Olfactory influences on the human menstrual cycle

Two groups of women were compared for the timing of the onset of their menstrual cycle. One group was rubbed on the upper lip (directly beneath the nose) with a mixture of alcohol and underarm perspiration collected from a single female donor. The other group was rubbed with plain alcohol. The group which received the perspiration showed a significant shift in the timing of their menstrual cycles which conformed closely with the donor's monthly cycle. This is a preliminary study which supports the hypothesis that the time of menstrual onset may be modified by olfactory cues.     

Action by and sensitivity to neuroactive steroids in menstrual cycle related CNS disorders

Neuroactive steroids are a large group of substances having effect in the brain and on brain function. The steroids most studied are allopregnanolone (ALLO), tetrahydrodesoxycorticosterone (THDOC), pregnenolone sulfate (PS) dihydroepiandrosteronesulfate (DHEAS), and estradiol (E₂). ALLO and THDOC are called gamma-aminobutyric acid (GABA) steroids as they are positive modulators of the GABA_A receptor in a similar way as benzodiazepines, barbiturates, and alcohol. GABA steroids not only have similar behavioral effects as benzodiazepines and barbiturates but, possibly, also similar adverse effects as well. This review aims to elucidate the possible role that neuroactive steroids play in the development of mood disorders in women. One of the most clear-cut examples of the interaction between mood, neuroactive steroids, and the GABA system is premenstrual dysphoric disorder (PMDD), which is a cluster of negative mood symptoms occurring during the luteal phase of the menstrual cycle in 2–6% of reproductive women. Furthermore, certain women also experience adverse mood effects during sequential progestin addition to postmenopausal estrogen treatment, which is why the role of neuroactive steroids in postmenopausal women is also addressed in this review.     

Acute effects of d-amphetamine during the follicular and luteal phases of the menstrual cycle in women

Rationale: Little is known about the interactions between ovarian hormones across the menstrual cycle and responses to psychoactive drugs in humans. Preclinical studies suggest that ovarian hormones such as estrogen and progesterone have direct and indirect central nervous system actions, and that these hormones can influence behavioral responses to psychoactive drugs. Objectives: In the present study, we assessed the subjective and behavioral effects of d-amphetamine (AMPH; 15 mg orally) at two hormonally distinct phases of the menstrual cycle in women. Methods: Sixteen healthy women received AMPH or placebo capsules during the follicular and mid-luteal phases of their cycle. During the follicular phase, estrogen levels are low initially and then rise while progesterone levels remain low. During the mid-luteal phase, levels of both estrogen and progesterone are relatively high. Dependent measures included self-report questionnaires, physiological measures and plasma hormone levels. Results: Although there were no baseline differences in mood during the follicular or luteal phase, the effects of AMPH were greater during the follicular phase than the luteal phase. During the follicular phase, subjects reported feeling more “High”, “Energetic and Intellectually Efficient”, and “Euphoric” after AMPH than during the luteal phase, and also reported liking and wanting AMPH more. Further analyses showed that during the follicular phase, but not the luteal phase, responses to AMPH were related to levels of estrogen. Higher levels of estrogen were associated with greater AMPH-induced increases in “Euphoria” and “Energy and Intellectual Efficiency”. During the luteal phase, in the presence of both estrogen and progesterone, estrogen levels were not related to the effects of AMPH. Conclusions: These findings suggest that estrogen may enhance the subjective responses to a stimulant drug in women, but that this effect may be masked in the presence of progesterone. Received: 26 August 1998/Final version: 19 February 1999     

Influence of the menstrual cycle on theophylline pharmacokinetics in asthmatics

Summary The effect of menstrual cycle on the pharmacokinetics of theophylline has been studied in 9 female asthmatic patients. At three different times during the cycle (first, tenth and twentieth days) each subject received an i.v. infusion of 240 mg theophylline. Significant changes were found in the kinetics of theophylline according to the menstrual cycle. The maximum plasma drug concentration, minimum mean residence time, and minimum elimination half-life were observed at mid-cycle. The lowest clearance was observed at D 20. The AUC and volume of distribution did not vary significantly during the cycle.     

Effects of triazolam at three phases of the menstrual cycle.

