Abstract
Long-term use of oral contraceptives (OCs) and of hormone replacement therapy (HRT) have been linked to increased blood coagulation, with its increased risk of cardiovascular problems. Their long-term use also has been linked to altered immune and inflammatory factors, suggesting an increased risk of chronic immune disorders with an inflammatory component, including cancer. This report reviews these various risks. Also discussed are 2 natural food extracts, one showing anticoagulant effects and the other exhibiting certain anti-inflammatory and immunomodulatory effects. New research finds indications that these extracts—Plasmanex1 and BRM4—offset these key risks among OC and HRT users and suggests the need for further research.
Introduction
During the 50 years since oral contraceptives (OCs) were first introduced, their widespread use by women throughout their reproductive life cycles has caused concern about their effects on risk factors for cardiovascular diseases and cancer.1
For some women, the benefits of OCs outweigh the side effects and risks. Certainly, the risks of OCs can be less than the risks of pregnancy and childbirth.2,3 Of course, those with certain medical conditions or those who, while using oral contraceptives, experience adverse side effects—including breakthrough bleeding, dizziness, headache, lightheadedness, bloating, or nausea—may need to choose alternative contraceptive methods.
Other hormonal contraceptives—such as birth control patches and injections—produce side effects and risks similar to oral contraceptives, because they involve the same synthetic hormones. For the same reason, these dangers also apply to women on hormone replacement therapy (HRT). Combined, this translates into a large at-risk population.
Although occurrences are rare and may disappear after several cycles, OC use can cause vitamin deficiencies or post-pill amenorrhea. Because OC use has been shown to result in deficiencies of magnesium;4 folic acid;5 vitamins B2, B6, B12, and C; and zinc,6 OC users with poor diets should be advised about nutrition and supplementation to ensure they get adequate intake of these nutrients.
Even among well-nourished women for whom OCs are not contraindicated, the pill can result in other biological changes that pose long-term health risks. These include serious risks stemming from the negative influence of OCs and HRT on blood fluidity, resulting in increased risks of blood coagulation and leading to cardiovascular problems, including ischemic stroke, myocardial infarction, and deep venous thrombosis.7–9
Also of concern is the effect of OCs/HRT on the risks of the many disorders with an inflammatory component, ranging from clinical depression10,11 to cancer.12,13 The evidence for cancer risks is complex and possibly sometimes confusing to users. For instance, OCs seem to lower the risks of some cancers,12,14–16 while increasing the risks of others.12–13,16–23
OCs have evolved through various modifications to reduce the dosages of the different hormonal components to minimize the risk of thrombotic events, such as stroke. Some oral contraceptive pills contain progestin alone, while others contain both estrogen and progestin. The first-generation OCs contained relatively high doses of each. The second and later generations contained 2 to 5 times lower estrogen doses and up to 10 times lower progestin doses.
But because both OC use and some level of thrombotic risk are expected to continue, strategies to minimize the risk are needed.
Although some evidence suggests that newer formulations present a reduced risk of ischemic stroke,24 numerous studies consistently have found an elevated risk of venous thromboembolism, even among users of low-estrogen dose OCs,25 which also may be slightly less effective in preventing pregnancy. In general, there is simply insufficient information to determine whether major differences in the risk of ischemic stroke exist among the different formulations.24 Today, the overall leading cause of mortality for women in developed countries remains coronary artery disease,26 and researchers have suggested that further research on OCs and coagulation risk would be beneficial.24,27
Dietary supplements may serve as antithrombotic agents. About 180 dietary supplements are listed in the Natural Medicines Comprehensive Database as having the potential to interfere with the blood thinner warfarin (Coumadin). Yet few studies have been published so far to help establish the antithrombotic effects of these supplements.28 Also, no studies have compared the effectiveness of naturally derived supplements to the pharmaceutical blood thinners; consequently, information does not exist on the dosages required to reproduce the effects of drugs. The standard anticoagulant treatment continues to be warfarin, clopidogrel (Plavix), and other medications.
