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Abstract
PRIMARY OBJECTIVE: To evaluate the effectiveness of Neptune Krill Oil[TM] (NKO[TM]) for the management of premenstrual syndrome and dysmenorrhea. SECONDARY OBJECTIVE: To compare the effectiveness of NKO for the management of premenstrual syndrome and dysmenorrhea with that of omega-3 fish oil. METHODS/ DESIGN: Double-blind, randomized clinical trial. SETTING: Outpatient clinic. PARTICIPANTS: Seventy patients of reproductive age diagnosed with premenstrual syndrome according to the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R). INTERVENTIONS: Treatment period of three months with either NKO or omega-3 fish oil. OUTCOME MEASURES: Self-Assessment Questionnaire based on the American College of Obstetricians & Gynecologists (ACOG) diagnostic criteria for premenstrual syndrome and dysmenorrhea and number of analgesics used for dysmenorrhea. RESULTS: In 70 patients with complete data, a statistically significant improvement was demonstrated among baseline, interim, and final evaluations in the self assessment questionnaire within the NKO group as well as between-group comparison to fish oil, after three cycles or 45 and 90 days of treatment. Data analysis showed a significant reduction of the number of analgesics used for dysmenorrhea within the NKO group (comparing baseline vs. 45- vs. 90-day visit). The between-groups analysis illustrated that women taking NKO consumed significantly fewer analgesics during the 10-day treatment period than women receiving omega-3 fish oil. CONCLUSION: Neptune Krill Oil can significantly reduce dysmenorrhea and the emotional symptoms of premenstrual syndrome and is shown to be significantly more effective for the complete management of premenstrual symptoms compared to omega-3 fish oil.
Introduction
Premenstrual syndrome (PMS) and dysmenorrhea are characterized by a combination of cyclic symptoms that occur during the luteal phase of the menstrual cycle. Symptoms are practically absent in the follicular phase of the menstrual cycle, begin at varying points after ovulation, peak in the late luteal phase, and subside with the onset of menses or shortly thereafter. The diagnostic criteria based on the Diagnostic and Statistical Manual of Mental Disorders (DSM III-R), Third Edition, Revised are outlined in Table 1. (1)
Multiple causes have been attributed to the complex interplay of neuroendocrine, chronobiological, and psychosocial interactions that comprise the symptomatology of PMS. (2-8) A review reveals more than 200 symptoms that have been reported to occur premenstrually. (2,7) Depending on the symptom, the causative factors include hormonal imbalance, psychological abnormalities, nutritional deficiency or excess, increased inflammatory prostaglandin synthesis, and neurotransmitter imbalance. (2,8) Nevertheless, laboratory findings vary from being completely normal in some women to an excess or deficiency of certain hormones, neurotransmitters, or nutrients in others. The most probable cause of the physical symptoms of PMS seems to be the combined interaction of hormones and essential nutrients leading to an increased inflammatory response. On the other hand, the emotional symptoms of PMS seem to be propagated by an exaggerated response of neurotransmitters to psychosocial stresses. These imbalances have been shown to differ extensively from person to person, as well as from cycle to cycle within the same person.
