Premenstrual Asthma Research Articles

Premenstrual asthma: epidemiology, pathogenesis and treatment.

The exacerbation of asthma in the premenstrual period has long been of interest. Premenstrual asthma has been estimated to affect up to 40% of females with asthma, although the exact prevalence of this phenomenon is unclear as studies have involved small numbers in hospital clinics. Large-scale community-based studies are required to estimate its true prevalence. Researchers are slowly piecing together clues as to the aetiology and pathogenesis of the disorder. Female sex-steroid hormones play an important role but the exact mechanism is still unknown. Recent evidence suggests that increased airway hyperresponsiveness, an indicator of underlying airway inflammation, during the luteal phase of the menstrual cycle may account for premenstrual exacerbations. In addition, there is now evidence of impaired or altered beta2-adrenoceptor function and regulation in females with asthma, which may have a part to play. Accurate diagnosis is dependent on a detailed history and the demonstration of premenstrual dip in peak expiratory flow. Exacerbations in the majority of women will respond to the usual treatment of bronchial asthma. However, a few women will experience significant morbidity or treatment-related adverse effects. Case reports suggest that the combined oral contraceptive pill or gonadotrophin-releasing hormone analogues may be effective in these patients. This requires substantiation by randomised controlled trials.

Asthma and sex hormones.

A chronic in ammatory state of the airways is considered the hallmark of asthma (1). However, the incidence, severity, and prognosis of asthma can be affected by a number of factors, including the patient's sex and age. The sex of the fetus seems to in uence the development of the respiratory apparatus. In fact, between weeks 28 and 40 of gestation, the lungs are in a more advanced state in females than in males (2), a fact which could explain, at least in part, the higher incidence of respiratory distress in male infants (3). Clinical observations and epidemiologic studies agree that childhood asthma is more frequent in boys than in girls (4). Moreover, in some children, usually boys, asthmatic symptoms that started in infancy disappear around puberty (5), while many girls have the disease only during adolescence (6). Age has been implicated in the severity of asthma. Asthma beginning during adulthood is generally more severe than childhood-onset asthma (7). Asthma that starts around the menopause or in old age is generally quite severe (5). According to two recent epidemiologic investigations, the patient's sex and age affect the hospitalization rate for asthma (8, 9), which is a marker of severity. In the ®rst study (a retrospective study of 33 269 patients), the admission rate of boys in the 0±10-year age group was almost twice that of girls. In the next decade, sex differences in the hospitalization rate were irrelevant, although there was a small, but signi®cant prevalence of females. At all ages above 20 years, hospital admission rates were higher in women than men, with a female/ male ratio ranging from 3:1 in subjects aged 20±50 years to 2.5:1 in those over 50 years of age (8). Similar data were reported by Elliasson (9). Both studies found a relationship between the age and sex of the patient and the severity of the asthma attack as indicated by duration of hospitalization. In fact, the duration of hospitalization increased with age in both sexes; moreover, hospital stays were longer in women over 30 years of age than in men of the same age (8, 9). Abbreviations. FSH: follicle-stimulating hormone; LH: luteinizing hormone; NK cell: natural killer cell; IL-1, -4, -5, -6: interleukin-1, -4, -5, -6; TGF-b: tumor growth factor-beta; PEFR: peak expiratory ow rate. Allergy 2001: 56: 13±20 Printed in UK. All rights reserved Copyright # Munksgaard 2001

Is pre-menstrual asthma related to use of aspirin or non-steroidal anti-inflammatory drugs?

Is pre-menstrual asthma related to use of aspirin or non-steroidal anti-inflammatory drugs?