Similarly, a host of studies has shown the potential effectiveness of a number of natural agents against inflammation, including omega-3 essential fatty acids (EFAs), white willow bark, curcumin, and pycnogenol. However, further study on these or other natural agents would be welcome, because at present, little is known about many of their biological actions or their potential interactions with other nutraceuticals and medications. Also, so far, dosage levels for specific treatment goals have not yet been well defined, and the standard treatment for a number of inflammation-related conditions remains nonsteroidal anti-inflammatory drugs (NSAIDs).29
With OC- and HRT-caused changes suspected in the long-term development of serious health risks, safe interventions that may ameliorate the coagulant and inflammatory risks of OCs would be of great interest. It is proposed here that 2 functional foods offer promise as a natural, dual-extract agent that may attenuate these risks.
One is derived from the fermented Japanese soybean food, nattoÂ; the other is an extract of rice bran, modified enzymatically with an extract of shiitake mushroom. The natto derivative acts as an anticoagulant, while the modified rice bran extract is an immunomodulatory product.
Some published studies have found the natto derivative has anticoagulant and antithrombotic benefits,30–35 subjective benefits,36 and noninterference with the drug warfarin.37 Similarly, some published studies have found immunomodulatory benefits of modified rice bran extract.38–45
Because the combination of these 2 supplements may have a synergistic effect that offsets many of the risks of OCs/HRT, further research is needed, especially on the combined effects of these functional food supplements when taken together.
In 2011, an exploratory study46 was conducted in which 2 natural supplements were administered together for the purpose of uncovering potential benefits of combined use, as well as areas that may prove fruitful for further research into ways to prevent serious side effects from OCs/HRT. The 6-week private practitioner research study included case study results that demonstrated the significant impact of 2 extracts—Plasmanex1 and BRM4—on OC users and HRT users, with regard to offsetting thrombotic risk and improving inflammatory symptoms.
In this report, we examine general information about the major risks of OCs/HRT, as well as current evidence suggesting specific benefits of the safe intervention of these 2 food supplements.
Thrombotic Risks
Health practitioners are well-advised to screen women—both those initiating OC use, and those who have been on OCs long-term—for contraindications, such as suspected breast cancer, uterine cancer, blood clot disorders, hypercholesterolemia, liver disease, severe obesity, smoking beyond the age of 35, or cardiovascular disease. However, many of these independent risk factors first become apparent only after OCs have been taken for many years. Also, for many women, the risks—although real—do not outweigh the benefits of OC use, so health concerns continue. Research continues to substantiate the thrombotic risks for estrogen-containing OCs, and “these negative effects should not be underestimated.”47
Cardiovascular problems in OC users include ischemic stroke, myocardial infarction, and deep venous thrombosis.7–9 Of course; HRT therapy involves the same synthetic hormones. A 1990 study concluded that oral contraceptives lower the risks of some conditions, such as ectopic pregnancy, ovarian and endometrial malignancy, benign breast disease, and benign ovarian cysts; but the same study found a 3- to 6-fold increase in the risk of venous thromboembolism (VTE).8 Also, one study has noted a significant increase in free cholesterol among OC users.48 In another study, OC use among African American women was linked with an increase in cardiovascular risk markers, shown by elevated triglycerides, increased insulin resistance, and glucose intolerance.49 Therefore, some researchers suggest that women on oral contraceptive pills should be regularly monitored for signs of hypertension, hypercholesterolemia, hypercoagulability, and diabetes.7
Various formulations of the different hormonal components have been introduced in an attempt to minimize thrombotic problems, and to provide options for women with different risk factors. As mentioned earlier, compared to first-generation OCs, the second and later generations contained 2 to 5 times lower estrogen doses and up to 10 times lower progestin doses. Both the second and third generations used 1 of 2 potent (“gonane”) progestins, desogestrol or gestodene. And a fourth generation has been proposed to contain 2 new progestins (nontestosterone-derived progestins called chlormadinone acetate and drospirenone).
With the new formulations, researchers anticipated finding lower risks for thromboembolism, myocardial infarction, and stroke.50 The actual findings were more variable.
