The effect of the menstrual cycle on asthma presentations in the emergency department.

BACKGROUND: Seventy-five percent of all adult hospital admissions for asthma are women. OBJECTIVE: To determine whether a relationship exists between phases of the menstrual cycle and asthma exacerbations in adult females. METHODS: Data were analyzed from 182 nonpregnant, adult females with asthma aged 13 years to menopause. Date of presentation, patient age, duration of asthma attack, date of last menstrual period, regular interval between menses, presenting peak expiratory flow rate, and admission and discharge decision were recorded prospectively. Treatment interventions abstracted retrospectively from patient charts included use of oxygen, xanthines, beta-adrenergic agonists, corticosteroids, and magnesium sulfate. The menstrual cycle was divided into 4 phases based on fluctuations in serum estradiol levels. The 4 intervals were preovulatory (days 5-11), periovulatory (days 12-18), postovulatory (days 19-25), and perimenstrual (days 26-4). RESULTS: Data were analyzed with a goodness-of-fit chi 2. Between June 1991 and May 1992, 182 females (mean +/- SD age, 28.5 +/- 8.0 years) were surveyed. No significant differences were noted for use of oxygen, beta-adrenergic agonists, xanthines, or magnesium among members of the 4 menstrual groups. Intervention with corticosteroids was least in the postovulatory interval (y:n) 0.5:1 and greatest in the preovulatory interval 3.0:1 (alpha = .03) Presentations by menstrual interval were as follows: preovulatory, 36 (20%); periovulatory, 43 (24%); postovulatory, 18 (10%); and perimenstrual, 85 (46%) (alpha < .01). CONCLUSIONS: Asthma presentations are least frequent when serum estradiol levels are at a sustained peak. We observed a 4-fold variation in asthma presentations during the perimenstrual interval, when serum estradiol levels decrease sharply after that prolonged peak. These findings suggest that monthly variations in serum estradiol levels may influence the severity of asthma in adult females.

Effect of age on cardiac norepinephrine release in the female rat.

We previously demonstrated an age-related decline in K(+)-induced norepinephrine (NE) release from cardiac synaptosomes prepared from 6- and 24-month-old male F344 rats. The purpose of the present study was to determine if the age-related decrease in NE release seen in male F344 rats is also present in female F344 rats. K(+)-induced NE release was assessed in cardiac synaptosomes prepared from 6-, 12-, 18-, and 24-month-old male and female F344 rats. NE release was significantly greater in young male rats, compared to old male rats. However, no age-related decrease in NE release was observed in the female rats. In contrast to previous observations in male rats, raising extracellular [Mg2+], an inorganic Ca2+ channel blocker, reduced NE release to the same extent in all female ages. Omega-conotoxin, an organic Ca2+ channel blocker, also decreased NE release to the same extent in all female ages. These studies suggest that in contrast to aging male rats, cardiac adrenergic nerve terminals of aging female rats maintain their capacity to release NE.

Different tissue responses for iodine and iodide in rat thyroid and mammary glands.

This research describes the effects of short-term elemental iodine (I2) and iodide (I-) replacement on thyroid glands and mammary glands of iodine-deficient (ID) Sprague-Dawley female rats. Iodine deficiency causes atypical tissue and physiologic changes in both glands. Tissue histopathology and the endocrine metabolic parameters, such as serum TT4, tissue and body weights, and vaginal smears, are compared. A moderate reduction in thyroid size from the ID control (IDC) was noted with both I- and I2, whereas serum total thyroxine approached the normal control with both I- and I2, but was lower in IDC. Thyroid gland IDC hyperplasia was reduced modestly with I2, but eliminated with I-. Lobular hyperplasia of the mammary glands decreased with I2 and increased with I- when compared with the IDC; extraductal secretions remained the same as IDC with I2, but increased with I-; and periductal fibrosis was markedly reduced with I2, but remained severe with I-. Thus, orally administered I2 or I- in trace doses with similar iodine availability caused different histopathological and endocrine patterns in thyroid and mammary glands of ID rats. The significance of this is that replacement therapy with various forms of iodine are tissue-specific.

Prolactin secretion following repetitive seizures.

We studied serum prolactin levels after 24 seizures occurring in eight subjects. Video-EEG intracranial monitoring confirmed temporal or frontal partial seizures. Seizure type, focus, and duration were similar for seizures with and without significant postictal prolactin elevations. The seizure-free interval (the time between seizures) varied considerably. Seizures occurring after longer seizure-free intervals (31.75 to 240 hours) showed robust prolactin responses. After shorter seizure-free intervals (1.07 to 25.42 hours), prolactin responses were reduced. This suggests that the amount of releasable prolactin is limited, depleted by seizures, or perhaps inhibited by prolactin feedback. Seizure-free intervals should be considered when interpreting prolactin levels.