Prevention of severe premenstrual asthma attacks by leukotriene receptor antagonist

Background: The etiology and treatment of premenstrual exacerbations of asthma (PMA) remain uncertain. Objective: We investigated the role of cellular mediators released from inflammatory cells in the airflow limitation during PMA. Methods: Serum levels of leukotriene (LT) B 4 , LTC 4 , platelet- activating factor, histamine, IL-1β, IL-4, IL-5, IL-6, and GM-CSF were measured at different time points, first just before or during menstruation when the peak expiratory flow rate (PEFR) began to decrease precipitously and second during the menstrual midcycle week (days 10-16) when the PEFR returned to baseline values in patients with PMA and in age-matched asthma patients without PMA at the same intervals. Results: Serum levels of LTC 4 were significantly higher during exacerbations of asthma than after recovery (69.0 ± 16.0 pg/mL vs 24.0 ± 9.5 pg/mL, P < .05), whereas those of IL-1β, IL-4, IL-5, IL-6, GM-CSF, histamine, LTB 4 , and platelet-activating factor did not differ between 2 periods in 5 patients with PMA. In contrast, in 5 asthmatic patients without PMA serum levels of cellular mediators did not differ between corresponding periods. Oral administration of pranlukast, an LT receptor antagonist (225 mg twice daily), significantly reduced decreases in PEFR from the baseline values (110 ± 21 L/min with pranlukast vs 233 ± 20 L/min without pranlukast, P < .01) in association with an improvement of asthma symptom scores (6.5 ± 1.1 with pranlukast vs 9.8 ± 0.7 without pranlukast, P <0.05) in 5 patients with PMA. Conclusion: LTs are partly involved in the pathogenesis of PMA, and LT receptor antagonists may be useful for preventing airflow obstruction in patients with PMA. (J Allergy Clin Immunol 1999;104:585-8.)

β2-Adrenoceptor Regulation and Function in Female Asthmatic Patients Receiving the Oral Combined Contraceptive Pill

Previously it has been shown that there is abnormal hormonal control of beta2-adrenoceptors in asthmatic women. Exogenous progesterone but not estradiol produces paradoxic downregulation and desensitization of beta2-adrenoceptors in asthmatic women when compared with nonasthmatic subjects. This study investigates the effect of the oral combined contraceptive pill (OCP) on beta2-adrenoceptor regulation and function in female asthmatic patients. The study population was comprised of 11 women with stable mild to moderate asthma. The mean age was 25 years; the FEV1 was 89% of predicted, and the forced expiratory flow, mid-expiratory phase (FEF25-75%) was 69% of predicted. Patients were evaluated while on (day 20 to 21) and off (day 5 to 7) the OCP during a 28-day calendar period. Serum sex hormones, lymphocyte beta2-adrenoceptor parameters, and bronchodilator and systemic dose-response curves (DRCs) to albuterol (Salbutamol) (100 to 1,600 microg) were measured at both on and off periods. Serum levels of endogenous estradiol and progesterone were both suppressed by the OCP. Baseline FEV1 were not different while patients were on (2.70 L) and off (2.72 L) the OCP. There were no significant differences in lymphocyte beta2-adrenoceptor parameters between the two phases of the cycle. Receptor density (geometric mean Bmax) was 1.78 (on OCP) vs 1.86 (off OCP) fentomole/10(6) cells, maximal cyclic adenosine monophosphate response to isoprenaline was 6.60 (on OCP) vs 7.58 (off OCP) pmol/10(6) cells, and binding affinity was 14.0 (on OCP) and 13.6 (off OCP) pmol/L. Likewise, there were no significant differences in the bronchodilator and systemic DRCs constructed at both phases of the cycle as evaluated: area-under-curve (AUC) FEV1 was 0.53 (on OCP) vs 0.56 (off OCP) L.h; and AUC FEF25-75% was 3,130 (on OCP) vs 3,640 (off OCP) L. Potassium (K) and finger tremor responses were unaltered between the two periods: AUC K was 0.50 (on OCP) vs 0.44 (off OCP) mmol . h/L and AUC tremor was 0.72 (on OCP) vs 0.89 (off OCP) log units.h. The OCP did not alter beta2-adrenoceptor regulation and function in stable female asthmatic patients. Further studies are required in patients who have premenstrual asthma.