Some researchers concluded that risks for thrombotic events had been diminished by reformulations and looked ahead to further analysis;27 others determined that the estrogen component continued to be responsible for increased risks of VTE;51 and still others found that the increased coagulation activity appeared to be balanced by the rise in fibrinolytic activity, thus preserving hemostatic balance.52
Aside from their physical health implications, thrombotic risks represented a source of stress to many OC users.
In 2002, researchers concluded that third-generation OCs confer the same risk of first ischemic stroke as second-generation oral contraceptives.9 In 2003, Tanis et al. found a 3- to 6-fold higher risk of venous thrombosis for women using low-dose oral contraceptive compared with that of nonusers; also, in that study, the risk of myocardial infarction and stroke during low-dose OC use was determined to be 2- to 5-fold greater.53 Again in 2009, a study team concluded that newer OC formulations still presented a persistent increased risk of VTE.25 In fact, some studies even suggest that third generation OCs are associated with a higher risk of venous thrombosis than the second-generation of oral contraceptives.24,53,54 Progestin-only formulations were associated with a 2-fold increased risk of nonfatal VTE; in the same study, it was also concluded that women with a history of unexplained VTE should not use OCs at all.54
The bottom line is that “numerous studies have found, with remarkable consistency, an elevated risk of venous thromboembolism among current users of low estrogen dose [oral contraceptives].”24
Aside from their physical health implications, thrombotic risks represented a source of stress to many OC users. In a questionnaire completed by 145 women on OCs, blood clots stood out as the greatest concern, cited by 45 percent of respondents.55
In addition to the long-term risks of OC use, surgery has been determined to present a particular danger of blood clotting for women on low-dose oral contraceptives. Among a list of unacceptable health risks for those considering taking the pill, the World Health Organization listed “planning to undergo major surgery” that would involve long-term immobility.56
Although OCs are associated with altered blood proteins resulting in reduced anticoagulant factors and increased procoagulant factors,57 a 1981 study presented evidence that some of the thrombotic risks of OCs are immunoreactive. In 20 percent of healthy women, there was a significant correlation between thrombosis and the presence in the serum of immune complexes and antiethinylestradiol antibodies. “Thus, it is possible to suggest that synthetic hormone use can provoke in certain predisposed subjects, the apparition of antihormonal antibodies able to cause vascular lesions.” (The researchers also noted an 11-fold greater risk of vascular thrombosis among OC users.)58 A year later, these researchers further confirmed this finding and discovered that synthetic estrogens and progestogens, but not nonsynthetic hormones, induced circulating immune complexes within as little as 3 weeks.59 Concentrations of circulating immune complexes were significantly higher in women with pulmonary embolism who had used oral contraceptives than in healthy controls or in those with pulmonary embolism who had never used these pills.60
Users of third generation OCs, as well as women on HRT, experience a strong increase in plasma concentrations of the inflammation marker C-reactive protein (CRP). The team called for further study on the relationship between the proinflammatory effect of OCs and the increased risk of thromboembolism for both oral contraceptives and HRT.61
Inflammatory and Immune Risks
OCs may induce the production of antiethinylestradiol antibodies circulating as immune complexes, which may be responsible for vascular thrombosis.58 The effects of OCs and HRT on inflammatory and immune factors are linked to a greater risk of chronic immune disorders that have an inflammatory component. A 1980 study found that the sex hormones in OCs and HRT have a profound effect on the efferent phase of immunity.62
A year later, a researcher noted a higher rate of hospital admissions for inflammatory diseases of the respiratory, digestive, urogenital, and musculoskeletal systems among women under age 40 who had used OCs at some point and suggested this may explain the higher level of white blood cells observed in OC users,63 an observation confirmed by others.64
OCs may alter the metabolic determinants and genetic regulation of CRP.65 The underlying mechanism that raises serum CRP in OC users appears to be related to a direct effect on hepatocyte CRP synthesis.66 The inflammatory and immune effects of OCs and HRT may be linked to a variety of disorders.67
Although OCs appear to help prevent colorectal,12,15 endometrial,14,67 and ovarian cancer,67 they appear to increase the risks of cervix and liver cancer,12,13 as well as cutaneous melanoma.23
