-dose), 5, 10, 15, 20, 30 and 45 min, and at 1, 2, 4, 6, 8, 12 and 24 h post-dosing, and serum samples were analysed. PK parameters and oral bioavailability of purified lignans were determined by non-compartmental methods. In general, administration of the flaxseed lignans SDG, SECO and ED demonstrated a high systemic clearance, a large volume of distribution and short half-lives, whereas administration of EL at the doses of 1 mg/kg (intravenously) and 10 mg/kg (orally administered) killed the rats within a few hours of dosing, precluding a PK analysis of this lignan. PK parameters of flaxseed lignans exhibited the following order: systemic clearance, SDG < SECO < ED; volume of distribution, SDG < SECO < ED; half-life, SDG < ED < SECO. The percentage of oral bioavailability was 0, 25 and < 1 % for SDG, SECO and ED, respectively.

Contact allergy to reactive diluents and related aliphatic epoxy resins.

BACKGROUND: Diglycidyl ether of bisphenol A resin (DGEBA-R) is the most common sensitizer in epoxy systems, but a minority of patients also develop contact allergy to reactive diluents. OBJECTIVES: To analyse the frequency and clinical relevance of allergic reactions to different epoxy reactive diluents and related aliphatic epoxy resins. METHODS: Test files (January 1991 to June 2014) were screened, and the clinical records of patients with allergic reactions were analysed for occupation, concomitant allergic reactions, and exposure. RESULTS: A total of 67 patients reacted to at least one of the compounds. The largest numbers of allergic reactions were to phenyl glycidyl ether (PGE; n = 41), 1,4-butanediol diglycidyl ether (BDDGE; n = 34), and p-tert-butylphenyl glycidyl ether (PTBPGE; n = 19). Ten of the patients did not have contact allergy to DGEBA-R. The reactions of 5 of these were related to the use of BDDGE-containing products. We found no significant exposure to PGE or PTBPGE in patients sensitized to them, but some of the patients had used cresyl glycidyl ether-containing products. CONCLUSIONS: Allergic reactions to reactive diluents and related aliphatic epoxy resins usually occurred together with reactions to DGEBA-R. BDDGE was the clinically most significant compound, and was the sole cause of occupational allergic contact dermatitis in 3 patients.

Case of allergic contact dermatitis due to 1,3-butylene glycol.

1,3-Butylene glycol (1,3-BG) is widely used in cosmetics, including low-irritant skin care products and topical medicaments, as an excellent and low-irritation humectant. We report a case of allergic contact dermatitis caused by 1,3-BG. A 28-year-old woman suffered from an itchy erythematous eruption on her face. By 2 days of closed patch testing, her own cosmetics and many of the hypo-irritant skin care products showed positive results. A second patch testing showed positive reaction to 1,3-BG (1% and 5%). 1,3-BG was a common component in most of the products that had elicited a positive reaction in the first patch testing. Although allergic contact dermatitis due to 1,3-BG is not so common, we have to consider 1,3-BG as a possible contact allergen in the patients presenting with allergic contact dermatitis due to various cosmetics.

Combined effects of urinary phytoestrogens metabolites and polymorphisms in metabolic enzyme gene on idiopathic male infertility.

