Introduction

The desire for safe, cost-effective and therapeutic alternatives for the alleviation of PMS symptoms has prompted patients and medical professionals to examine the use of dietary supplements, such as calcium carbonate, as a treatment option.

The relationship between calcium and the menstrual cycle is not a new finding, as demonstrated in a study in which plasma calcium levels were lower in the premenstrual period compared to levels seen in the week following menstruation (Okey R et al., 1930).

Recent evidence has suggested that the pathophysiology of premenstrual syndrome (PMS) may be related to disturbances in calcium regulation and that the use of calcium supplements may be an effective means of managing PMS symptoms.

Calcium treatment has been shown to relieve symptoms including irritability, depression, anxiety, social withdrawal, headache, and cramps in two clinical investigations (Thys-Jacobs S et al., 1989; Penland JG, Johnson PE, 1989). Prospective and retrospective investigations have determined that there is a relationship between PMS and bone loss (Lee SJ et al., 1994; Thys-Jacobs S et al., 1995).

Additionally, one recent investigation suggested that hyperfluctuations of calcium-regulating hormones across a normal menstrual cycle may precede PMS in women with secondary hyperparathyroidism (Thys-Jacobs S, Alvir J, 1995).

PMS refers to a number of symptoms that occur within the luteal phase-7 to 14 days prior to menses-of the menstrual cycle that subside with the initiation of menses. Symptoms associated with PMS include fatigue, irritability, abdominal bloating, breast tenderness, labile mood with alternating sadness and anger, and moodiness and/or depression, according to the American College of Obstetricians and Gynecologists. For some women, symptoms are no more intrusive than that of menstruation itself, but for others, symptoms may hinder normal daily living.

While as many as 80% of women of reproductive age may experience emotional and physical symp-toms that can be attributed to the menstrual cycle, nearly 40% experience symptoms that noticeably affect their daily lives (Bendich A, 2000). Of this 40%, 3 to 5% experience premenstrual dysphoric disorder (PMDD), a disease state with symptoms that are very severe and incapacitating (Daugherty JE, 1998). However, many other women with PMS-excluding the symptoms characteristic of PMDD-often require medical attention and treatment.

Mild symptoms are often treated through educational and supportive counseling interventions, as well as lifestyle changes such as dietary and exercise modifications. Severe symptoms are often treated with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac®), anxiolytic drugs such as alprazolam (Xanax®), nonsteroidal anti-inflammatories (NSAIDs) such as ibuprofen, oral contraceptives, diuretics, or, in the most severe cases, gonadotropin-releasing hormone agonists (buserelin), which cause a temporary halt of the menstrual cycle.

Therapeutic modifications are not always associated with symptom alleviation for women with moderate symptoms because many presently used medications are associated with side effects. In addition, many women may be reluctant to take them for the management of symptoms associated with a normal biological function. Elemental calcium-given in the form of calcium carbonate-offers a safe, cost-effective alternative to prescription medications.

Evidence-based Safety and Efficacy of Calcium Carbonate

In one US-based, double-blind, two-way parallel, placebo-controlled, multicenter trial, 466 women with moderate to severe PMS were randomized to receive 1200 mg/day of elemental calcium (n = 231)-given as 750 mg chewable calcium carbonate tablets (TUMS® EX)-or placebo (n = 235) for three menstrual cycles (Thys-Jacobs S et al., 1998). All women in this study were between the ages of 18 and 45, in good health, and had normal complete blood counts (CBC), serum chemistry panels, and urinalyses, along with negative pregnancy tests and regular menses.

The outcome measure in this study was a 17-symptom complex score, including mood swings, depression, tension, anxiety, anger, crying spells, swelling of extremities, breast tenderness, abdominal bloating, headache, fatigue, insomnia, increased or decreased appetite, cravings for sweets or salts, lower abdominal cramping, generalized aches and pains, and low backache. Outcome was assessed via daily self-report in a PMS diary, biweekly telephone follow-up, and monthly follow-up office visits on days 7-10 of the menstrual cycle.

