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A randomized double blind placebo controlled trial was conducted in patients with chronic primary insomnia in West Bengal, India. Individuals were randomly assigned to receive 1 tablet of an herbal combination or 10 mg of zolpidem for 2 weeks. The herbal combination contained 300 mg valerian extract (standardized to 0.8% total valerenic acid), 80 mg passionflower extract (standardized to 4% isovitexin), and 30 mg hops extract (standardized to 0.35% rutin). Dosing was 1 tablet at bedtime and a sleep diary was conducted along with the Insomnia Severity Index and Epworth Sleepiness Scale.

Individuals ranged in age from 20-80 y.o. Of the 91 patients enrolled, 78 completed the study with 39 in each group. Eligibility was determined if they had an average of < 6 hours of sleep per night and a score of > 7 on the Insomnia Severity Index. Patients were excluded if they were taking medications that affect sleep, had a psychiatric diagnosis, had a history of substance abuse, had a dependence on sedative-hypnotic drugs, or if they worked night shifts.

The average sleep duration increased significantly from 3.4 to 5.9 hours in the herbal combination group and from 3.5 to 5.7 hours in the zolpidem group after the 2 week study period, which was considered similar results for both treatments. The average amount of time it took to fall asleep, called sleep latency, was also similar in both groups and decreased significantly from 84.0 to 23.6 minutes in the herbal group and from 90.0 to 26.4 minutes in the zolpidem. Night time awakenings decreased and quality of life scores improved in both groups, compared to baseline and with no significant differences between the two treatment groups. Daytime sleepiness was not a problem in either group, adverse events were similar in both groups, and no serious adverse events were reported in either group.

Commentary: Chronic insomnia is fraught with significant quality of life issuesmore insomnia including mood and cognitive changes. The results of this study indicate that this combination of valerian, hops and passion flower is a safe and effective alternative to zolpidem, at least for short term treatment of insomnia. Chronic insomnia is more common in women, with an exacerbation in perimenopause and early menopause. This herbal combination, along with seeing their insomnia as a perimenopause/menopause symptom and addressing the core physiological changes, bodes well for using these three herbs to treat insomnia.

Reference

Maroo N, Hazra A, Das T. Efficacy and safety of a polyherbal sedative-hypnotic formulation NSF-3 in primary insomnia in comparison to zolpidem: A randomized controlled trial. Indian J Pharmacol. January-February 2013;45(1):34-39.

Iron deficient anemia affects 38% of pregnant women around the world and is clearly one of the reasons prenatal iron supplements are recommended. Researchers in this systematic review and meta-analysis analyzed 48 randomized trials of iron supplementation, involving 17,793 women and 44 cohort studies of maternal anemia and birth outcomes involving 2 million women.

Iron supplementation was associated with a significant reduction in risk for low birth weight in the randomized trials. However, iron supplementation did not have a significant effect on the risk for preterm birth or small for gestational age births. In the other studies, first or second trimester iron deficient anemia was associated with significantly higher risk for babies with low birth weight.

clip_image002Commentary: Iron deficient anemia is one of the simplest conditions to test for and diagnose, and simple and inexpensive to treat. It should especially be treated during pregnancy due to the potential impact on the birth weight, size, and preterm births. There are of course other key supplements that determine a healthy pregnancy, developing fetus and infant. These include, but are not limited to folic acid, omega-3 fatty acids from fish oil, probiotics, and more. Some women will acquire nausea from iron supplements. This can often be mitigated by taking iron in some different forms that are easier on the digestive tract including iron aspartate, ferrous succinate and ferrous fumarate. In addition, taking the iron with vitamin C enhances iron absorption and taking iron with food tends to minimize or even bypass nausea, constipation, or gas, a frequent occurrence with iron supplements.

Reference

Haider B, et al. Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: Systematic review and meta-analysis. BMJ 2013 June 21:346.

Coenzyme Q10 deficiency has been implicated in fibromyalgia (FM). Past studies have demonstrated significant improvement in FM after oral CoQ10 supplementation. In the current study, the effects of oral CoQ10 was evaluated in four case reports of women with fibromyalgia.