Phytoestrogens are plant-derived compounds that may interact with estrogen receptors and mimic estrogenic effects. It remains unclear whether the individual variability in metabolizing phytoestrogens contributes to phytoestrogens-induced beneficial or detrimental effects. Our aim was to determine whether there is any interaction between metabolic rates (MR) of phytoestrogens and genetic polymorphisms in related xenobiotic metabolizing enzyme genes. MR was used to assess phytoestrogen exposure and individual metabolic ability. The amount of phytoestrogens in urine was measured by ultra-high performance liquid chromatography-tandem mass spectrometry in 600 idiopathic infertile male patients and 401 controls. Polymorphisms were genotyped using the SNPstream platform combined with the Taqman method. Prototypes and metabolites of secoisolariciresinol (SEC) have inverse effects on male reproduction. It was found that low MR of SEC increased the risk of male infertility (OR 2.49, 95 % CI 1.78, 3.48, P trend = 8.00 × 10(-8)). Novel interactions were also observed between the MR of SEC and rs1042389 in CYP2B6, rs1048943 in CYP1A1, and rs1799931 in NAT2 on male infertility (P inter = 1.06 × 10(-4), 1.14 × 10(-3), 3.55 × 10(-3), respectively). By analyzing the relationships between urinary phytoestrogen concentrations, their metabolites and male infertility, we found that individual variability in metabolizing SEC contributed to the interpersonal differences in SEC's effects on male reproduction.

GHB, GBL and 1,4-BD addiction.

A growing body of evidence shows that gamma-hydroxybutyric acid (GHB) is an addictive substance. Its precursors gammabutyrolactone (GBL) and 1,4-butanediol (1,4-BD) show the same properties and may pose even more risks due to different pharmacokinetics. There are indications that problematic GHB use is increasing in the European Union. This review investigates the existing literature on the neurochemistry of GHB and its precursors, their acute toxicity, addiction potential and withdrawal, the proposed molecular mechanism underlying addiction and the treatment of withdrawal and addiction. Current evidence shows that GHB and its precursors are highly addictive, both in humans and animals, probably through a GABAB receptor related mechanism. Severity of withdrawal symptoms can be considered as a medical emergency. Recent studies suggest that benzodiazepines are not very effective, showing a high treatment resistance, whereas detoxification with pharmaceutical GHB proved to be successful. However, relapse in GHB use is frequent and more research is warranted on relapse prevention. This might aid medical practitioners in the field and improve general understanding of the severity of addiction to GHB, GBL and 1,4-BD.

Urinary phytoestrogen levels related to idiopathic male infertility in Chinese men.

Phytoestrogens (PEs) are naturally occurring chemical constituents of certain plants. The internal PE exposures, mainly from diet, vary among different populations and in different regions due to various eating habits. To investigate the potential relationship between urinary PE levels and idiopathic male infertility and semen quality in Chinese adult males, 608 idiopathic infertile men and 469 fertile controls were recruited by eligibility screening procedures. Individual exposure to PEs was measured using UPLC-MS/MS as spot urinary concentrations of 6 PEs (daidzein, DAI; equol, EQU; genistein, GEN; naringenin, NAR; coumestrol, COU; and secoisolariciresinol, SEC), which were adjusted with urinary creatinine (CR). Semen quality was assessed by sperm concentration, number per ejaculum and motility. We found that exposures to DAI, GEN and SEC were significantly associated with idiopathic male infertility (P-value for trend=0.036; 0.002; and 0.0001, respectively), while these exposures had stronger association with infertile subjects with at least one abnormal semen parameter than those with all normal semen parameters. Exposures to DAI, GEN and SEC were also related to idiopathic male infertility with abnormal sperm concentration, number per ejaculum and motility (P-value for trend<0.05), while these exposures had stronger association with the infertile men with abnormal sperm number per ejaculum. These findings provide the evidence that PE exposures are related to male reproductive function and raise a public health concern because that exposure to PEs is ubiquitous in China.

Hypospadias and maternal intake of phytoestrogens.

Experimental data indicate that gestational exposures to estrogenic compounds impact risk of hypospadias. We examined whether risk of hypospadias (i.e., a congenital malformation in which the opening of the penile urethra occurs on the ventral side of the penis) was associated with maternal intake of phytoestrogens, given their potential impact on estrogen metabolism. The analysis included data on mothers of 1,250 hypospadias cases and 3,118 controls who delivered their infants from 1997 to 2005 and participated in the National Birth Defects Prevention Study, a multistate, population-based, case-control study. After adjustment for several covariates, high intakes of daidzein, genistein, glycetin, secoisolariciresinol, total isoflavones, total lignans, and total phytoestrogens were associated with reduced risks; odds ratios comparing intakes ≥90th percentile with intakes between the 11th and 89th percentiles ranged from 0.6 to 0.8. For example, the odds ratio for total phytoestrogen intake was 0.7 (95% confidence interval: 0.5, 1.0). This study represents the first large-scale analysis of phytoestrogen intake and hypospadias. The observed associations merit investigation in additional populations before firm conclusions can be reached.