Of the calcium-treated women, 55% had more than 50% symptom improvement as compared to 36% of women in the placebo-treated group. Further, the symptom complex scores of calcium-treated women were significantly lower than those of the placebo-treated women in the second and third treatment cycles (p = 0.007 and p < 0.001, respectively). By the third treatment cycle, total symptom scores within the calcium-treated group demonstrated a 48% reduction compared with baseline values, while the placebo-treated group showed a 30% reduction.

According to Dr. Susan Thys-Jacobs, Metabolic Bone Center, St. Luke's- Roosevelt Hospital Center, Columbia University, New York, calcium carbonate was effective for the management of 15 out of 17 PMS symptoms assessed in the luteal phase of the second and third treatment cycles, with the exception of insomnia and fatigue. No significant effect of calcium treatment was shown during or between menstrual phases. Only the symptom of generalized aches and pains proved significantly different from placebo within the first treatment cycle (p = .031).

By the third treatment cycle, there was a 36% reduction in bloating in the calcium-treated group, compared to a 24% reduction in the placebo-treated group; there was a 54% reduction in food cravings in the calcium-treated group, and a 34% reduction in the placebo-treated group; and there was a 54% discomfort reduction in the calcium-treated group, and a 15% reduction in the placebo-treated group. Seventy-one women (15%) experienced worse symptoms at the end of the trial than at baseline screening-54 had received placebo while the remaining 17 had received calcium treatment. Within this subset, three times as many placebo-treated women as calcium-treated women experienced worsening of symptoms. By the third treatment cycle, calcium treatment proved most effective against negative affect symptoms, including mood swings, depression, tension, anxiety, anger, and crying spells. While the calcium-treated group experienced a 45% reduction in symptoms, the placebo-treated group reported a symptom reduction of only 28%.

Of the 466 women participating in this study, 422 reported various adverse events-216 for the calcium-treated group and 206 for the placebo-treated group. The side effects most-often reported included headache, rhinitis, and pain. Five patients in the calcium-treated group discontinued treatment due to nausea, and 2 women-1 in the calcium-treated group and 1 in the placebo-treated group-discontinued treatment due to the development of kidney calculi. Other women who discontinued treatment cited such adverse events as menorrhagia, pinched nerves, or emergency surgery, but whether these adverse events were related to calcium treatment is unknown.

From Clinical Trials to Recognized Treatment

Exactly how calcium treatment reduces PMS symptoms is not understood, due to the many symptoms associated with PMS and the complex hormonal interactions that are thought to be involved.

According to Dr. Thys-Jacobs, there are two key pieces of evidence that relate PMS to a calcium metabolism defect. The first is that the symptoms of PMS are similar to those associated with hypocalcemia. The second is the clinical efficacy observed during calcium treatment related to a decrease in the severity of the symptoms associated with PMS.

In one study, it was determined that women with PMS had reduced lower vertebral and femoral bone densities compared to asymptomatic controls, suggesting that PMS symptoms and calcium deficiency may be entwined (Thys- Jacobs et al., 1995). Pointedly, changes in calcium metabolism occur throughout the menstrual cycle due to the concentrations of ovarian steroid hormones, and such changes may account for some of the symptoms associated with PMS (Medical Crossfire 2000).

In terms of the reduction of negative affect symptoms in the 1998 Thys-Jacobs study, the 45% calcium- treated vs. 28% placebo-treated symptom reduction rates are similar to those reported in one study that examined the use of SSRIs to treat PMDD. In this study, a 44% symptom reduction was seen in the fluoxetine (Prozac®)-treated group, while a 24% symptom reduction was seen in the placebo-treated group (Steiner M et al., 1995). This finding allowed Dr. Thys- Jacobs and colleagues to state in their 1998 study that, although their trial investigated women with PMS and not specifically premenstrual dysphoria, calcium treatment is similar to treatment with fluoxetine for the management of negative affect symptoms.

