Micronutrients and the premenstrual syndrome: the case for calcium.

Premenstrual syndrome afflicts millions of premenopausal women and has been described as one of the most common disorders in women. Research over the past few years suggests that a variety of nutrients may have an important role in the phase related mood and behavioral disturbances of the premenstrual syndrome. There is scientific evidence, at least for a few of these micronutrients, specifically calcium and vitamin D, supporting cyclic fluctuations during the menstrual cycle that may help explain some features of PMS. Ovarian hormones influence calcium, magnesium and vitamin D metabolism. Estrogen regulates calcium metabolism, intestinal calcium absorption and parathyroid gene expression and secretion, triggering fluctuations across the menstrual cycle. Alterations in calcium homeostasis (hypocalcemia and hypercalcemia) have long been associated with many affective disturbances. PMS shares many features of depression, anxiety and the dysphoric states. The similarity between the symptoms of PMS and hypocalcemia is remarkable. Clinical trials in women with PMS have found that calcium supplementation effectively alleviates the majority of mood and somatic symptoms. Evidence to date indicates that women with luteal phase symptomatology have an underlying calcium dysregulation with a secondary hyperparathyroidism and vitamin D deficiency. This strongly suggests that PMS represents the clinical manifestation of a calcium deficiency state that is unmasked following the rise of ovarian steroid hormone concentrations during the menstrual cycle.

Vitamin D and calcium dysregulation in the polycystic ovarian syndrome.

Over the past 30 years, numerous studies in invertebrates and vertebrates have established a role of calcium in oocyte maturation as well as in the resumption and progression of follicular development. Polycystic ovarian syndrome (PCO) is characterized by hyperandrogenic chronic anovulation, theca cell hyperplasia, and arrested follicular development. The aim of this observational study was to determine whether vitamin D and calcium dysregulation contribute to the development of follicular arrest in women with PCO, resulting in reproductive and menstrual dysfunction. Thirteen premenopausal women (mean age 31 +/- 7.9 years) with documented chronic anovulation and hyperandrogenism were evaluated. Four women were amenorrheic and nine had a history oligomenorrhea, two of whom had dysfunctional bleeding. Nine had abnormal pelvic sonograms with multiple ovarian follicular cysts. All were hirsute, two had alopecia, and five had acanthosis nigricans. The mean 25 hydrovitamin D was 11.2 +/- 6.9 ng/ml [normal (nl): 9-52], and the mean 1,25 dihydroxyvitamin D was 45.8 +/- 18 pg/ml. with one woman with a 1,25 dihydroxyvitamin D <5 pg/ml (nl: 15-60). The mean intact parathyroid hormone level was 47 +/- 19 pg/ml (nl: 10-65), with five women with abnormally elevated parathyroid hormone levels. All were normocalcemic (9.3 +/- 0.4 mg/dl). Vitamin D repletion with calcium therapy resulted in normalized menstrual cycles within 2 months for seven women, with two experiencing resolution of their dysfunctional bleeding. Two became pregnant, and the other four patients maintained normal menstrual cycles. These data suggest that abnormalities in calcium homeostasis may be responsible, in part, for the arrested follicular development in women with PCO and may contribute to the pathogenesis of PCO.

Is premenstrual dysphoric disorder a distinct clinical entity?

Does the evidence now available support the concept of premenstrual dysphoric disorder (PMDD) as a distinct clinical disorder such that the relative safety and efficacy of potential treatment can be evaluated? In a roundtable discussion of this question, a wealth of information was reviewed by a panel of experts. The key characteristics of PMDD, with clear onset and offset of symptoms closely linked to the menstrual cycle and the prominence of symptoms of anger, irritability, and internal tension, were contrasted with those of known mood and anxiety disorders. PMDD displays a distinct clinical picture that, in the absence of treatment, is remarkably stable from cycle to cycle and over time. Effective treatment of PMDD can be accomplished with serotinergic agents. At least 60% of patients respond to selective serotonin reuptake inhibitors (SSRIs). In comparison with other disorders, PMDD symptoms respond to low doses of SSRIs and to intermittent dosing. Normal functioning of the hypothalamic-pituitary-adrenal (HPA) axis, biologic characteristics generally related to the serotonin system, and a genetic component unrelated to major depression are further features of PMDD that separate it from other affective (mood) disorders. Based on this evidence, the consensus of the group was that PMDD is a distinct clinical entity. Potential treatments for this disorder can now be evaluated on this basis to meet the clear need for effective therapy.

