Hexachlorobenzene (HCB) suppresses circulating progesterone concentrations during the luteal phase in the cynomolgus monkey.

Hexachlorobenzene (HCB) is a known reproductive toxin. However, the full spectrum of its reproductive toxicity is unknown. Consequently, the effect of HCB on serum oestradiol (E2) and progesterone (P4) concentrations during the follicular (days 1-9), periovulatory (days 10-14) and luteal (days 15 to beginning of next menses) phases was investigated in the spontaneously cycling cynomolgus monkey. Adult female cynomolgus monkeys (n = 16) were randomly assigned to one of four treatment groups and orally doses with gelatin capsules containing HCB (0.0, 0.1, 1.0 and 10.0 mg kg-1 body wt. day-1) mixed with glucose. A 10-week acclimitization phase was followed by 13 weeks of dosing. HCB induced a dose-dependent suppression of serum P4 concentrations during the luteal phase. However, circulating levels of P4 were unaffected during the follicular and periovulatory phases of the menstrual cycle. Serum E2 concentrations, body weight, menstrual cycle length and duration of menses were not affected by HCB treatment. The range of menstrual cycle length and duration range of menses, however, were broader in the highest dose group. We conclude that HCB interfers with mechanisms regulating ovarian steroidogenesis and suppresses P4 levels during the luteal phase in the cynomolgus monkey.     

Comparative pharmacokinetics of paracetamol in men and women considering follicular and luteal phases

The pharmacokinetics of paracetamol administered in a single dose were investigated and compared in young male and female subjects, considering follicular and luteal phase of the menstrual cycle. The mean AUC for paracetamol in the blood of female subjects was significantly increased by 39% and 51%, respectively, taking into account the follicular and luteal phase, in comparison with the AUCs of male volunteers. The peak plasma concentration revealed significantly higher values in women in both phases, by 48% and 66%, respectively. The time to reach the peak concentration was shorter by 8% in follicular phase than in males. The difference was statistically insignificant. Elimination constant decreased in follicular phase by 15% and in luteal phase by 21% in comparison with males (the difference--statistically insignificant). The paracetamol half-life was longer (although not significantly) in women than in men: in follicular phase by 29 min, i.e. 15%, and in luteal phase by 65 min, i.e. 33%. The apparent volume of distribution was found to be significantly lower in the female group by 35% and 40% in follicular and luteal phase, respectively. Comparing data obtained in the follicular and luteal phase, it was shown that the AUC was larger, peak plasma concentration was higher and biological half-life was longer in luteal phase. It is likely that the differences in some pharmacokinetic parameters between men and women, as well as in women considering both phases of menstrual cycle, might be of clinical significance.     

Patients with premenstrual dysphoric disorder have increased startle response across both cycle phases and lower levels of prepulse inhibition during the late luteal phase of the menstrual cycle.

Patients with premenstrual dysphoric disorder (PMDD) experience their most intense symptoms during the late luteal phase. The aim of the current study was to compare acoustic startle response and prepulse inhibition in PMDD patients and controls during the follicular and late luteal phases of the menstrual cycle. Following two months of prospective daily ratings on the Cyclicity Diagnoser scale, 30 PMDD patients and 30 asymptomatic controls, between the ages of 20 and 46, were included in the study. The eyeblink component of the acoustic startle reflex was assessed using electromyographic measurements of m. orbicularis oculi. Twenty pulse-alone trials (115 dB 40 ms broad-band white noise) and 40 prepulse-pulse trials were presented. The prepulse stimuli consisted of a 115 dB 40 ms noise burst preceded at a 100 ms interval by 20 ms prepulses that were 72, 74, 78, or 86 dB. PMDD patients had a significantly higher startle response than controls during both phases of the menstrual cycle (p<0.05). PMDD patients exhibited lower levels of prepulse inhibition with 78 dB and 86 dB prepulses compared to control subjects in the luteal (p<0.01) but not in the follicular phase. Whereas control subjects displayed increased PPI during the late luteal phase compared to the follicular phase (p<0.01), PPI magnitude remained unchanged in PMDD patients between cycle phases. Relative to controls, PMDD patients displayed increased startle reactivity across both menstrual cycle phases and deficits in prepulse inhibition of acoustic startle during the late luteal phase. These findings are consistent with an altered response to ovarian steroids among PMDD patients.     