Four women, ages 49, 43, 65 and 66 were diagnosed with FM using conventional American College of Rheumatology diagnostic criteria. All patients had high scores of pain, fatigue and sleep problems. All four women were treated with 300 mg/day of CoQ10 given in three divided doses of 100 mg, three times daily for 9 months. After 9 months, they were re-evaluated. A statistically significant improvement of pain, fatigue, sleep and tender points were observed. All women reported an improvement in pain, fatigue, sleep and tender points. Woman covering his face with her hands and crying

Commentary: Fibromyalgia is an all too common chronic pain syndrome that includes chronic pain, fatigue, headache, sleep disturbances and depression. CoQ10 supplementation of cultured blood cells from individuals with FM resulted in a restoration of the mitochondrial dysfunctions found within these blood cells. In addition, a 2002 study saw a benefit of CoQ10 supplementation in FM patients and the group of researchers in the current study, also found clinical improvement in patients with oral CoQ10 in two other published results in 2011 and 2012.

CoQ10 deficiency is considered a potential intervention for FM due to its ability to improve mitochondrial function and also it’s ability as a free radical scavenger. Oxidative stress is one of the proposed mechanisms involved in the symptoms of FM. CoQ10 can induce biochemical changes that allow for recovery from inflammation, antioxidant enzymes, mitochondrial genesis and activated protein kinase activity. Through these mechanisms, CoQ10 may be able to restore mitochondrial function and reduce the lipid peroxidation and DNA damage caused by oxidative stress, resulting in improvement in symptoms of fibromyalgia.

Reference

Alcocer-Gomez E, Cano-Garcia F, Cordero M. Effect of coenzyme Q10 evaluated by 1990 and 2019 ACR diagnostic criteria for fibromyalgia and SCL-90-R: Four case reports and literature review. Nutrition 2013;29:1422-1425

A multicenter, double-blind, placebo-controlled trial was conducted by Mayo Clinic researchers involving patients who had a cancer diagnosis within the previous two years of entry into the study. These cancer patients reported moderate fatigue and were given American ginseng root capsules, two capsules of 500 mg each twice daily or placebo. After 4 weeks, the patients who received ginseng reported somewhat less fatigue than placebo patients but after 8 weeks, there was a statistical and clinically significant difference between the ginseng group and placebo group. The results were even more clinically important for 83 patients who received ginseng and were undergoing chemotherapy or radiation during the study. They had significant improvements at 4 and 8 weeks.

HeadacheCommentary: Fatigue is a symptom of many patients with cancer, and fatigue during cancer treatments of chemotherapy and/or radiation is one of the most common side effects of these treatments. Ginseng has a long tradition of being used for fatigue and is one of the most well known adaptogens– i.e. plants that help us to adapt to stressors and help restore our homeostasis, including improving our energy.

Reference

Barton DL et al. Wisconsin ginseng (Panax quinquefolius) to improve cancer-related fatigue: A randomized, double-blind trial, N07C2. J Natl Cancer Inst 2013 Aug 21; 105:1230.

Green Japanes soybeanThe aim of this study was to determine if long-term isoflavone soy protein (ISP) in supplement form, could affect endometrial thickness (lining of the uterus), endometrial hyperplasia (potentially precancerous cells of the lining of the uterus) and endometrial cancer in postmenopausal women.

This randomized, double-blind, placebo-controlled trial matched 350 postmenopausal women ages 45-92 with a placebo group, for a period of 3 years. Women were randomized to take either a daily dose of 154 mg of ISP or a milk-protein placebo. The final study population was 224 women. The primary outcome measures were the average change in endometrial thickness as detected on transvaginal ultrasound from baseline up to 36 months, and the biopsy incidence of endometrial hyperplasia and endometrial cancer.

Transvaginal ultrasound was done at baseline, 18 months, 30 months and 36 months. Any woman with an endometrium greater than 5 mm was biopsied, as well as any woman with postmenopausal bleeding. In the soy group that in the end evaluated 121 postmenopausal women, 9 (7.4%) underwent endometrial biopsy based on transvaginal ultrasound. The results were benign in all of these 9 cases. In the placebo group of 103 women, 7 (6.8%) underwent endometrial biopsy and 6 of these 7 were benign with one woman diagnosed with complex endometrial hyperplasia with atypia. She then proceeded to a hysterectomy.