Iodine replacement in fibrocystic disease of the breast.

OBJECTIVE: To determine the response of patients with fibrocystic breast disease to iodine replacement therapy. DESIGN: Review of three clinical studies beginning in 1975: an uncontrolled study with sodium iodide and protein-bound iodide; a prospective, control, crossover study from iodide to molecular iodine; and a prospective, control, double-blind study with molecular iodine. SETTING: University affiliated breast-treatment clinics. PATIENTS: Study 1: 233 volunteers received sodium iodide for 2 years and 588 received protein-bound iodide for 5 years. Study 2: the treatment of 145 patients from study 1 treated with protein-bound iodide for several months who still had symptoms was switched to molecular iodine 0.08 mg/kg; 108 volunteers were treated initially with molecular iodine. Study 3: 23 patients received molecular iodine, 0.07 to 0.09 mg/kg body weight; 33 received an aqueous mixture of brown vegetable dye and quinine. The numbers in study 2 increased over the review period so that 1365 volunteers were being treated with molecular iodine by 1989. INTERVENTIONS: All patients in study 3 had pre- and post-treatment mammography and measurement of serum triiodothyronine, thyroxine and thyroid-stimulating hormone levels. MAIN OUTCOME MEASURES: Subjective evaluation--freedom from pain--and objective evaluation--resolution of fibrosis. RESULTS: Study 1: 70% of subjects treated with sodium iodide had clinical improvement in their breast disease, but the rate of side effects was high; 40% of patients treated with protein-bound iodide had clinical improvement. Study 2: 74% of patients in the crossover series had clinical improvement, and objective improvement was noted in 72% of those who received molecular iodine initially. Study 3: in the treatment group 65% had subjective and objective improvement; in the control group there was a subjective placebo effect in 33% and an objective deterioration of 3%. CONCLUSIONS: The fibrocystic breast reacts differently to sodium iodide, protein-bound iodide and molecular iodine. Molecular iodine is nonthyrotropic and was the most beneficial.

Ovulation induction with clomiphene and the rise in heterotopic pregnancies. A report of two cases.

Two women were treated for heterotopic pregnancies, the simultaneous occurrence of an intrauterine pregnancy and an ectopic pregnancy. The commonly accepted incidence is 1:30,000. The actual rate appears to be significantly higher; the two most prominent reasons are today's increased rate of ectopic pregnancies and the increased use of clomiphene in infertile women. A rigorous evaluation is required in all early pregnancies in which an ectopic is suspected to rule out the presence of a heterotopic pregnancy.

Iodoprotein formation by rat mammary glands during pregnancy and early postpartum period.

Iodide organification by rat mammary glands was studied during the trimesters of pregnancy and early postpartum period. Organification was followed by measuring trichloroacetic acid (TCA) precipitation of delipidated tissue homogenates. The radiolabeled material was sensitive to proteolytic cleavage by a bacterial protease indicating that the 125I was protein-bound. Gel filtration column chromatography in the presence of sodium dodecyl sulfate (SDS) of delipidated mammary tissue homogenates of pregnant and postpartum rats reproducibly resolved several iodoproteins from free iodide. The Kav value for each iodoprotein peak was calculated and was used to estimate each subunit molecular weight which averaged 37,500, 25,100, and 8500. Another iodoprotein with a very large subunit molecular weight of greater than 300,000 was also detected in mammary tissue. Incorporation of 125I-iodide into the three smaller iodoproteins increased logarithmically from the start of the second trimester of pregnancy through the early postpartum period when approximately 20% of the total 125I uptake by mammary tissue was incorporated into protein. Hyperplasia, acinar development, and intracytoplasmic vacuolization of mammary tissue correlated with the increased incorporation of 125I-iodide into these iodoproteins. The characterization and quantitation of specific iodoproteins in mammary tissue may be important as organification of iodide is believed to be a marker for normal hormone-responsive cells.

Iodine and breast cancer A 1982 update.

Research has been directed towards investigating the role of the trace element, iodine, in breast cancer etiology, diagnosis, and therapy. In many controled studies, iodine has been established as a requirement for breast tissue normalcy, since deficiency of the element results in histopathology consistent with dysplasia and atypia in rodents. Clinically severe hyperplasia and fibrocystic disease is seen in the breasts of women who have low iodine levels. These precancerous lesions result in a high-risk state as well as persistent symptomatology in women. Iodine replacement therapy has been shown to be efficacious in reducing these conditions in clinical trials. Basic research is directed towards intracellular pathways and metabolism for breast iodide, emulating those seen in the thyroid gland. Thus, using a rat model, iodine intracellular organification is being correlated with risk factors for breast cancer including early and late pregnancies, onset of puberty, menopause, and aging. From our research there is significant evidence that iodine maintains homeostasis in reproductive, effected tissues and is responsible for breast tissue growth and development.