Evidence suggests that alpha-tocopherol can significantly reduce symptoms of PMS. (2,9-16) Tocopherol reduces release of arachidonic acid from phospholipids, resulting in a decrease in formation of prostaglandin [E.sub.2] (PG[E.sub.2]) (inflammatory prostaglandins). (16) Alpha-tocopherol, which crosses the blood-brain barrier, also has modulating effects on neurotransmitters. (16) Several studies suggest a beneficial effect of vitamin A for the treatment of PMS, particularly for premenstrual headaches. (17,18)
The balance of polyunsaturated (essential) fatty acids in the body is critical for the maintenance of healthy cell membranes and hormone regulation. During the last several decades, the average Western diet has shifted to much higher levels of omega-6 and less omega-3 fatty acid intake. Long-chain omega-6 fatty acids, such as arachidonic acid, predominating in the phospholipids of cell membranes can encourage the production of pro-inflammatory type-2 prostaglandins (PG[E.sub.2]), while omega-3 fatty acids promote the production of anti-inflammatory prostaglandins. (19-20)
Omega-6 fatty acids, mainly arachidonic acid, are released following the reduction of progesterone prior to menstruation, (21,22) initiating an inflammatory process by triggering a flux of inflammatory prostaglandins and leukotrienes in the uterus. (21,22) At the same time, cyclooxygenase metabolites of arachidonic acid, prostaglandins E, and [F.sub.2], cause vasoconstriction and myometrial contractions that lead to ischemia and eventually the pain of menstrual cramps. (21,22)
Research has uncovered abnormal fatty acid metabolism in women with PMS. Brush and colleagues examined plasma fatty acid levels in 42 women with premenstrual syndrome. They found that although levels of linoleic acid, the body's main dietary source of omega-6 fatty acids, were significantly above normal in all the women, levels of its anti-inflammatory metabolites, including gamma-linolenic acid, were all deficient, (23) reinforcing the theory that one of the main causes of PMS is inflammation.
The role of long-chain fatty acids for the management of PMS has been evaluated in several studies. (2,19-27) Omega-3 fatty acids, mainly eicosapentanoic acid (EPA) and docosahexanoic acid (DHA), compete with the omega-6 species for the enzyme prostaglandin synthetase. The omega-3 fatty acids trigger secretion of less potent leukotrienes and anti-inflammatory prostaglandins of the 3 series (P[E.sub,3], P[I.sub.3], and thromboxane [A.sub.3]). (22,28-32) The result is a decrease of myometrial contractions and uterine vasoconstriction, relieving ischernia and reducing pain. This effect may be due to an increase in sensitivity of the uterus to the relaxing effects of beta-adrenergic catecholamines. (2,33-37)
While prostaglandin [E.sub.1] (PG[E.sub.1]) inhibits glucose-induced insulin secretion, a deficiency--occurring either as a result of an inadequate intake of essential fatty acids in the form of cis-linoleic acid or problems with conversion to gamma-linolenic acid (GLA)--could result in symptoms of hypoglycemia, cravings for sweets, and increase in appetite reported by many PMS patients. (26,27) Long-chain omega-3 fatty acids in fish oil have been shown to be effective for the control of cravings occurring prior to menstruation. (2,22-32,34-36)
Neptune Krill Oil[TM] (NKO[TM]) is a natural health product extracted from Antarctic krill also known as Euphausia superba. Euphausia superba, a zooplankton crustacean, is rich in phospholipids and triglycerides carrying long-chain omega-3 polyunsaturated fatty acids, mainly EPA and DHA, and in various potent antioxidants including vitamins A and E, astaxanthin, and a novel flavonoid (similar to the 6,8-Di-C-glucosylluteolin, but with two or more glucose molecules and one aglycone).
Patients, Materials, and Methods
Women of reproductive age who fulfilled the DSM-III-R diagnostic criteria for PMS were eligible for the study. Women who were pregnant or breast feeding, on concomitant anticoagulant therapy, receiving psychotherapy, experiencing alcohol or drug dependence, on sex hormones except for oral contraceptives, with a known seafood allergy, or diagnosed with dementia, pituitary disease, coagulopathy, or a serious medical condition were not eligible for enrollment. Patients taking other dietary supplements or vitamins were asked to stop supplementation for two weeks at which time they were randomized in the trial.
The study was described to potentially eligible patients by the treating physician. Once the patient agreed to participate, an "eligibility form" was completed by the physician according to the patient's answers. If the patient (referred as "she") was eligible, she signed a written Patient Informed Consent Form and was enrolled for randomization. Patients were randomly allocated according to a list of random numbers. Once the patient was randomized to either the NKO or an omega-3 fish oil group, she underwent a physical examination for screening purposes. If the physical examination revealed no reason for the patient to be excluded from the study, she was asked to complete an initial self-assessment questionnaire, as well as to record her usual daily consumption of analgesics (including type and frequency) for menstrual pain.
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