Self-administration of gamma-hydroxybutyric acid (GHB) precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) in baboons.

RATIONALE: Gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) are gamma-hydroxybutyrate (GHB) pro-drugs and drugs of abuse. OBJECTIVE: Given the reports of abuse, and the ease at which GBL and 1,4-BD may be obtained, we investigated the reinforcing effects of GBL (n = 5) and 1,4-BD (n = 4) in baboons using IV self-administration procedures. METHODS: Sessions ran 24 h/day. Each injection was contingent upon completion of a fixed number (120 or 160) of lever responses. A 3-h timeout period followed each injection, limiting the total number of injections to eight per day. Self-administration was first established with cocaine (0.32 mg/kg/injection). GBL (10-130.0 mg/kg/injection), 1,4-BD (10-100 mg/kg/injection), or vehicle was substituted for cocaine for at least 15 days. Food pellets were available ad libitum 24 h/day and were contingent upon completion of ten lever responses. RESULTS: GBL (32-100 mg/kg/injection) maintained significantly greater numbers of injections when compared to vehicle in four of five baboons, and the mean rates of injection were high (more than six per day) in three baboons and moderate in the fourth baboon (four to six per day). 1,4-BD (78-130 mg/kg/injection) maintained significantly greater numbers of injections when compared to vehicle in only two out of four baboons, and mean rates were moderate to high in both baboons. Self-injection of these doses of GBL and 1,4-BD generally inhibited food-maintained responding. CONCLUSIONS: GBL and 1,4-BD have abuse liability. Given that GBL and 1,4-BD are self-administered, are easier to obtain than GHB, and are detected in seized samples, additional legal control measures of these GHB pro-drugs may be needed.

Evaluation of the efficacy of flaxseed meal and flaxseed extract in reducing menopausal symptoms.

The objective of this study was to evaluate the efficacy of flaxseed meal and flaxseed extract in reducing climacteric symptoms of menopausal women. Ninety menopausal women were randomly distributed into three study groups: group I received 1 g per day of flaxseed extract containing at least 100 mg of secoisolariciresinol diglucoside (SDG), group II received 90 g per day of flaxseed meal containing at least 270 mg of SDG, and group III received 1 g per day of collagen (placebo group). Subjects were assessed for menopausal symptoms by the Kupperman index at the beginning and at the end of the 6 months of treatment. Subjects were also assessed for endometrial thickness and vaginal cytology. The Kupperman index values at the beginning and end of the treatments were analyzed using the paired t-test. Both the flaxseed extract (P=.007) and the flaxseed meal (P=.005) were effective in reducing the menopausal symptoms when compared with the placebo control (P=.082). Alternatively, the changes in Kupperman index were also computed and submitted to analysis of variance. In this case, no significant differences were found (P=.084) although the data indicate a decreasing tendency for the Kupperman index by both the flaxseed extract and the flaxseed meal groups. Neither the flaxseed extract nor the flaxseed meal exerted clinically important estrogenic effects on the vaginal epithelium or endometrium as revealed by the absence of changes in the blood levels of follicle stimulating hormone and estradiol, as well as in the endometrial thickness, and vaginal epithelial maturation value. No serious adverse events related to the treatments were reported. Although the results of the present study do not allow an unequivocal conclusion about the action of flaxseed on the menopausal symptoms, they suggest that it could be premature to conclude that no such action exists. Clearly the matter still deserves further experimental attention.