This study investigated the subjective and behavioral effects of a commonly used benzodiazepine, triazolam, in healthy women at three phases of the menstrual cycle: follicular, periovulatory, and luteal. Ovarian hormones or their metabolites have direct and indirect actions on neuronal receptors, which may affect responses to psychoactive drugs acting on the same central nervous system receptors. This study explored the effect of menstrual cycle phase on the mood-altering and performance effects of a single oral dose of the benzodiazepine triazolam. Twenty women received triazolam (0.25 mg orally) or placebo at the follicular, periovulatory, and luteal phases of their menstrual cycles in a within-subject design. Dependent measures included self-reported mood states, psychomotor performance, and plasma levels of triazolam, estradiol, progesterone, and allopregnanolone. After administration of triazolam, most subjects reported the expected increases in fatigue and decreases in arousal and psychomotor performance. Neither plasma levels nor mood and performance effects of triazolam differed across the three phases. This study illustrates a useful methodology for assessing responses to psychoactive drugs in normally cycling women and shows that the effects of this drug were highly stable across the cycle.     

The effect of the menstrual cycle on the pharmacokinetics of caffeine in normal, healthy eumenorrheic females

  Objective: Hormonal fluctuations of estrogen and progesterone in eumenorrheic women may be capable of altering the pharmacokinetics of certain agents. The objective of this study was to determine the effect of the luteal, ovulatory and follicular phases of the menstrual cycle on the pharmacokinetics of caffeine, a low clearance, flow-independent drug. Methods: Subjects were ten healthy, non-smoking, eumenorrheic females who were not pregnant and had not used oral contraceptives for a minimum of 3 months prior to the study. Blood samples were collected during one menstrual cycle for the determination of estradiol and progesterone concentrations during the follicular (days 2–6 post-onset of menses), ovulatory (days 13–16 post-onset of menses) and luteal (days 22–26 post-onset of menses) phases. Caffeine was administered over a single menstrual cycle during the follicular, ovulatory and luteal phases. Each subject was administered a single oral dose of caffeine (300 mg) in 100 ml of lemonade during each phase of the menstrual cycle. A venous catheter was used to collect blood samples at pre-dose and at the following time points: 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 and 24 h. Plasma caffeine concentrations were determined using a validated ultraviolet high-performance liquid chromatography method. Results: There were no significant (P < 0.05) differences in the pharmacokinetic parameters of caffeine across the menstrual cycle phases. The average area under the plasma concentration–time curve (AUC_inf) was 93.01 mg l^−1.h and the absorption rate constant (k _a) was 2.88 h⁻¹ during the ovulatory phase, 83.0 mg l⁻¹ h and 2.06 h⁻¹, respectively, during the luteal phase and 84.7 mg l^−1.h and 1.84 h⁻¹, respectively, during the follicular phase. Conclusions: These findings suggest that the menstrual cycle does not significantly alter the pharmacokinetics of caffeine. Received: 16 November 1998 / Accepted in revised form: 19 April 1999     

Platelet 3H-imipramine binding and steroid hormones serum concentrations during the menstrual cycle

The presence of high affinity binding sites for ³H-imipramine (³H-IMI) in human platelets is by now well established. This recognition site is associated with the transporter for 5HT, and may be a biological marker in depression. Fluctuations of other putative biological markers of depression (i.e. platelet MAO activity) have been demonstrated and shown to be correlated with variations in steroid hormones. Therefore, the K_D and B_max of ³H-IMI binding was determined in platelets of young women during the menstrual cycle. Our results indicate that within the limits of intraindividual variations, neither the K_D or the B_max of ³H-IMI binding in platelets is significantly modified during the menstrual cycle.     

Association between paraben exposure and menstrual cycle in female university students in Japan

Parabens have been known to have estrogenic activity in many in vivo and in vitro studies and biomonitoring data indicated ubiquitous exposure in general populations. However, there are few human studies on reproductive effects of parabens. In this study, menstrual cycle length and its intra-individual variation were investigated by bleeding record over the period of 5 months and urinary concentrations of parabens were measured for 128 female Japanese university students. We found significantly negative relationships between menstrual cycle length and urinary estrogen-equivalent total paraben (odds = 0.73, 95% CI 0.56–0.96) and butyl paraben concentrations (odds = 0.83, 0.70–0.99), which indicated shortened cycle length in women with high urinary paraben concentrations.This study indicated that paraben exposure at not excessive levels is associated with menstrual cycle length or its variability among general female subjects. These results suggest a possibility that parabens exposure is one of the environmental causes of human reproductive problem.     