Evidence for a Role of Progesterone in Menstrual Cycle-Related Variability in Prepulse Inhibition in Healthy Young Women

Prepulse inhibition (PPI) of the startle response is sensitive to sex, with healthy young women showing less PPI compared with age-matched men, and varies according to the menstrual cycle phase in women. Relatively less is known regarding sex and hormonal influences in prepulse facilitation (PPF). Menstrual phase-related variability in PPI is suggested to be mediated by fluctuating estrogen level, based on the observations of more PPI in women during the follicular, relative to the luteal, phase. No study has directly assessed the relationship between fluctuating hormones and PPI or PPF levels over the human ovarian cycle. To examine the roles of circulating ovarian hormones in PPI and PPF, 16 non-smoking regularly menstruating healthy women were tested during both the follicular and luteal phases on PPI and PPF and provided saliva samples for measurement of 17β-estradiol (estrogen), progesterone and testosterone. The results showed higher levels of 17β-estradiol and progesterone during the luteal, relative to the follicular, phase; and more PPI during the follicular phase and more PPF during the luteal phase with comparable startle amplitude and habituation during the two phases. A larger increase in progesterone was associated with a smaller decrease in PPI from the follicular to the luteal phase. No significant associations were found between changes in PPI/PPF and estrogen levels. The findings confirm lower PPI during the luteal, compared with the follicular, phase and suggest a role for progesterone, more specifically an antipsychotic-like PPI-restoration action of progesterone, during the luteal phase in PPI of young women.     

Effects of the menstrual cycle on timing and depth of breathing at rest

Volume and timing components of resting ventilation were measured serially in 40 women aged 18 to 36 yr, during menstrual, follicular and luteal phases of menstrual cycle. Resting minute ventilation (VE) was significantly higher (P < 0.001) in luteal phase than in menstrual and follicular phases; in the two latter phases VE was almost equal. This increment in VE during the luteal phase was due to a significant rise (P < 0.001) in tidal volume (VT). Respiratory frequency (f) was unchanged throughout the cycle. Although there was a mean increases in inspiratory time (T1) during the luteal phase compared to the other two phases, the difference did not reach statistical significance. Duty cycle, T1/Ttot, was also unchanged throughout menstrual cycle. However, mean inspiratory flow, VT/T1, was significantly higher (P < 0.05 and P < 0.01) during luteal phase as compared to that during menstrual or follicular phases respectively. Pulmonary mechanics, as measured by forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and forced mid expiratory flow rate (FEF25%, 75%), were within normal limits and remained unaltered during the menstrual cycle. Therefore, in the absence of alteration of pulmonary mechanics, the luteal increase in ventilation and inspiratory flow suggests a possible role for progesterone in stimulating the respiratory drive, either centrally or through the peripheral chemoreceptors or by both.     

Influence of sex-steroid hormones on the regulation of lymphocyte beta 2-adrenoceptors during the menstrual cycle.

1. Up to 40% of female asthmatic subjects suffer a premenstrual deterioration in their condition which may be ameliorated by progesterone supplementation, although the mechanism responsible for this phenomenon is not understood. In vitro studies have shown that female sex-steroid hormones potentiate the bronchorelaxant effect of isoprenaline, whilst in vivo it has been shown that females exhibit greater sensitivity of systemic beta 2-adrenoceptor responses. 2. The aim of the present study was to determine whether cyclical alterations in beta 2-adrenoceptor expression, occurring under the influence of ovarian sex-steroid hormones, may offer an explanation for these findings. In vitro parameters of lymphocyte beta 2-adrenoceptor function were investigated in nine normal female subjects (aged 24 +/- 2 years) during the follicular (day 2-4) and luteal (day 21-23) phases of their menstrual cycle, and results were compared with those of nine age-matched healthy male controls studied at the same time intervals. 3. In female subjects there were significant increases in serum concentrations of oestradiol (3.3-fold) and progesterone (10.6-fold) between the follicular and luteal phases of the menstrual cycle, whereas no changes occurred in males. 4. In females during the luteal phase, the increase in sex-steroid hormones was mirrored by an increase in lymphocyte beta 2-adrenoceptor density (Bmax) and in maximal cyclic AMP response to isoprenaline (Emax), which were significantly higher than in male subjects. Mean differences (95% CI) between male and female subjects on visit 2 were 1.09 (0.49 to 1.69) fmol/10(6) cells (P = 0.001) for Bmax, and 3.42 (0.80 to 6.04) pmol/10(6) cells (P = 0.02) for Emax.(ABSTRACT TRUNCATED AT 250 WORDS)     