Increased theophylline metabolism in the menstrual phase of healthy women

Background: We previously reported on a Japanese woman with premenstrual asthma whose serum theophylline concentration was lower before the onset of her menstrual period. We evaluated the clearance of theophylline in each phase of her menstrual cycle and found an increase in clearance in the premenstrual and menstrual phases. Objective: This study was designed to investigate whether changes in theophylline clearance may occur with the menstrual cycle in nonasthmatic women. Methods: Aminophylline, 250 mg, was infused intravenously for 45 minutes, and the clearance of theophylline was calculated in seven healthy, ovulatory women on days 1 or 2, 10, and 20 or 25 of the menstrual cycle. The serum concentration of theophylline was determined with an enzyme immunoassay (homogeneous). Results: Theophylline clearance was significantly higher and its half-life was significantly shorter in the menstrual phase than in the follicular phase. Conclusion: The metabolism of theophylline, and consequently, its clearance were increased in healthy women around the onset of menses. Clinicians must therefore consider the menstrual variation in theophylline metabolism when prescribing this drug to female patients. (J Allergy Clin Immunol 1997;100:39-43.)

Loss of normal cyclical beta 2 adrenoceptor regulation and increased premenstrual responsiveness to adenosine monophosphate in stable female asthmatic patients.

BACKGROUND: A study was undertaken to investigate the influence of the menstrual cycle on airway responsiveness and beta 2 adrenoceptor function in female asthmatic patients. It has previously been shown...

Premenstrual asthma: still poorly understood.

<h3>ABSTRACT</h3> Accurate characterization of the tropical moist forests changes is needed to support conservation policies and to better quantify their contribution to global carbon fluxes. We document - at pantropical...

Paradoxical Down-Regulation and Desensitization of β2-Adrenoceptors by Exogenous Progesterone in Female Asthmatics

We have demonstrated previously that exogenous progesterone, but not estrogen, up-regulated lymphocyte beta2-adrenoceptors (beta2-AR) when given during the follicular phase in healthy women. Female asthmatics exhibit loss of the cyclical pattern of beta2-AR regulation seen in healthy women, in that there is no luteal phase rise in beta2-AR. It has been postulated that abnormal cyclical regulation of beta2-AR might be a possible mechanism for premenstrual asthma. In this study, we were interested to see how exogenous female sex-steroid hormones altered beta2-AR regulation in female asthmatics during the follicular phase, when endogenous hormone levels are normally low. Seven nonsmoking female subjects with mild asthma, with a mean (SEM) age of 26 (2) years and FEV1 of 94.7% (6.4) of predicted, completed this randomized, double-blind, crossover study. They were evaluated at two successive menstrual cycles, during the follicular phase (day 1 to 6). They were randomized to receive single oral doses of either ethinyl estradiol (ethinyloestradiol), 50 microg, or medroxyprogesterone, 10 mg. Lymphocyte beta2-AR parameters were evaluated at baseline (T0), 24 h (T24), and 72 h (T72) after ingestion. Baseline levels of progesterone and estradiol were comparable on both cycles. Receptor binding density (log Bmax; fmol/10(6) cells) decreased significantly after progesterone but not after estrogen at T24: amounting to a 1.34-fold mean difference (95% confidence interval [CI], 1.01 to 1.78) between T24 vs T0 with progesterone. Comparing Bmax for progesterone with estrogen at T24 amounted to a 1.25-fold significant difference (95% CI, 1.00 to 1.56). This was associated with a trend (p=0.06) toward a lower cyclic-adenosine monophosphate (AMP) response to isoproterenol hydrochloride (isoprenaline) 10(-4) M (Emax) at T24 vs T0 with progesterone. Receptor binding affinity (Kd) was not altered by either treatment. These results show that exogenous progesterone, but not estrogen, given during the follicular phase, decreased beta2-AR density and cyclic-AMP response in female asthmatics, in contrast to the previously observed up-regulating effect of progesterone seen in healthy women. This paradoxical effect of progesterone in female asthmatics suggests an abnormal regulation of beta2-AR and might be a possible mechanism for premenstrual asthma when progesterone levels are high during this period of the cycle.