Commentary: Previous studies on the effect of ISP and its effect on the endometrium have been conflicting. One pilot study in 2002 demonstrated no effect but the study was small, 27 women and the duration was only 6 months. A larger 5 year study in 2004 found a small increase in endometrial hyperplasia in the soy group (5 of 6=3.8% and none in the placebo group. However, 5 of the 6 cases were simple hyperplasia with no atypia and only one case of complex hyperplasia and again, no atypia. Unfortunately, this 2004 study did not report on any cases of postmenopausal bleeding or ultrasound monitoring but instead did uniform biopsies on all women. This current study, had no effect on the thickness of the endometrium or on the rates of endometrial hyperplasia or endometrial cancer in postmenopausal women who took 154 mg/day of ISP for 3 years. The only case of endometrial hyperplasia (with atypia/precancerous cells), that did occur was in the placebo group. This confirms my comfort with daily intake of soy phytoestrogens both in the diet and in supplemental form, in postmenopausal women. This amount of 154 mg of total isoflavones per day is well above 2 servings of soy in the diet daily.

Seventy-four healthy individuals participated in a double-blind, randomized placebo-controlled study and were given oral green tea (400 mg powder three times daily) or placebo for 5weeks. The evaluation of reward learning and response to reward was conducted as well as mood, using the Montgomery-Asberg depression rating scale (MADRS) and the Hamilton Rating Scale for Depression (HRSD-17).

Green tea had significantly decreased reaction time in response to reward trial compared to placebo, meaning that those who took green tea showed a significantly increased reward learning. In addition, individuals who took the green tea had a reduction in the MADRS and HRSD-17 scales demonstrating improvement in depression, when compared with placebo group.

These findings suggest that reduced reward learning might be associated with depression. The regulatory role of green tea on the reward learning raises the possibility that it may be a supplemental treatment in reversing depression via its ability to normalize the reward function.

Commentary: Other studies have demonstrated that regular intake of green tea could reduce depressive symptoms. There is also evidence that a disturbance in reward learning can be associated with anhedonia, a frequent core symptom of depression and a requirement, along with depression for a diagnosis of major depressive disorder. The definition of anhedonia, per The American Psychological Association is feeling less interest in hobbies, apathy, and lack of enjoyment in activities that were previously enjoyed. Past research has linked dopamine deficiency and the reduction of dopamine transmission with anhedonia. Even though conventional medications address many depressive symptoms, it seems these do not adequately address motivation and reward deficits in depression. It has been proposed that the active components in green tea, EGCG, work in part by modulating dopamine transmission.

Reference

Zhang Q, Yang H, Wang J, et al. Effect of green tea on reward learning in healthy individuals Nutrition Journal 2013; 12:82 2013

NAC and PCOS

Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders in reproductive aged women with multiple manifestations and consequences. It affects approximately 6-10% of reproductive aged women and the metabolic disturbances associated with it have immediate and long term potential outcomes including infertility, hyperandrogenism, type 2 diabetes, cardiovascular disease and even uterine cancer.

Insulin-sensitizing agents have emerged as an important strategy in addressing the fundamental underlying cause of PCOS, insulin resistance. In conventional medicine, the focus has been on metformin which is an insulin sensitizing agent and can decrease the levels of insulin, improve glucose tolerance, increase sex hormone binding globulin (SHBG), decrease circulating androgens and increase ovulation rates in women with PCOS. N-acetyl-cysteine (NAC) is used by many alternative practitioners as a mucolytic medication and for antioxidant effects. Lesser known is its role as an insulin regulatory agent. And previous studies have shown that it can improve circulating insulin levels and insulin sensitivity in hyperinsulinemic women with PCOS as well as being successful as an adjunct treatment with clomiphene citrate for ovulation in women with PCOS.

The purpose of the study reported on here was to evaluate the effects of metformin and NAC in patients with PCOS. This prospective trial randomly divided 100 women to receive either metformin, 500 mg three times daily or NAC, 600 mg three times daily for 24 weeks. Evaluations included hirsutism scoring, body mass index, serum samples for follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone-sulphate (DHEAS), 17 OH-progesterone, total testosterone, free testosterone, androstenedione, thyroid stimulating hormone (TSH), SHBG, prolactin, glucose tolerance tests (including glucose and insulin), tumor necrosis factor-alpha (TNF-alpha) and lipids.