Menstrual cycle effects on caffeine elimination in the human female

Summary Increases in the levels of sex steroids due to pregnancy or oral contraceptive steroid use are known to decrease significantly the rate at which caffeine is eliminated from the body. An investigation has now been made into whether the changes in sex steroid levels that occur during normal menstrual cycling also affect the rate of caffeine elimination, especially whether hormonal shifts in the luteal phase are associated with slower elimination of caffeine. Repeated 24-hour caffeine elimination studies were conducted during the follicular and luteal phases of the menstrual cycle in 10 healthy women.Comparisons of the follicular and luteal phases revealed that systemic clearance of caffeine was slower in the luteal phase, although the t1,2 did not differ. The slowing effect was related to the proximity to onset of menstruation and to levels of progesterone.The evidence suggests that caffeine elimination may be slowed in the late luteal phase, prior to the onset of menstruation. Such a reduction would lead to increased accumulation of caffeine with repeated self-administration during the day, but the effect may be too small to be of clinical significance in the majority of women.     

Effects of oral contraceptives on plasma neutral amino acids and cholesterol during a menstrual cycle

Objective: Concentrations of plasma neutral amino acids, i.e. threonine, serine, asparagine, glycine, alanine, citrulline, α-aminobutyric acid, valine, methionine, isoleucine, leucine, tyrosine, phenylalanine, and tryptophan, and serum cholesterol, were determined at the follicular (Day 4), mid-cycle (Day 16) and luteal (Day 25) phases of the menstrual cycle in 15 users of the new generation of combined oral contraceptives (OC), 11 on multiphase combined OC, and 17 controls. Results: The controls showed a decrease in the sum of amino acids to 95% at mid-cycle and 90% in the luteal phase relative to the follicular phase, and a significant decrease in the tyrosine level at the luteal relative to the follicular phase. Since there was no significant difference between the two OC subgroups in the levels of the specified variables at either of the phases, the two groups were considered together. The sum of amino acids in the OC group decreased to 89% at mid-cycle and 91% at the luteal phase relative to the follicular phase, indicating less metabolic effect than reported for older OC formulations. Compared to the controls, the OC group showed significant increased threonine level at the luteal phase, decreased glycine levels at mid-cycle and the luteal phases, decreased citrulline level at mid-cycle, and markedly decreased tyrosine levels at the mid-cycle and luteal phases. Neither total nor high density lipoprotein (HDL) cholesterol differed significantly between the control and OC groups. Conclusion: The results suggest that the metabolic effects of the new generation combined OC on neutral amino acids and cholesterol are only modest to slight, except for the effect on tyrosine, the brain noradrenaline precursor, which may cause disturbances of various noradrenaline-mediated central functions in susceptible subjects.     

The influence of menstrual cycle phase on sensitivity to ethanol-like discriminative stimulus effects of GABA(A)-positive modulators.