月経喘息の臨床的意義とその発症機序に関する研究

月経喘息の臨床的意義とその発症機序に関する研究

Influence of the menstrual cycle on airway function in asthmatic and normal subjects.

Investigations of premenstrual asthma (PMA) have been based on studies of asthmatics already aware of a deterioration of asthma premenstrually. Little is known, therefore, about relationships between the menstrual cycle and airway function in asthmatics who do not complain of PMA or in normal subjects. We investigated airway function in both of these groups for three or four consecutive menstrual cycles. Daily records of asthma symptoms and peak expiratory flow rates were maintained by 11 asthmatics and 29 normal control subjects. Standard spirometry and serum estradiol and progesterone levels were measured during the follicular, midluteal, and late luteal phases of the menstrual cycle. Airway reactivity to methacholine was tested during the follicular and luteal phases. The normal group showed no significant changes in symptoms, peak flow rates, spirometric parameters, or airway reactivity. Although the asthmatic group also demonstrated no significant changes in spirometry and airway reactivity, asthma symptoms (shortness-of-breath, cough, wheeze, and chest tightness) deteriorated significantly (p less than 0.001) from the follicular to the luteal phase, as did the morning peak flows of the asthmatics (p = 0.045). Airway function and reactivity were not related to hormone levels in either group. This study indicates that asthmatics not previously aware of PMA will record a premenstrual worsening of asthma symptoms and peak expiratory flow rates. These changes are not related to a deterioration in spirometry and airway reactivity or to the absolute levels of circulating progesterone and estradiol.

The effect of sodium meclofenamate in premenstrual asthma: A controlled clinical trial

We speculated that changes in endogenous prostaglandin synthesis might be responsible for the syndrome of premenstrual asthma (worsening of asthma in relation to menstruation). To test our hypothesis, we compared the effects of sodium meclofenamate, a prostaglandin synthesis inhibitor, and placebo on premenstrual asthma in a 4-month, double-blind, crossover study of 17 women with asthma. Day-by-day evaluation revealed that peak expiratory flow reached a nadir during menstruation on both meclofenamate and placebo therapy and varied inversely with menstrual symptoms and asthma symptoms. Meclofenamate therapy resulted in significant improvement in peak expiratory flow during the early premenstrual period but had no treatment effect on the exacerbation of asthma during the late premenstrual period and early menstruation. The overall improvement in pulmonary function caused by meclofenamate therapy was correlated with the treatment effect on menstrual symptoms. Meclofenamate caused a small, nonsignificant decrease in use of theophyllin and oral β-agonist agents, whereas corticosteroid use increased slightly but not significantly. This study demonstrates the temporal relationship between menstrual symptoms and asthma. The study also demonstrates that inhibition of prostaglandin synthesis does not prevent exacerbation of asthma in relation to menstruation.

Morbidity in asthma in relation to the menstrual cycle

After observing three cases of severe recurrent exacerbations of asthma in relation to menstruation, we conducted a survey among women with asthma inquiring about the relationship of asthma symptoms to the menstrual cycle. Of 57 women with asthma, 19 (33%) had significant worsening ( p = 0.006) of total pulmonary symptom scores during either the premenstrual period, the menstrual period, or both with maximum increase in dyspnea, wheezing, and chest tightness during the premenstrual period ( p = 0.002). The other 38 (66%) women noted no such changes in their asthma. Logistic regression analysis comparing women with and without worsening of their asthma around menstruation revealed that the former group reported significantly more severe wheezing in general ( p < 0.05) and also more severe pulmonary symptoms during the premenstrual period ( p < 0.05). Of the women whose asthma was affected by menses, 13 (68%) had been hospitalized for asthma but only 10 (26%) of the women who were unaffected ( p = 0.002). Both dysmenorrhea scores and premenstrual syndrome scores correlated significantly with baseline pulmonary symptom scores in the premenstrual asthma group. It appears that asthma morbidity is affected by the menstrual cycle in a subgroup of women with asthma.