Women were ages 17-38 and 75 of the 100 women with PCOS completed the study. All women in the NAC group completed the study and 5 of the 35 women in the metformin group did not complete the study. At baseline, there were no differences between the treatment groups. Following treatment, LH, total testosterone and free testosterone decreased significantly and SHBG increased significantly in both groups. Hirsutism improved significantly in both groups and the difference between the metformin group and NAC group was not significant. Menstrual regularity was restored in 9 patients in the metformin group and 11 patients in the NAC group (36% vs. 34 %) and both metformin and NAC women significantly improved menstrual irregularity. In the metformin group, total serum cholesterol levels were significantly lowered but no significant changes were observed in LDL, triglycerides and HDL. In the NAC group, total cholesterol and LDL decreased significantly but no changes were observed in triglycerides and HDL. The changes in lipid profiles between the two groups were not significant.

Both metformin and NAC had positive effects on reducing fasting insulin levels, without change in fasting glucose, but this means that glucose-insulin ratios were increased significantly following treatment with both medicines and in addition, both led to a significant improvement in the HOMA (homeostatic model assessment; a method used to quantify insulin resistance) and were considered comparable. TNF-alpha levels were increased in both groups but not significant from baseline and similar in both groups.

Commentary: Conventional medical treatments for PCOS have come to include a combination of hormonal contraceptives, progestins, statins and insulin-sensitizing agents, especially metformin. This combination of treatments have not clearly led to adequate prevention of consequences of PCOS such as cardiovascular disease and type 2 diabetes and insufficient treatment of anovulatory related infertility, hirsutism, and weight management in those PCOS women who are overweight/obese. In addition, these approaches are fraught with side effects, and for metformin this typically includes gastrointestinal symptoms that can lead to intolerance of the drug, as it did with the high dropout rate in the metformin group in the current study. However, metformin has been a very important addition to PCOS management and two systemic reviews have shown that metformin reduces menstrual irregularity, improves ovulation rates, although poor impact on hirsutism.

A treatment such as NAC is a welcomed addition to improve insulin sensitivity in the management of PCOS. It turns out to be very well tolerated with no adverse effects. In the current study, both metformin and NAC reduced menstrual irregularity, resulted in regression of hirsutism and reduced hyperinsulinemia in women with PCOS. Also in the current study, there were significant reductions in free testosterone and total testosterone in both groups, likely due to decreasing insulin levels and increasing SHBG levels, and decreases in total cholesterol and insulin which bodes well for long term prevention issues as they related to cardiovascular disease and type 2 diabetes.

Reference

Oner G, Muderris I. Clinical, endocrine and metabolic effects of metformin vs N-acteyl-cytseine in women with polycystic ovary syndrome. European Journal of Obstetrics and Gynecology and Reproductive Biology. 2011;159:127-131.

clip_image001The purpose of this study was to investigate if iron deficiency has a role in unexplained chronic cough by contributing to irritability of the larynx.

Twenty-two non-smoking women with chronic unexplained cough and iron deficiency (a serum ferritin below 15 ng/ml) were examined initially, and then again after 2 months of treatment with an anti-histamine and proton pump inhibitor. After assurance that their cough would not respond to those two treatments, and they had normal lung function tests, no respiratory infections and no relevant systemic disease, women with a ferritin less than 15 ng/ml were given iron supplementation for 2 months in the form of iron sulphate tablets daily of 330 mg-660 mg.

The cough dramatically improved in all of the patients after iron supplementation.

Commentary:

Chronic cough is a common condition with known and easy to diagnose causes and successful treatments the majority of the time. However, in up to 20% of patients, the cough remains unexplained or does not improve to targeted treatments. Cough is much more frequent and severe in women than in men, although the reason for this is unknown. One line of reasoning though is the different hormonal environment in men and women, and the other line of reasoning is a decrease in iron stores that differentiate adult women from adult men and pubertal girls. Nearly 20% of childbearing women have iron deficiency, because of menstruation and pregnancies. While we do not yet know how iron deficiency may be related to chronic cough, there is a reduced epithelial tongue thickness in those with iron deficiency, suggesting that the cough could be a result of increased mucosal surface permeability of irritants.