Calcium carbonate and the premenstrual syndrome: effects on premenstrual and menstrual symptoms. Premenstrual Syndrome Study Group.

OBJECTIVE: Previous reports have suggested that disturbances in calcium regulation may underlie the pathophysiologic characteristics of premenstrual syndrome and that calcium supplementation may be an effective therapeutic approach. To evaluate the effect of calcium carbonate on the luteal and menstrual phases of the menstrual cycle in premenstrual syndrome, a prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial was conducted. STUDY DESIGN: Healthy, premenopausal women between the ages of 18 and 45 years were recruited nationally across the United States at 12 outpatient centers and screened for moderate-to-severe, cyclically recurring premenstrual symptoms. Symptoms were prospectively documented over 2 menstrual cycles with a daily rating scale that had 17 core symptoms and 4 symptom factors (negative affect, water retention, food cravings, and pain). Participants were randomly assigned to receive 1200 mg of elemental calcium per day in the form of calcium carbonate or placebo for 3 menstrual cycles. Routine chemistry, complete blood cell count, and urinalysis were obtained on all participants. Daily documentation of symptoms, adverse effects, and compliance with medications were monitored. The primary outcome measure was the 17-parameter symptom complex score. RESULTS: Seven hundred twenty women were screened for this trial; 497 women were enrolled; 466 were valid for the efficacy analysis. There was no difference in age, weight, height, use of oral contraceptives, or menstrual cycle length between treatment groups. There were no differences between groups in the mean screening symptom complex score of the luteal (P = .659), menstrual (P = .818), or intermenstrual phase (P = .726) of the menstrual cycle. During the luteal phase of the treatment cycle, a significantly lower mean symptom complex score was observed in the calcium-treated group for both the second (P = .007) and third (P < .001) treatment cycles. By the third treatment cycle calcium effectively resulted in an overall 48% reduction in total symptom scores from baseline compared with a 30% reduction in placebo. All 4 symptom factors were significantly reduced by the third treatment cycle. CONCLUSIONS: Calcium supplementation is a simple and effective treatment in premenstrual syndrome, resulting in a major reduction in overall luteal phase symptoms.

Short-term inhibition of parathyroid hormone secretion by a calcium-receptor agonist in patients with primary hyperparathyroidism.

BACKGROUND: Surgery is the usual therapy for patients with primary hyperparathyroidism. We investigated the ability of a calcimimetic drug that inhibits parathyroid hormone secretion in vitro to decrease serum parathyroid hormone and calcium concentrations in patients with this disorder. METHODS: We performed a randomized, placebo-controlled study of single oral doses of 4 to 160 mg of the calcium-receptor agonist drug R-568 in 20 postmenopausal women with mild primary hyperparathyroidism. At base line, the mean (+/-SE) serum calcium concentration was 10.7+/-0.2 mg per deciliter (2.67+/-0.05 mmol per liter). Serum parathyroid hormone and calcium were measured repeatedly after each dose, and safety was assessed. RESULTS: Administration of R-568 resulted in a dose-dependent inhibition of parathyroid hormone secretion. The mean serum parathyroid hormone concentration, which was 77+/-11 pg per milliliter (18.8+/-2.7 pmol per liter; normal range, 16 to 65 pg per milliliter [3.9 to 15.9 pmol per liter) at base line, fell by 26+/-8 percent after 20 mg of R-568 (P=0.03), by 42+/-7 percent after 80 mg (P = 0.01), and by 51+/-5 percent after 160 mg (P=0.005). Serum ionized calcium concentrations fell only after the 160-mg dose, with the decrease closely following the decrease in the serum parathyroid hormone concentration. CONCLUSIONS: The calcimimetic drug R-568 reduces serum parathyroid hormone and ionized calcium concentrations in postmenopausal women with primary hyperparathyroidism.