Pure gonadal dysgenesis with microscopic ovarian streak and gonadoblastoma.

A phenotypic female with an XY karyotype and no grossly demonstrable streak gonads is described. She had a microscopic focus of gonadoblastoma developing in a 3 X 2 mm area in the region of the ovarian vessels. The case stresses the importance of a careful search of the pelvic cavity in phenotypic females with a 46, XY karyotype.

Age-related changes resembling fibrocystic disease in iodine-blocked rat breasts.

It has been reported that dietary restriction and chemical blockade of iodine causes histopathologic changes in peripubertal female rat breasts. This study extended the age range to include midreproductive life and perimenopausal rats; there is a wider spectrum of structural alterations that are associated with the older breast, with sodium perchlorate as the blocking agent. In 16-week-old rats, breasts showed general increased parenchymal activity and growth, regressing after removal of the block. In 42-week-old rats, breasts showed noticeable calcospherite deposition, intralobular fibrosis, and cystic changes resembling human fibrocystic disease. In 52-week-old rats, breasts exhibited atypical lobules cytologically, papillomatosis, sclerosing adenosis, calcifications, and a lobular transformation of a histologically dysplastic type. It is the older rat that experiments will more closely parallel the human condition.

The intracellular metabolism of iodine in carcinogenesis.

Research from this laboratory and others have concluded that significant glandular atypia, and often neoplasia, occurs in the breast tissues of rodents and humans under conditions of iodine deprivation. These cellular changes caused by iodine deficiency are intensified, by aging, steroid hormones, and pituitary hormones. There has been controversy concerning the effect of iodine deficiency on stimulation and maintenance of cancer of the breast in rodents when the cancer is induced chemically or by transplantation. However, neither within this induced neoplastic framework nor with the dysplastic changes seen by deficiency alone have laboratory studies of thepathway of intracellular iodine been previously possible.The new research data addresses the question of whether organification occurs and whether iodine significantly affects the intracellular structures. An hypothesis will be presented that places the inorganic element, iodine, into association with receptor protein complexes that may be responsible for intracellular sex hormone activity. The relationship of this mechanism to carcinogenesis in breast tissue will be considered.

Iodine and mammary cancer.

From laboratory studies presented, iodine appears to be a requisite for the normalcy of breast tissue in higher vertebrates. When lacking, the parenchyma in rodents and humans show atypia, dysplasia, and even neoplasia. Iodine-deficient breast tissues are also more susceptible to carcinogen action and promote lesions earlier and in greater profusion. Metabolically, iodine-deficient breasts show changes in RNA/DNA ratios, estrogen receptor proteins, and cytosol iodine levels. Clinically, radionuclide studies have shown that breast atypia and malignancy have increased radioactive iodine uptakes. Imaging of the breasts in high-risk women has localized breast tumors. The potential use of breast iodine determination to determine estrogen dependence of breast cancer has been considered and the role of iodide therapy discussed. In conclusion, iodine appears to be a compulsory element for the breast tissue growth and development. It presents great potential for its use in research directed toward the prevention, diagnosis, and treatment of breast cancer.

Rat mammary gland atypia produced by iodine blockade with perchlorate.

Prior published work from our laboratory concluded that there was a need for appropriate metabolic activity of iodine in breast tissue for normal growth and development. Results from studies in rats that were made iodine deficient showed histological changes in the breasts that were atypical and dysplastic. These tissue findings were further affected by the presence of estrogen and thyroxine. These changes parallel the iodine uptake of the tissues, thus representing a difference in the utilization of iodine by the mammary glands. Using an ion blockade agent, sodium perchlorate, breast tissues lacking iodine were evaluated by both endocrine and histological techniques. A dose-response series was completed that showed that perchlorate therapy for 8 weeks at 400 mg/100 ml produced breast blockade by a reduction in iodine uptake of greater than 52% of the control. At these levels, the histological experimentation showed atypia and some pleomorphism of the cells, particularly in the glands of the lobules. Blockade was less effective in estrogen-treated groups. It is especially notable that both histological changes and uptake reduction were greatest in those breasts that had been rendered euthyroid by thyroxine replacement, thus clearly indicating the necessity of iodine itself for maintenance of normal breast development. By this blockade the responses of iodine inadequacy in the breast were shown to cause abnormal tissue changes relative to the percentage of the block obtained.