Effects of menstrual cycle on gene transfection through mouse vagina for DNA vaccine

Human immunodeficiency virus (HIV) infections mainly occur through the vaginal and rectal mucosal membranes. In the present study, to develop a DNA vaginal vaccine against viral and bacterial infections, the effects of the menstrual cycle on DNA transfection through the vaginal mucosa in female mice and transfection enhancement by electroporation, a chelating agent, cell-penetrating peptides (CPP) and nuclear localizing signals (NLS) were investigated. The transfection efficiencies of a marker plasmid DNA (pDNA), pCMV-Luc, on the vaginal mucosal membrane in mice at the stages of metestrus and diestrus were significantly higher than those at the stages of proestrus and estrus. The gene expression was markedly enhanced by electroporation and by pretreatment with the chelating agent. The highest level of expression was obtained by 2h pretreatment with 5% citric acid solution combined with electroporation with 15 pulses at 250 V/cm for 5 milliseconds (ms). Furthermore, a synergistic promoting effect on pDNA transfection was obtained by co-administration of CPP, the Tat peptide analog, and NLS, the NF-kappaB analog. These results indicate that effective DNA vaccination administered through the vaginal tract is possible by selecting the menstrual stage and overcoming the mucosal barrier using a combination of methods that promotes uptake.     

Estrous cyclicity in rats fed an ethanol diet for four months

This study is designed for better understanding the effect of chronic ethanol treatment on ovarian function in sexually mature rats by assessing the estrous cycle. Rats were fed the following diets for 17 weeks: a liquid diet containing 5% (w/v) ethanol, a liquid diet without ethanol (pair-fed) or laboratory chow and water ad lib. Estrous cycles were determined throughout the 17 weeks and the rats were necropsied at proestrus and metestrus. Ethanol-fed rats had significantly more irregular estrous cycles than did controls, and the duration of an estrous cycle in the ethanol-treated rats was statistically longer than that of controls. However, ovarian and uterine weights and ovarian and vaginal morphology of ethanol-fed rats were similar to those of controls.     

Levels of urinary human chorionic gonadotrophin (hCG) following conception and variability of menstrual cycle length in a cohort of women attempting to conceive

ABSTRACT

Objectives: To define the variability of menstrual cycle length and contribution of follicular and luteal phases to overall cycle variability, and to examine the rise in urinary hCG in early pregnancy.

Methods: Menstrual cycle study. Urine samples from 101 women (recruited from two south-east counties in the UK) were assayed to determine day of luteinising hormone (LH) surge, lengths of follicular and luteal phases and correlations with total menstrual cycle length. HCG study. Daily urine samples collected from 86 women prior to conception until 43 days post-conception were assayed for hCG and examined versus time since LH surge, determined using fertility test kits.

Results: Mean menstrual cycle length was 27.7?±?3.4 days, mean follicular phase length was 14.5?±?3.4 days and mean luteal phase length was 13.2?±?1.9 days. Total cycle lengths varied between and within women. There was a significant correlation (r²?=?0.70) between follicular phase length and total cycle length; luteal phase length was less variable and showed no association with total cycle length. Concentrations of hCG were significantly similar between women when referenced against the day since LH surge. Three thresholds were determined to indicate time since conception as 1–2 weeks, 2–3 weeks and 3+ weeks.

Conclusions: Total cycle length variation is mainly determined by follicular phase variation and predicting menses onset to estimate time of pregnancy testing is unreliable. Evaluating concentrations of hCG relative to LH surge results in consistent increases between women up to 21 days after conception. Therefore, urinary hCG concentration can be used to accurately estimate time since conception.     

Severity of withdrawal symptomatology in follicular versus luteal quitters: The combined effects of menstrual phase and withdrawal on smoking cessation outcome

Women are at an increased risk of relapse after a smoking cessation attempt. While the reasons for this phenomenon are not fully understood, recent research indicates that both the menstrual cycle and negative symptomatology may play a role. The goal of this study was to describe the association between withdrawal symptoms during attempted smoking cessation, and to investigate the impact of these symptoms on smoking cessation outcomes as defined by 7-day point prevalence at 14 and 30 days. Negative symptoms associated with the premenstrual period were also assessed. Participants (n = 202) were 29.8 (SD ± 6.6) years old and smoked 16.6 (SD ± 5.6) cigarettes per day. They were randomly assigned to quit smoking in the follicular (n = 106) or luteal (n = 96) menstrual phase. We observed several significantly more severe premenstrual and withdrawal symptoms in the luteal phase. Regardless of quit phase, most withdrawal symptoms were associated with an increased risk of relapse at 14 and 30 days post quit date. Participants attempting to quit smoking in the follicular phase who had higher levels of Anger and Craving were more likely to relapse to smoking at 14-days (OR = 2.00, p-value = 0.026; OR = 2.63, p-value = 0.006; respectively). These data suggest that the menstrual cycle may play a role in smoking cessation outcome, as well as in the symptomatology experienced during a cessation attempt.     