Calcium-regulating hormones across the menstrual cycle: evidence of a secondary hyperparathyroidism in women with PMS.

Calcium metabolism across one menstrual cycle was studied in 12 healthy, premenopausal women. Seven women had documented premenstrual syndrome (PMS), and five were asymptomatic controls. Fasting blood samples were drawn at six points throughout the ovulatory cycle. In both the asymptomatic and the PMS groups, total and ionized calcium declined significantly at midcycle with the increase of estradiol. In the PMS group only, peak midcycle intact PTH was significantly elevated by approximately 30% compared with early follicular levels (49 +/- 25 vs. 37 +/- 22 ng/L, t = 3.79, P = 0.009). In the asymptomatic group, iPTH did not vary during the menstrual cycle. Midcycle iPTH was significantly higher in the PMS group compared with that of the control group (49 +/- 25 vs. 26 +/- 7 ng/L, Wilcoxon Z = 2.28, P = 0.02). Multivariate analysis showed that total and ionized calcium both varied significantly across the menstrual cycle. Significant differences between groups were found for total calcium, 25OHD, and 1,25-(OH)2D. One woman with PMS was treated with oral elemental calcium and cholecalciferol daily for 3 months, with amelioration of her symptoms. Midcycle iPTH and 1,25-(OH)2D declined after repletion of 25OHD. In conclusion, we found that concentrations of total and ionized calcium significantly fluctuate during the menstrual cycle both in symptomatic and in asymptomatic women. We also found that concentrations of iPTH, 25OHD, and 1,25-(OH)2D differed between groups during specific phases of the menstrual cycle. Our data suggest that women with PMS have midcycle elevations of iPTH with a transient, secondary hyperparathyroidism.

Comparative analysis of three PMS assessment instruments--the identification of premenstrual syndrome with core symptoms.

Premenstrual syndrome (PMS) is a commonly encountered complaint among women. This study compared the PMS Diary (PMSD), which measures core menstrual symptoms (negative affect, water retention, and pain symptoms), with two commonly used self-rating forms, the Menstrual Distress Questionnaire (MDQ) and the Daily Rating Form (DRF). Thirty-seven premenopausal women with documented PMS completed the forms. A multitrait-multimethod analysis was performed to determine overall agreement and reliability. The three instruments and their component scale scores had strong internal consistency. Correlations between overall scores and between scales measuring similar constructs were strong. Correlations were 0.77 between PMSD and MDQ; 0.67 between PMSD and DRF; and 0.81 between MDQ and DRF. The PMSD performs as effectively as more extensive questionnaires in measuring symptoms in women with PMS. The PMS Diary is a concise yet reliable and valid instrument that can be easily administered in ambulatory care and longitudinal research.

Alleviation of migraines with therapeutic vitamin D and calcium.

Two postmenopausal migraineurs who developed frequent and excruciating migraine headaches (one following estrogen replacement therapy and the other following a stroke) were treated with combination vitamin D and calcium. Therapeutic replacement with vitamin D and calcium resulted in a dramatic reduction in the frequency and duration of their migraine headaches.

Vitamin D and calcium in menstrual migraine.

Two premenopausal women with a history of menstrually-related migraines and premenstrual syndrome were treated with a combination of vitamin D and elemental calcium for late luteal phase symptoms. Both cited a major reduction in their headache attacks as well as premenstrual symptomatology within 2 months of therapy. These observations suggest that vitamin D and calcium therapy should be considered in the treatment of migraine headaches.

Premenstrual and menstrual symptom clusters and response to calcium treatment.