Previous studies showed that sensitivity to the ethanol-like discriminative stimulus effects of allopregnanolone and ethanol are enhanced during the luteal phase of the menstrual cycle when progesterone levels peak in monkeys trained to discriminate 1.0 g/kg ethanol. The present study further explored the influence of the menstrual cycle phase on the discriminative stimulus effects of ethanol, allopregnanolone, and midazolam. Female adult cynomolgus monkeys (Macaca fascicularis) were trained to discriminate 1.0 g/kg ethanol (n = 3) or 2.0 g/kg ethanol (n = 4) (20% w/v; i.g.) from water (i.g.). A cumulative dosing procedure was used to test discriminative stimulus effects of ethanol (0.5-2.5 g/kg; i.g.) and the ethanol-like discriminative stimulus effects of allopregnanolone (0.1-1.0 mg/kg; i.v.) or midazolam (1.0-17 mg/kg; i.g.) during the follicular vs. luteal phase of the menstrual cycle. In the 2.0-g/kg group, sensitivity to the ethanol-like effects of allopregnanolone was increased during the luteal vs. follicular phase in two of three monkeys. In contrast, average sensitivity to ethanol was not different in the luteal compared to the follicular phase in the 2.0-g/kg group. Finally, there was no difference in sensitivity to midazolam between the follicular and luteal phases in monkeys trained with either 2.0 g/kg or 1.0 g/kg ethanol. Overall, the ethanol-like discriminative stimulus effects of midazolam are not sensitive to the menstrual cycle phase. In addition, there was less influence of the menstrual cycle phase on allopregnanolone and ethanol sensitivity in a 2.0-g/kg compared to a 1.0-g/kg ethanol training dose.     

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 sex, menstrual cycle and oral contraception on the disposition of nitrazepam.

1 The effects of sex and oral contraceptives (OC) on the disposition of oral nitrazepam were studied in six healthy young males, in six healthy young females in the follicular and luteal phase of the menstrual cycle and in six healthy young females using OC-steroids in two stages of the pill cycle. 2 There was no influence of the menstrual cycle on the pharmacokinetic parameters of nitrazepam, nor was there a significant difference between these parameters in males and females in either phase of the cycle. The elimination half-life was 27.3 +/- 1.3 h in males, 27.7 +/- 1.5 h in females in the follicular phase and 29.6 +/- 1.4 h in the luteal phase of the menstrual cycle. Total plasma clearance was 59.3 +/- 2.7 ml/min, 58.2 +/- 3.3 and 55.8 +/- 5.0 ml/min respectively. 3 The use of OC-steroids did not significantly alter the elimination half-life of nitrazepam: 30.6 +/- 2.3 and 31.2 +/- 2.2 h in the first and second half of the pill cycle. The total nitrazepam clearance in these females (46.6 +/- 4.6 and 45.6 +/- 4.1 ml/min) was significantly lower than in males (P less than 0.05). 4 The protein unbound fraction of nitrazepam was progressively higher going from males (11.4 +/- 0.1%) to females in the luteal phase of the cycle (12.4 +/- 0.5%) to females using OC-steroids (13.5 +/- 0.4%). Only the difference between males and females using OC-steroids was statistically significant. 5 The clearance calculated relative to the unbound drug (intrinsic clearance) was significantly decreased in females taking OC-steroids as compared to males and females not taking them (Cli = 323 +/- 30 ml/min in females using OC-steroids, 530 +/- 37 ml/min in males and 459 +/- 40 ml/min in females). 6 The results of this study are not likely to have important consequences for dosage of nitrazepam as an hypnotic. The most pronounced effect observed was inhibition of nitrazepam clearance and especially intrinsic clearance by OC-steroids. Females on OC-steroids taking a nitrazepam tablet every evening, will have highly steady levels of nitrazepam (and certainly of unbound nitrazepam) than males or females not taking OC-steroids.     

怀孕周期对人工流产的临床疗效分析

目的了解人工流产后患者的内分泌生殖系统的激素分泌情况,并分析怀孕周期对人工流产的疗效影响以及临床应用价值。方法选取2011年3月-2012年3月在我院住院进行人工流产的患者74例作为研究对象,同时选取同期到本院检查的正常孕妇74例作为对照研究对象。在患者的排卵前后测定尿样采用放射免疫法测定各项激素指标。结果正常妊娠周期组尿中EIC浓度在卵泡晚期以及黄体中期明显低于人工流产组,两组比较差异具有统计学意义（P〈0．05）。正常妊娠组的PdG／EIC在黄体期d4～8明显高于人工流产组,两组比较差异具有统计学意义（P〈0．05）。两组的FSH比较差异无统计学意义（P〉0．05）。人工流产组患者经过雌-孕激素联合用药疗效比较显著。结论人工流产患者可能与卵泡晚期和黄体中期患者的PdG／EIC降低、黄体中期的EIC升高等因素有关,采取激素治疗疗效显著。     