Reproductive state modulates ethanol intake in rats: Effects of ovariectomy,ethanol concentration,estrous cycle and pregnancy

Intact adult female rats had a greater preference for a 4% (v/v) ethanol solution than ovariectomized (OVX) rats in a two-tube preference situation. This preference difference was not particular to the 4% concentration, but was exhibited for solutions ranging from 1–9% ethanol. OVX animals reached peak preference at weaker ethanol concentrations than did control animals, while the volume of absolute ethanol consumed by each group was highly dependent on the concentration of ethanol offered. OVX, but not intact, rats showed a strong positive correlation between alcohol preference and preference for a saccharine solution. Pregnant and lactating rats exhibited depressed preference for 4% ethanol. Preference returned to control levels following weaning. Ethanol intake and preference varied systematically over the four-day estrous cycle, being lowest on the day of proestrus.     

乳腺癌患者月经周期中性激素、VEGF及NK细胞的变化与手术时间选择的关系探讨

目的　从乳腺癌患者月经周期中性激素、血清血管内皮生长因子 (VEGF)及自由杀伤细胞 (NK)细胞的变化探讨手术时间选择的必要性。方法　对月经周期规则的乳腺癌患者 ,抽血检测雌孕激素、VEGF及NK细胞四项指标 ,比较她们在卵泡期与黄体期的不同水平变化 ,分析其对手术时间选择的意义。结果　雌孕激素的波动符合正常生理变化规律 ;卵泡期的VEGF水平高于黄体期 ,分别为 2 79.6 pg/ml和 2 33.9pg/ml;卵泡期血NK细胞浓度低于黄体期 ,分别为 0 .16 5× 10 6/ml及 0 .2 36× 10 6/ml,特别是在围排卵期 (17、13d) ,血NK细胞数有明显的升高。结论　从检测的可能影响术后生存率的四项指标看 ,在黄体期手术更为有利 ,但尚需以后的生存率统计证实。     

Effects of the menstrual cycle of white women on ethanol toxicokinetics

OBJECTIVE: The aim of this study was to investigate the existing variations of the kinetics of ethanol in white women during the menstrual and luteal phases to further current understanding of the role of the menstrual cycle in gender differences in ethanol's adverse effects. METHOD: In a within-subjects design, 10 female white volunteers were administered a moderate dose of ethanol (0.3 g/kg) in the morning after an overnight fast. On each test day, blood samples were collected before ethanol administration so that hormonal (estrogen, progesterone, luteinizing hormone and follicle stimulating hormone) and biochemical (hepatic and renal functions) analyses could be performed. Blood samples were also drawn from each volunteer to determine BAC and to examine toxicokinetic differences between the two phases using classical and Widmark's measures. RESULTS: The analysis of time-to-peak BAC in the two menstrual phases shows that there was no significant statistical difference when each phase was evaluated and in the interaction of the phase with time. The estimated toxicokinetic parameters did not show significant differences when the two phases were compared. CONCLUSIONS: Despite careful experimental design, which considered present debate and discussion in the literature, no significant differences between the two phases studied (menstrual and luteal) were observed.     

Relationship between variations in estradiol and progesterone levels across the menstrual cycle and human performance

RATIONALE: Studies about whether or not the cognitive performance of women is influenced by changes in levels of sex steroid hormones across the menstrual cycle have produced ambiguous results. OBJECTIVES: This study tested whether flight simulator performance differs significantly between the menstrual and the luteal phase of the menstrual cycle. METHODS: In a within-subjects design, 24 female pilots were tested twice during their menstrual cycle: once during the menstrual and once during the luteal phase. On both test days they performed a 75-min simulator flight in a Frasca 141, a popular pilot training device. RESULTS: Despite highly significant differences in estradiol (E2) as well as progesterone (P) levels on the 2 test days, and despite excluding subjects with anovulatory cycles from the analyses, there were no significant differences in overall flight performance between the menstrual and luteal phases. We found no significant correlations between E2 or P levels and flight performance. CONCLUSIONS: We found no evidence that the tested menstrual cycle phases and their associated E2 and P levels significantly influence flight simulator performance. We consider these negative findings based on 24 subjects meaningful because previous studies on the influence of menstrual cycle on cognitive performance have not involved complex "real world" tasks such as piloting an aircraft and they obtained inconsistent results.     

