Saturday, December 19, 2009

Think You're Goin' Crazy During Perimenopause?

You are. We lose our minds, can't remember sh%@,  & don't sleep restoratively. --SG

Role of psychiatric comorbidity on cognitive function during and after the menopausal transition
Jeanne Leventhal Alexander†, Barbara R Sommer, Lorraine Dennerstein, Miglena Grigorova, Thomas Neylan, Krista Kotz, Gregg Richardson and Robert Rosenbaum

While cognitive complaints are common during the menopausal transition, measurable cognitive decline occurs infrequently, often due to underlying psychiatric or neurological disease. To clarify the nature, etiology and evidence for cognitive and memory complaints during midlife, at the time of the menopausal transition, we have critically reviewed the evidence for impairments in memory and cognition associated with common comorbid psychiatric conditions, focusing on mood and anxiety disorders, attention-deficit disorder, prolonged stress and decreased quantity or quality of sleep. Both the evidence for a primary effect of menopause on cognitive function and contrarily the effect of cognition on the menopausal transition are examined. Impairment in specific aspects of executive function is explored. Evaluation and treatment strategies for the symptomatic menopausal woman distressed by changes in her day-to-day cognitive function with or without psychiatric comorbidity are presented.

Expert Rev. Neurotherapeutics 7(11), S155–S178 (2007)

Hormone Therapy Helps Brain Fog

Here's a study showing that hormone therapy helps women in perimenopause, which can last 10 years, with brain fog, memory trouble, word finding & other cognitive problems. However, you get better if you start hormones before your final menstrual period (this is a recurring theme in the hormone literature). If you start hormones after your final menstrual period, you get worse. That sucks. More good news: postmenopause, your cognition rebounds back to premenopausal levels. -- SG

Effects of the menopause transition and hormone use on cognitive performance in midlife women.
Greendale GA, Huang MH, Wight RG, Seeman T, Luetters C, Avis NE, Johnston J, Karlamangla AS.

Division of Geriatrics, David Geffen School of Medicine at UCLA, 10945 Le Conte Avenue, Suite 2339, Los Angeles, CA 90095-1687, USA.
BACKGROUND: There is almost no longitudinal information about measured cognitive performance during the menopause transition (MT). METHODS: We studied 2,362 participants from the Study of Women's Health Across the Nation for 4 years. Major exposures were time spent in MT stages, hormone use prior to the final menstrual period, and postmenopausal current hormone use. Outcomes were longitudinal performance in three domains: processing speed (Symbol Digit Modalities Test [SDMT]), verbal memory (East Boston Memory Test [EBMT]), and working memory (Digit Span Backward). RESULTS: Premenopausal, early perimenopausal, and postmenopausal women scored higher with repeated SDMT administration (p < or = 0.0008), but scores of late perimenopausal women did not improve over time (p = 0.2). EBMT delayed recall scores climbed during premenopause and postmenopause (p < or = 0.01), but did not increase during early or late perimenopause (p > or = 0.14). Initial SDMT, EBMT-immediate, and EBMT-delayed tests were 4%-6% higher among prior hormone users (p < or = 0.001). On the SDMT and EBMT, compared to the premenopausal referent, postmenopausal current hormone users demonstrated poorer cognitive performance (p < or = 0.05) but performance of postmenopausal nonhormone users was indistinguishable from that of premenopausal women. CONCLUSIONS: Consistent with transitioning women's perceived memory difficulties, perimenopause was associated with a decrement in cognitive performance, characterized by women not being able to learn as well as they had during premenopause. Improvement rebounded to premenopausal levels in postmenopause, suggesting that menopause transition-related cognitive difficulties may be time-limited. Hormone initiation prior to the final menstrual period had a beneficial effect whereas initiation after the final menstrual period had a detrimental effect on cognitive performance.