OCs raise the risk of breast cancer,12,16–22,68 especially among women who used them during the 5 years before diagnosis69 and among women who started using OCs as teenagers.70 The risk extends to HRT as well.16–19,71 Further, the October 20, 2010, issue of JAMA reported that among postmenopausal women, use of HRT composed of estrogen plus progestin is linked with a greater incidence of breast cancers that are further advanced or have lymph node involvement, and with a higher risk of deaths attributable to breast cancer.22 OC use has also been associated with a 60 percent higher risk of squamous cell carcinoma.72
Locally increased estrogens can activate humoral immune response and proliferation of cells, including macrophages and fibroblasts. This suggests estrogens play a role in autoimmunity. For instance, increased estrogens in synovial tissue, or skin, may be involved in the autoimmune conditions rheumatoid arthritis and systemic lupus erythematosus (SLE), respectively.73,74 OCs are linked with an increased risk of SLE.76
Sex hormone balance is crucial in the regulation of inflammatory and immune responses, as estrogens play a role in enhancing immune function while androgens and progestogens have a suppressive function.76
OC users may have a greater risk of inflammatory bowel diseases. Women on OCs have a higher incidence of Crohn’s disease, regardless of estrogen potency;77 those on high-estrogen OCs exhibit higher risk of ulcerative ulcers.77
Women on the pill show a significant increase in the incidence of severe periodontitis;78 greater prevalence of certain Candida species in periodontal pockets;78 and higher levels of gingival inflammation.79
Researchers have found a direct association between several endocrinologic changes among long-term users of OCs, and clinical depression.11 Chronic inflammation could be behind some cases of clinical depression, according to a theory published in 2010.80 Previously, numerous studies had linked inflammatory immune cytokines with clinical depression.81–84 Also, high levels of estrogen or progestin increase a brain enzyme that reduces serotonin.85 Depression itself is associated with increased morbidity and mortality.86 With a heightened expression of inflammatory markers, it is implicated in the pathogenesis of cardiovascular heart disease.87
BFPB: Plasmanex1
Natto is a popular Asian food made by fermenting boiled soybeans. When natto itself is fermented with the culture filtrate of Bacillus subtilis natto, it produces 5 different enzymes. One of these enzymes is the serine protease; another is Bacillopeptidase F.
Nattokinase (pronounced nat-oh-KY-nase), an extract of serine protease, is available as a food supplement. Bacillopeptidase F Proprietary Blend (BFPB) is a functional food supplement—derived from the fermentation of natto—that appears to have a strong anticoagulant effect.30–36
BFPB is different in that the characteristic odor of nattoÂ, almost all of its high content of vitamin K, and all bacterial bodies have been removed. This functional food supplement is known by several names: Plasmanex1, Bacillopeptidase F Proprietary Blend (BFPB), Bacillus Natto Productive Protein (BNPP), and NKCP. (The nattokinase supplement is known as NSK-SD, and Lexirin.)
Overall, BFPB improves blood fluidity, decreases whole blood passage time, and reduces euglobulin lysis time.30 Many studies have shown BFPB to exert effects that are anticoagulant, fibrinolytic, and antithrombotic, both in vitro and in vivo, both in rodents and in human patients.30–36 BFPB’s antithrombotic activity could lead to therapies for the prevention of myocardial and cerebral infarctions, stroke, dementia, and other disorders.
Anticoagulant and fibrinolytic benefits have been shown for nattokinase, but only at extremely high concentrations.33 A 2007 study comparing the 2 products found that BFPB exhibits an anticoagulant effect that is over 100 times greater than nattokinase. The same study determined that BFPB has a 2.5-fold greater plasmin-like activity than nattokinase.33
Like most food-derived substances, BFPB is considered safe for clinical use, especially because it has been used in a number of studies and preliminary trials and has consistently been found to be safe, even in high doses.30–33,37
Natto and nattoÂ-derived products contain large quantities of vitamin K, which is procoagulant and interferes with the actions of anticoagulant medications such as warfarin. In fact all nattoÂ-derived products except BFPB have high vitamin K content. Almost all of the vitamin K content has been removed from BFPB as part of the extraction process. This explains why a study found BFPB does not interfere with warfarin’s efficacy,38 although all other natto products are, like all vitamin K foods, generally presumed to pose a potential risk for patients taking warfarin.