Effects of oral contraceptives on acute cocaine response in female volunteers

A growing number of recent reports have demonstrated sex and menstrual cycle differences in the subjective, physiological and pharmacokinetic effects of stimulant drugs in humans. The present study was conducted to further investigate the relationship between gonadal hormones and cocaine effects by examining whether oral contraceptives (OCs) alter the acute effects of cocaine. Seven female volunteers, who were taking triphasic OCs and who were occasional users of cocaine, provided informed consent and participated in this placebo-controlled, four-visit study. Subjects were studied twice during days 6-10 of the menstrual cycle (equivalent to the follicular phase) and twice during days 21-28 of the menstrual cycle (equivalent to the luteal phase) and were challenged with an acute dose of intranasal (in) cocaine (0.9 mg/kg or placebo). There were no differences in cocaine-induced subjective, physiologic or plasma cocaine and metabolite levels during the times equivalent to the follicular and luteal phases of the menstrual cycle. Our findings provide evidence that OCs do not present an added risk of cocaine-induced cardiovascular effects and that exogenous administration of estrogen and progesterone at the physiologic doses found in OCs do not alter the subjective responses to acute cocaine.     

Pharmacokinetics and safety of oral eletriptan during different phases of the menstrual cycle in healthy volunteers.

The purpose of this study was to determine the pharmacokinetics and safety of eletriptan in different phases of the menstrual cycle. Female volunteers (n = 16) with a regular menstrual cycle (28 +/- 4 days) received a single oral dose of 80 mg eletriptan during each of the four cycle phases: phase 1 (menses), days 1 to 4; phase 2 (follicular), days 6 to 10; phase 3 (ovulatory), days 11 to 13; and phase 4 (luteal), days 21 to 24. Eletriptan plasma concentrations were determined from serial plasma samples taken during a 24-hourperiod after dosing. Blood pressure, pulse rate, and ECG measurements were performed at baseline, 1 and 24 hours after dosing. No significant differences between phases were observed for maximum plasma concentration (cmax, range of means = 188-234 ng/ml), time to maximum concentration (tmax, range of means = 1.8-2.5 h), or systemic exposure (area under the curve [AUC], range of means = 1194-1514 ng x h/ml). Although there was a statistically significant difference in the terminal phase elimination rate constant (kel) between phases 1 and2 (0.175/h vs. 0.158/h, p = 0.044), the corresponding difference in terminal phase half-life (t 1/2) (4.0 h vs. 4.4 h) was not considered to be clinicallyrelevant. No clinically relevant differences in blood pressure, pulse rate, or ECG were observed, and the incidence, nature, and severity of adverse events were similar in all phases. The different phases of the menstrual cycle had no clinically significant effect on the pharmacokinetics, safety, or tolerability of oral 80 mg eletriptan in healthy females.     

PLASMA CATECHOLAMINE CONCENTRATIONS DURING MORPHINE WITHDRAWAL IN CONSCIOUS GUINEA-PIGS

1. Plasma noradrenaline (NA) and adrenaline (AD) concentrations and locomotor activity were measured in conscious normal and adrenalectomized guinea-pigs before and after injection of a single dose of morphine (15 mg/kg) and following precipitation of withdrawal with naloxone 2 h later. Arterial blood samples were obtained via carotid catheters inserted 3 days before experiment. Normal guinea-pigs given saline instead of morphine were used as controls. 2. Increased locomotor activity occurred following naloxone injection in both intact and adrenalectomized morphine-treated guinea-pigs. 3. Plasma AD concentration was significantly elevated only during the naloxone-precipitated withdrawal period, whereas plasma NA concentration was also elevated during the morphine treatment period. No significant changes occurred in saline-treated guinea-pigs given naloxone. 4. In adrenalectomized guinea-pigs AD did not reach detectable levels in the plasma at any time during the experiments, thus showing that the increased plasma AD level during morphine withdrawal in normal animals reflected adrenal medullary release. 5. It was concluded that measurements of plasma AD concentration and locomotor activity in guinea-pigs should be useful for the study of the interactions between behavioural and autonomic mechanisms involved in opiate dependence and withdrawal, since the effects of morphine and morphine withdrawal on the autonomic nervous system are clearly different in this species.     