It is also suggested that since in children, gender does not influence cough, but perhaps puberty does. Researchers theorize that because asthma becomes more prevalent in girls than in boys after puberty, perhaps this is also true of chronic coughs.

This study offers a welcome new insight into chronic cough in women with one more reason to test ferritin levels; when ferritin levels are < 15 ng/ml in women with chronic unexplained cough, a simple experiment of iron supplementation is a welcomed safe treatment.

Reference

Bucca C, Culla B, Burssino L, et al. Effect of iron supplementation in women with chronic cough and iron deficiency. Int J Clin Pract 2012;66(11): 1095-1100.

This year’s Primary Care for Women seminar is chock-full of new speakers and new information critical to treating women for primary care issues.

Features of our August 9-11, 2013 seminar include:IWHIM_logo_sm

- Integrating natural medicine and prescription meds in the management of hypertension

- Using medical apps to enhance your practice and patient care

- An update and essential guide for the primary care practitioner on chemotherapeutic agents

- A clinical guide to testing for anxiety and insomnia

- Advanced treatment strategies for anxiety disorders

- Recent and new prescriptions in women’s health

- Healing sexual dysfunction

- Research update on treating chronic pain and chronic inflammation

- Sterols vs. statins in cholesterol management

Other features include lectures on ethics and learning from our mistakes; product ingredients/extraction methods/bio-availability issues; a lunch time presentation on CCOs, Primary Care Homes and the Affordable Care Act and a special evening dinner and presentation with Lise Alschuler, N.D.

Full program, lecture descriptions, speakers and bios can be found on the Institute of Women’s Health and Integrative Medicine website:

www.instituteofwomenshealth.com

Date: August 9-11, 2013

Location: Portland, Oregon

Registration: www.instituteofwomenshealth.com or call 503-222-2322

Dry Eyes

One of the most common but frequent consequences of hormonal changes associated with perimenopause and menopause is dry eyes. In fact, the majority of those who suffer dry eye, are midlife women and older. In one study, presented at the annual meeting of the North American Menopause Society, 96% of 582 women with dry eye symptoms were perimenopausal or menopausal. Unfortunately, only 27% of these women had actually been diagnosed with dry eye syndrome by a practitioner and most did not know that there was any relationship with menopause. In this same study 95% of gynecologists and primary care provider never asked about dry eyes during a medical history. Clearly, health care providers need more information about this common and problematic health care problem.

dry eyesDry eye is a condition in which there are either insufficient tears to lubricate the eyes or the tears are poor quality or there is an imbalance between tear production and drainage. Tears are essential for lubrication, to reduce the risk of eye infections, to wash away foreign bodies in the eye and to keep the eye surface smooth and clear. Symptoms of dry eyes include irritation, gritty/scratchy or burning eyes, sensation of something in the eyes, tearing and blurred vision. In advanced dry eyes, damage to the cornea can occur and even impaired vision.

There are some simple self care habits one can acquire to prevent and manage dry eyes:

- Blink regularly with prolonged reading and computer screen work- to spread the tears evenly over the eyes

- Take eye breaks- close eyes for a few minutes with reading, computer work that requires visual concentration

- Position computer screen below eye level-so that the eyes don’t open overly wide as it would if the screen was higher. A lower screen may help to slow the evaporation of tears between blinks

- Increase level of humidity indoors

- Sunglasses worn outdoors helps to prevent exposure to wind and sun

- Avoid dehydration

- Avoid air blowing in the eyes

- Warm wet compresses- applied over the eyes for five minutes then gently rub the washcloth over the eyelids to loosen any particulate debris.

- Mild soap wash with baby shampoo or another soap intended to wash the eyes. The soap is applied to clean fingertips and gently massed into closed eyes near the base of the eyelashes then rinsed.