Fourteen perimenstrual symptoms were rated daily by 33 women in a randomized, double-blind, crossover trial of calcium supplementation. Factor analysis was performed on these symptoms using 2,413 daily ratings during the luteal and menstrual phases with at least one symptom present. Four factors (negative affect, water retention, food, and pain) accounting for 67 percent of the total variance were extracted. Internal consistency was high for scales based on these factors. Correlations between the scores ranged from .35 to .69. Scores were low during the intermenstrual phase and much higher during both luteal and menstrual phases. Paired t-tests comparing the intermenstrual phase with both luteal and menstrual phases all resulted in significant differences at p less than .01. There was more pain reported during the menstrual compared with the luteal phase (p less than .01). Calcium supplementation reduced negative affect (p = .045), water retention (p = .003), and pain (p = .036) during the luteal phase and pain (p = .02) during the menstrual phase.

Calcium supplementation in premenstrual syndrome: a randomized crossover trial.

OBJECTIVE: To determine the efficacy of calcium supplementation in women with premenstrual syndrome (PMS). DESIGN: Randomized, double-blind crossover trial. SETTING: Outpatient medical clinic of a large city hospital. PARTICIPANTS: Seventy-eight women were initially screened. Trial selection was based on a history of recurrent PMS symptoms and on the results of a prospective assessment of daily symptom scores. Only women with symptom scores during the late luteal phase that were at least 50% greater than those during the intermenstrual phase were selected. Thirty-three women completed the trial. INTERVENTION: A preliminary evaluation included physical examination, routine laboratory tests, dietary assessment, and psychiatric evaluation. Each participant received six months of treatment involving three months of daily calcium supplementation (1,000 mg of calcium carbonate) and three months of placebo. MEASUREMENTS: Efficacy was assessed prospectively by changes in daily symptom scores over a six-month period and retrospectively by an overall global assessment. Multivariate repeated measures analysis of variance on symptom ratings derived from daily PMS symptom scores demonstrated a reduction in symptoms on calcium treatment during both the luteal (p = 0.011) and the menstrual phases (p = 0.032) of the reproductive cycle. Calcium supplementation had no effect during the intermenstrual phase. Retrospective assessment of overall symptoms confirmed this reduction: 73% of the women reported fewer symptoms during the treatment phase on calcium, 15% preferred placebo, and 12% had no clear preference. Three premenstrual factors (negative affect [p = 0.045]; water retention [p = 0.003]; pain [p = 0.036]) and one menstrual factor (pain [p = 0.02]) were significantly alleviated by calcium. CONCLUSION: Calcium supplementation is a simple and effective treatment for premenstrual syndrome, but further studies will be needed to determine its precise role in PMS.

Evaluation of isradipine (PN 200-110) in mild to moderate hypertension.

The efficacy and safety of isradipine (PN 200-110), a new dihydropyridine calcium antagonist, was evaluated in 87 hypertensive patients in a placebo-controlled, double-blind, randomized multicenter trial. After a 3-week single-blind washout phase, isradipine (or matching placebo) was administered for 4 weeks, beginning at 2.5 mg b.i.d. with increments of 2.5 mg b.i.d. at weekly intervals if supine diastolic blood pressure remained greater than or equal to 90 mm Hg. At the end of 1 week average supine blood pressure in the isradipine group (n = 45) fell from a baseline of 156 +/- 13/104 +/- 4 mm Hg to 146 +/- 14/97 +/- 7 mm Hg. By week 4 blood pressure was reduced by 19/14 mm Hg compared with 4/5 mm Hg in the placebo group (P less than 0.001 between groups). Supine and standing pulse rates were slightly increased initially with isradipine therapy but returned to baseline with increasing isradipine doses. Blood pressure responses at week 4 were good or excellent (supine diastolic less than or equal to 90 mm Hg or greater than or equal to 10 mm Hg decrease from baseline) in 87% of isradipine-treated patients and in 26% of placebo-treated patients. Headache, edema, abdominal discomfort, and constipation occurred slightly more frequently in isradipine-treated patients than in placebo-treated control subjects. The results indicate that isradipine, administered as monotherapy in doses of 2.5 to 10 mg b.i.d., is safe and effective in patients with mild to moderate essential hypertension.