Differential subjective effects of D-amphetamine by gender,hormone levels and menstrual cycle phase

Estrogen and progesterone interact with monoamines in ways that suggest the potential modulation of responses to psychoactive drugs by endogenous steroids, both between menstrual phases and between the sexes. The present study assessed the subjective and physiological effects of a single dose of D-amphetamine (AMPH; 15 mg oral) in healthy, normally cycling women (n=13), who received amphetamine and placebo (PL) during both the follicular and luteal phases of a single menstrual cycle, and in healthy men (n=7). Females reported greater amphetamine-induced subjective stimulation [Addiction Research Center Inventory (ARCI)-A, ARCI-MBG; Drug Effects Questionnaire (DEQ) Feel Drug, Feel High, Want More] during the follicular phase than the luteal phase. Within the follicular phase, the magnitude of individuals' AMPH-induced stimulation was positively associated with baseline (predrug) salivary estradiol [r=+.55-.78; Profile of Mood States (POMS) Vigor, Positive Mood, Elation], and negatively associated with salivary progesterone [r=-.66-.68; POMS Friendliness; Subjective States Questionnaire (SSQ) Pleasant Sedation]. Sex differences also emerged. Males reported feeling greater AMPH-induced stimulation (ARCI-A, ARCI-MBG; DEQ Feel Drug, Want More) than females in the luteal phase. Thus, higher levels of estrogen and lower levels of progesterone are associated with greater subjective stimulation after AMPH in women, and these hormonal influences contribute to sex differences in amphetamine responding.     

Role of endothelium in the human uterine arteries during normal menstrual cycle.

1. The present experiments were designed to investigate the role of endothelium in the human uterine arteries during the normal menstrual cycle. 2. Acetylcholine (ACh) produced a concentration-dependent relaxation response during the higher level of plasma 17 beta-oestradiol (E2) (follicular and luteal phases, E2 = 131.9 +/- 15.9 pg ml-1, n = 13; group I). However, the agent did not produce a definite relaxation, but produced a slight contraction during the ovulatory and menstruation phases (E2 = 19.8 +/- 2.9 pg mg-1, n = 5; group II). During the follicular and luteal phases (E2 = 181.1 +/- 9.0 pg ml-1, n = 6), ACh produced a slight contraction, but not relaxation in 6 cases (group III). Relaxation in response to A23187 in group II was not different from that in group I, while it was significantly (P < 0.05 and P < 0.005) reduced in group III. Sodium nitroprusside (SNP)-induced relaxation was similar in the three groups. 3. Correlation between the maximum response to ACh and the plasma E2 was highly significant (gamma = 0.8142, P < 0.001) in 18 cases of groups I and II, but not in all 24 cases including group III (gamma = 0.1183, NS). 4. Relaxations in response to ACh in group I or A23187 in all groups were abolished after removal of the endothelium. In group I, ACh- and A23187-induced relaxations were greatly inhibited by methylene blue or NG-nitro-L-arginine (L-NOARG) and partially inhibited by indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)     