Discriminative stimulus effects of ethanol and 3α-hydroxy-5α-pregnan-20-one in relation to menstrual cycle phase in cynomolgus monkeys (Macaca fascicularis)

 The present study was designed to characterize the discriminative stimulus effects of ethanol and the neurosteroid 3α-hydroxy-5α-pregnan-20-one (allopregnanolone) in nonhuman primates as a function of menstrual cycle phase. Female cynomolgus monkeys (Macaca fascicularis) were trained in a two-lever procedure to discriminate 1.0 g/kg ethanol (IG, 30 min pretreatment) from water using food reinforcement. A cumulative dosing procedure was used to assess changes in the potency of ethanol and an endogenous anxiolytic steroid in the follicular versus the luteal phase of the menstrual cycle. Plasma progesterone and allopregnanolone levels were determined within 24 h of testing to verify phase of menstrual cycle. The monkeys were more sensitive to the discriminative stimulus effects of ethanol and the ethanol-like effects of the endogenous neuroactive steroid allopregnanolone during the luteal phase of the menstrual cycle. These findings suggest that changes in the endogenous levels of ovarian-derived progesterone and allopregnanolone alter sensitivity to the discriminative stimulus effects of ethanol. Received: 13 March 1996 / Final version: 26 September 1996     

Response to alcohol in women: role of the menstrual cycle and a family history of alcoholism

The present study determined whether: (1) the response to alcohol varied as a function of menstrual cycle phase and (2) women with a paternal history of alcoholism (FHP) were less sensitive to the effects of alcohol compared to women without a family history of alcoholism (FHN). The behavioral effects of alcohol (0.00, 0.25, and 0.75 g/kg) were evaluated in 21 FHN and 24 FHP women; each dose was tested during both the midfollicular and late luteal phases of the menstrual cycle. Baseline negative mood was increased during the luteal phase compared to the follicular phase (increased Beck Depression scores and decreased Vigor, Arousal, and Friendly scores). Alcohol increased ratings of Drug Liking and Good Drug Effect more in the luteal phase than the follicular phase. FHP women had greater negative mood during the luteal phase and some of these dysphoric effects were increased by alcohol more in FHP women than FHN women. Alcohol impaired performance, with no group or menstrual cycle differences. However, consistent with previous studies, FHP women were less impaired by alcohol than FHN women on the balance task. These data indicate that (1) the differences in response to alcohol across the menstrual cycle are subtle, although alcohol is liked more during the luteal phase; (2) increases in dysphoric mood during the luteal phase are more pronounced in FHP women compared to FHN women, particularly after alcohol; and (3) the differences observed in response to alcohol between FHP and FHN women are less pronounced than previously shown in men.     

Salt preference across different phases of menstrual cycle

It is well established that women experience food craving for particular foods and gain weight in relation to phases of menstrual cycle. In this study, the preference for different concentrations of salt sprayed on bland popcorn was assessed in 55 healthy women (age 18 to 22 yrs). Salt solutions of 0, 1, 2, 3 and +3 molar strength were used. Samples of sprayed popcorn were consumed in random order and preference marked on a Likert scale. It was observed that women preferred unsalted popcorn in the menstrual phase more than in the luteal phase. The preference for salted popcorn was most during the luteal phase and was proportionate to the strength of the salt solution used. Statistical analysis revealed significant differences in the preference rating between the menstrual phase and the other two phases. There was no significant difference in preference between the luteal and follicular phases.     

The effect of cannabidiol,alone and in combination with ethanol,on human performance

Fifteen volunteers received cannabidiol (CBD) (320 g/kg) or placebo (both orally, T₀), and 60 min later they consumed an ethanolic beverage (0.54 g/kg) or placebo. The effects were measured at T₁ (100 min after CBD ingestion), T₂ (160 min) and T₃ (220 min) using cognitive, perceptual and motor function tests. Factorial analysis indicated that test procedures could be adequately expressed by three rotated factors: A reaction speed factor (I), a standing steadiness factor (II) and a psychomotor coordination/cognitive factor (III). Ethanol produced a significant decrement in factor III. There was no demonstrable effect of CBD, either alone or in combination with ethanol. Neither CBD nor ethanol produced any significant effect on pulse rate. Prior administration of CBD did not significantly affect the blood ethanol levels. Whilst the subjects were able to identify correctly when they were given ethanol, they did not report any subjective effects of CBD.