Both flaxseed oil and fish oil have demonstrated some positive benefits in dry eye disease by decreasing inflammation and/or increasing tear production and/or decreasing the evaporation of the tears. Several studies have determined an association between the intake of omega-3 supplements and meibomian gland oils and the implication for dry eye disease. Meibomian gland oils have been positively influenced by dietary omega-3 intake in individuals with Sjogren’s syndrome. [i] In the Women’s Health Study, data from 32,470 women found that a low dietary intake of omega-3s and/or a high omega-6 to omega-3 ratio increased the risk of dry eye syndrome.[ii] In another study involving patients with Sjogren’s syndrome, researchers found that the severity of dry eye and dry mouth disease was inversely proportional to membrane and serum levels of docosahexaenoic acid (DHA). [iii] There have also been two published anecdotal reports of flaxseed oil improving dry eye symptoms and thinning meibomian gland secretions.[iv] , [v] In a randomized clinical trial, oral flaxseed oil improved ocular surface inflammation and tear tests in patients with rheumatoid arthritis or systemic lupus associated with Sjogren’s syndrome and dry eye.[vi] An omega-3 supplement combination of 450 mg EPA/300 mg DHA + 1,000 mg flax oil + 183 IU of vitamin E oil improved dry eye symptoms and increased salivary gland secretion in patients with dry eye and dry mouth associated with Sjogren’s syndrome.[vii] A pilot, prospective, randomized, double-masked study was conducted in 36 patients with dry eye. Patients received either a daily dose of fish oil (450 mg EPA, 300 mg of DHA) with 1,000 mg of flaxseed oil, or placebo for 90 days. [viii] By the end of the study, 90% had become asymptomatic in the treatment group and only 7% in the placebo group. While there was no effect of fish oil/flax oil on meibum lipid composition or aqueous tear evaporation rate, the average tear production and tear volume was increased in the fish oil/flax oil group. [ix] December, 2011, I wrote about a study on sea buckthorn oil for dry eyes. The effect of oral sea buckthorn (SB) oil was studied in 100 individuals ages 20-75 in a double-blind, placebo-controlled study.[x] Participants took 2 gm/day of SB oil or placebo oil for 3 months. Eighty six participants completed the study. While the SB oil in people with dry eyed participants for 3 months did not result in any changes in the fatty acid composition of the tears, it did have a positive effect on osmolarity and symptoms of dry eye including burning and redness.

Over the counter preservative free single vial eye drops are the mainstay of dry eyes, whether mild, moderate or severe. Other medications and/or procedures from eye specialists are also available when symptoms are not adequately addressed with self care, artificial tears and nutritional supplementation.

References


[i] Sullivan B, Cermak J, Sullivan R, et al. Correlations between nutriebnt intake and the polar lipid profiles of meibomian gland secretions in women with Sjogren’s syndrome. Adv Exp Med Biol. 2002; 506(pt AP: 441-447.

[ii] Miljanovic B, Trivedi K, Dana M, er al. Relation between dietary n-3 and n-6 fatty acids and clinically diagnosed dry eye syndrome in women. Am J Clin Nutr. 2005;82:887-893.

[iii]Oxholm P, Asmussen K, Wiik A, et al. Essential fatty acid status in cell membranes and plasma of patients with primary Sjogren’s syndrome. Correlations to clinical and immunologic variables using a new model for classification and assessment of disease manifestations. Prostaglandins Leukot Essent Fatty Acids. 1998;59:239-245.

[iv] Boerner C. Dry eye successfully treated with oral flaxseed oil. Ocular Surgery News. October 15, 2000: 147-148.

[v] Chan C, Boxer W. Evaluation of flaxseed oil and doxycycline on dry eye outcomes in patients undergoing LASIK. ASCRS Annual Meeting. March 2006. San Francisco, CA.

[vi] Pinheiro M, Dos Santos P, Dos Santos R, et al. Oral flaxseed oil in the treatment for dry-eye Sjogren’s syndrome patients. Arq Bras Oftalmol. 2007;70:649-655.

[vii] Papas A. Singh M. The effect of a unique omega-3 supplement on dry mouth and dry eye in Sjogren’s patients. ARVO Annual Meeting. 2007.

[viii] Wojtowicz J, Butovich I, Uchiyama E, et al. Pilot, prospective, randomized, double-masked, placebo-controlled clinical trial of an Omega-3 supplement for dry eye. Cornea 2011; 30(3):308-314.

[x] Jarvinen R, Larmo P, Setala N, et al. Effects of oral se buckthorn oil on tear film fatty acids in individuals with dry eye. Cornea 2011;30;9:1-13-1018.

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