FREE AND CONJUGATED CATECHOLAMINES IN HUMAN PLASMA DURING PHYSICAL EXERCISE

To investigate changes of free and sulfoconjugated catecholamines in response to alterations in sympatho-adrenal activity, free and conjugated noradrenaline, adrenaline and dopamine were determined radioenzymatically in plasma of 49 subjects. During brief vigorous bicycle exercise (8 min, maximal heart rate: 177 beats/min) mean free noradrenaline and adrenaline values of 2.0 and 0.51 nmol/l at rest, increased to 6.7 and 2 nmol/l (P less than 0.001) respectively, at the maximal workload of 200 watt, whereas conjugated noradrenaline and adrenaline decreased from 3.4 and 0.8 nmol/l to 2.1 and 0.4 nmol/l (P less than 0.001) respectively. In the tenth min of the recovery period basal free and conjugated noradrenaline and adrenaline levels were measured. The moderate stress of a steam bath (20 min, maximal heart rate: 131 beats/min) doubled free noradrenaline and adrenaline levels. However, conjugated noradrenaline and adrenaline concentrations remained unchanged. The increase in free catecholamine values during an exhausting cross-country march over 20 km was associated with an accumulation of sulfated catecholamines. After a rest of 30 min free noradrenaline and adrenaline reached basal values, whereas conjugated noradrenaline and adrenaline remained elevated by 64 and 70% respectively, compared to pre-exercise concentrations. It was concluded that conjugated noradrenaline and adrenaline may be used as pools for free noradrenaline and adrenaline during brief vigorous exercise. In addition, they may also be indicators of chronic activation of the sympatho-adrenal system.     

Effects of exogenous female sex-steroid hormones on lymphocyte β2-adrenoceptors in normal females

We have previously shown that lymphocyte β₂-adrenoceptors (AR) are under cyclical control of sex-steroid hormones with greater receptor density during the luteal phase of the menstrual cycle. It has also been postulated that abnormal cyclical regulation of β₂-AR might be a possible mechanism for premenstrual asthma. The effects of exogenous female sex-steroid hormones on lymphocyte β₂-AR function were studied in eight normal healthy females. They were evaluated at two successive menstrual cycles, during the follicular phase (day 1–6). They were randomized to receive single oral doses of either ethinyloestradiol 50 μg or medroxyprogesterone 10 mg in a cross-over study. Lymphocyte β₂-AR parameters were evaluated at baseline (t₀), 24 h (t₂₄) and 72 h (t₇₂) after ingestion. Baseline levels of progesterone and oestradiol were comparable on both cycles. Receptor density (B_max) increased significantly (P<0.01) from t₀ after progesterone but not oestradiol at t₂₄: a 1.39-fold geometric mean difference (95% CI 0.96–2.00) between t₂₄vs t₀. Receptor affinity (K_d) and maximal cAMP response to isoprenaline (E_max) were not altered by either treatment. These results show that exogenous progesterone but not oestradiol, given during the follicular phase, significantly increased β₂-AR. This, therefore, suggests that endogenous progesterone is probably responsible for previously observed increase in B_max during the luteal phase of the female menstrual cycle. These findings may suggest possible therapeutic strategies for modulation of β₂-AR in premenstrual asthma.     

Exogenous progesterone attenuates the subjective effects of smoked cocaine in women, but not in men.

In a previous study, we showed that the positive subjective effects of cocaine were higher during the follicular phase compared to the luteal phase of the menstrual cycle. The purpose of the present study was to determine if exogenously administered progesterone during the follicular phase in females would attenuate the response to cocaine compared to the normal follicular phase, thus making the response to cocaine similar to the luteal phase. To address the role of sex differences, males were also administered exogenous progesterone during one inpatient stay. In all, 11 female and 10 male non-treatment-seeking cocaine smokers participated. Females had three inpatient stays: one during a normal follicular phase, one during a normal luteal phase, and one during a follicular phase when exogenous progesterone was administered. Males had two inpatient stays: one when exogenous progesterone was administered and the other when placebo was administered. During each inpatient admission, there were four smoked cocaine administration sessions: participants were administered six doses of cocaine (0, 6, 12, or 25 mg cocaine base) at 14 min intervals. Smoked cocaine increased heart rate, blood pressure and several subjective effects such as 'good drug effect' and 'drug quality' cluster scores. Administration of progesterone during the follicular phase in women attenuated the positive subjective effects of cocaine, whereas only minimal changes were observed in men. These results indicate that progesterone modulates the response to cocaine in women and suggests that fluctuations in endogenous progesterone levels account for some of the sex differences observed in humans.