Calcium treatment is relatively inexpensive, does not result in bone loss, lessens negative affect symptoms, lessens most symptoms associated with water retention, food cravings, and pain symptom factors, and is associated with minimal adverse events. In contrast, gonadotropin-releasing hormone agonist therapy-although it has shown a 75% reduction in PMS symptoms (Bancroft J et al., 1987)-is known to have hypoestrogenic effects, thereby increasing the risks for bone loss. Such therapy is also more expensive than other treatment options.

For the management of PMS symptoms in women of ages 19 to 50 years, Dr. Thys-Jacobs recommends at least 1000 mg/day of elemental calcium, taken 3 times per day as chewable calcium carbonate. This suggested dose is in accordance with the revised adequate intake levels for calcium, which also state that young women between the ages of 14 and 18 years should take 1300 mg/day (Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, 1997).

Conclusion

The 1998 controlled trial conducted by Thys-Jacobs and colleagues demonstrates that calcium carbonate supplementation serves to alleviate PMS symptoms in healthy women during the luteal phase of the menstrual cycle.

If it is found that PMS is an indicator of low calcium levels in the blood-and if this finding encourages premenopausal women to increase their calcium intake- perhaps the risk of osteoporosis could be lessened. Further study is needed to determine adequate dosing of calcium treatment and duration of therapy for PMS symptoms.

"Versus birth control pills, versus other vitamin supplements, versus agents that haven't been proved effective in a placebo-controlled trial, calcium should be the first thing that people think of, both consumers and physicians, when they start to consider treatment of PMS symptoms," for patients who require pharmacological treatment, concluded Dr. Michael A. Thomas, Associate Professor and Director, Center for Reproductive Health, University of Cincinnati Medical Center, Ohio.

References

ACOG: Premenstrual syndrome (ACOG committee opinion). Int J Gynaecol Obstet 1995;50:80-84.

Bancroft J, Boyle H, Warner Fraser HM. The use of LHRH agonist, buserelin, in the long term management of premenstrual syndrome. Clin Endocrinol 1987;26:171-182.

Daugherty, JE. Treatment Strategies for Premenstrual Syndrome. Am Fam Physician 1998;58:183-192, 197-198.

Bendich A. The Potential for Dietary Supplements to Reduce Premenstrual Syndrome (PMS) Symptoms. Journal of the American College of Nutrition 2000;19(1):3-12.

Lee SJ, Kanis JA. An association between osteoporosis and premenstrual and postmenstrual symptoms. Bone Miner 1994;24:127-34.

Medical Crossfire. The Premenstrual Syndrome Challenge: Is It a Disease? What Is the Best Course of Treatment? New Jersey: Liberty Publishing; 2000.

Okey R, Stewart JA, Greenwood ML. Studies of the metabolism of women. IV. The calcium and inorganic phosphorus in the blood of normal women at the various stages of the monthly cycle. J Biol Chem 1930;87:91-102.

Penland JG, Johnson PE. Dietary calcium and manganese effects on menstrual cycle symptoms. Am J Obstet Gynecol 1993;168:1417-1423.

Standing Committee on the Scientific Evaluation of Dietary Intakes. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D and fluoride. Washington: National Academy Press; 1997.

Steiner M, Steinberg S, Stewart D, et al. Fluoxetine in the treatment of premenstrual dysphoria. N Eng J Med 1995;332:1529-34.

Thys-Jacobs S, Ceccarelli S, Bierman A, Weisman H, Cohen MA, Alvir J. Calcium supplementation in premenstrual syndrome: a randomized crossover trial. J Gen Intern Med 1989;4:183-9.

Thys-Jacobs S, Alvir J. Calcium regulating hormones across the menstrual cycle-evidence of secondary hypoparathyroidism in women with PMS. J Clin Endocrinol Metab 1995;80:2227-32.

Thys-Jacobs S, Silverton M, Alvir J, Paddison PL, Rico M, Goldsmith SJ. Reduced bone mass in women with premenstrual syndrome. J Women's Health 1995;4:161-168.

Thys-Jacobs S, Starkey P, Bernstein D, Tian J, and the Premenstrual Syndrome Study Group. Calcium carbonate and the premenstrual syndrome: effects on premenstrual and menstrual symptoms. Am J Obstet Gynecol 1998;179:444-452.