Given evidence of its safety and efficacy for attenuating thromboembolic risks, further research was conducted and presented in 2011 that suggests a role for BFPB in decreasing thrombotic risks specifically among OC/HRT users.47
RBAC: BRM4
Rice bran arabinoxylan compound (RBAC) is a rice bran and mushroom enzyme. It is a proprietary extract of arabinoxylan—a polysaccharide that is the principal constituent of the hemicellulose B found in rice bran—that has been modified by a beneficial carbohydrase enzyme complex extracted from shiitake mushroom mycelia culture. This extract is known by several names: RBAC, BRM4, MGN3, modified arabinoxylan rice bran, and in Europe, BioBran.
Evidence suggests that this modified extract promotes a number of positive immunomodulatory and anti-inflammatory effects.89 It holds promise as a possible therapy against a variety of disorders with an immune component, an inflammatory component, or both,76 including cancer, HIV activity,90 and clinical depression.81–85
OCs are associated with an effect on immune factors, and RBAC extract has been linked with immune activity. RBAC increases natural killer (NK) cell activity,43,91 increases other immune cells,91 and boosts NK cell cytotoxic function.45 This effect is greater among patients with compromised immune systems.
RBAC has an oncostatic effect, which may offset carcinogenic effects of OCs. The mechanism seems to be RBAC’s apparent ability to scavenge free radicals in the body after exposure to cancer cells; it modulates lipid peroxidation, augments the antioxidant defense system, and thus protects against oxidative stress following exposure to cancer cells.92 RBAC boosts tumor necrosis factor and interferon-alpha from peripheral blood lymphocytes, while down-regulating levels of the immune-suppressing cytokine interleukin-10.44 Research also shows that it induces apoptosis of cancer cells.46
Also relevant to the increased cancer risks associated with OCs, RBAC specifically and significantly suppresses the growth of tumors, both in volume and weight. This tumor suppression was found to be associated directly with the normalization of lipid peroxidation, and the enhancement of the activity of the endogenous antioxidant-scavenging enzymes, as well as an RBAC-induced increase in glutathione contents.40
RBAC may have a future role in treatment for cancer, whether related to OCs or not. Studies have shown that RBAC diminishes the toxicity to healthy cells of some chemotherapeutic agents.39,93 Rats receiving chemotherapy plus RBAC showed a greater weight increase than those on chemotherapy alone.39 On the other hand, RBAC increases the sensitivity of cancer cells to the effects of these chemotherapeutic agents.41,42 RBAC was shown to be completely safe in several types of toxicity tests,94 and the Ames test for mutagenicity proved negative.
Based on these studies, some researchers believe that RBAC may prove effective in reducing the higher risk of cancer in OC/HRT users. This has been further suggested by case study results from an open label, exploratory private practitioner research study, presented in 2011.47
Conclusions
This article has examined the major known risks inherent in OCs and HRT—which contain the same synthetic hormones—specifically those related to thrombotic and immune/inflammatory effects. It has highlighted research indicating that 2 functional food supplements may ameliorate these risks through separate mechanisms of action that are reproducible.
BFPB (Plasmanex1) modulates hematologic factors associated with blood coagulation and increases fibrinolytic activity, while RBAC (BRM4) elevates NK activity and exerts an immunomodulatory effect. It is suggested that an area worthy of investigation is the combined effect of both of these supplements, when taken together by OC/HRT users.
This article takes note that an exploratory, open-label research study presented in 2011 provides evidence of a role for BFPB (Plasmanex1) and RBAC (BRM4)—taken together—to decrease these health risks specifically among OC/HRT users.47 These results may help guide future research on the potential benefits of this combination therapy for OC/HRT users.