Neurology. 2009 May 26;72(21):1850-7

Thursday, December 17, 2009

Hormone Therapy: Continuous Progesterone Safer

Which is better: to take progesterone continuously or sequentially (e.g., day 12-26 each month)? There are arguments on both sides, but this latest study shows that continuous progesterone has a 76% lower risk of endometrial cancer after 3-5 years. That is why I recommend regular uterine monitoring every 6+ months in women on sequential progesterone. -- SG

The long-term safety of different hormone therapy regimens has not been adequately studied in the context of endometrial cancer risk. In a national cohort study, investigators followed 224,000 Finnish women (age, >50) who used oral or transdermal estrogen-progestin (E+P) HT from 1994 to 2006. HT regimens were considered to be sequential if daily estradiol was accompanied by 10 to 14 days of progestin monthly or, in long-cycle regimens, during each 3-month interval. In continuous regimens, both estradiol and progestin were used nonstop. Incidence of endometrial cancer in E+P users was compared with that in all Finnish women.

A total of 1402 cases of incident endometrial cancer were identified. Compared with the general population, E+P users overall had 54% and 23% higher relative risk for type I and type II endometrial tumors, respectively. Monthly sequential E+P HT was associated with 69% (5 years' use) and 156% (10 years' use) higher risk for type I tumors. At 5 and 10 years of use, long-cycle sequential HT was associated with substantially higher risk for type I tumors than was monthly sequential HT. The endometrial safety of transdermal and oral sequential HT was similar; sequential HT with medroxyprogesterone acetate and norethindrone acetate also exhibited similar endometrial safety. Use of continuous E+P HT was associated with lower risk for type I tumors than in the overall population (76% risk reduction after 3–5 years' use).

Comment: Unopposed estrogen therapy or E+P hormone therapy with inadequate progestin raises risk for low-grade endometrial adenocarcinoma (i.e., type I) in menopausal women. Risks for high-grade serous papillary carcinoma and clear-cell adenocarcinoma (i.e., type II) are less clearly associated with HT use. These results are important in clarifying that, although long-term continuous E+P HT is protective, sequential therapy substantially raises risk for endometrial adenocarcinoma. The authors estimate that among 1000 women who use E+P HT for 10 years, eight additional cancer cases will be diagnosed if HT is sequential and monthly, whereas three to four fewer cases will be diagnosed if HT is continuous. For women who use sequential E+P HT long term, endometrial monitoring is appropriate.
— Andrew M. Kaunitz, MD

Published in Journal Watch Women's Health December 17, 2009

Jaakkola S et al. Endometrial cancer in postmenopausal women using estradiol–progestin therapy. Obstet Gynecol 2009 Dec; 114:1197.

Wednesday, December 16, 2009

Iodine Deficiency

by Michael B. Zimmermann

Institution Human Nutrition Laboratory, Swiss Federal Institute of Technology Zurich, CH-8092 Zurich, Switzerland; and Division of Human Nutrition, Wageningen University, 6708 Wageningen, The Netherlands
Title Iodine Deficiency.[Review]
Source Endocrine Reviews. 30(4):376-408, June 2009.
Abstract Iodine deficiency has multiple adverse effects in humans, termed iodine deficiency disorders, due to inadequate thyroid hormone production. Globally, it is estimated that 2 billion individuals have an insufficient iodine intake, and South Asia and sub-Saharan Africa are particularly affected. However, about 50% of Europe remains mildly iodine deficient, and iodine intakes in other industrialized countries, including the United States and Australia, have fallen in recent years. Iodine deficiency during pregnancy and infancy may impair growth and neurodevelopment of the offspring and increase infant mortality. Deficiency during childhood reduces somatic growth and cognitive and motor function. Assessment methods include urinary iodine concentration, goiter, newborn TSH, and blood thyroglobulin. But assessment of iodine status in pregnancy is difficult, and it remains unclear whether iodine intakes are sufficient in this group, leading to calls for iodine supplementation during pregnancy in several industrialized countries. In most countries, the best strategy to control iodine deficiency in populations is carefully monitored universal salt iodization, one of the most cost-effective ways to contribute to economic and social development. Achieving optimal iodine intakes from iodized salt (in the range of 150-250 [mu]g/d for adults) may minimize the amount of thyroid dysfunction in populations. Ensuring adequate iodine status during parenteral nutrition has become important, particularly in preterm infants, as the use of povidone-iodine disinfectants has declined. Introduction of iodized salt to regions of chronic iodine deficiency may transiently increase the incidence of thyroid disorders, but overall, the relatively small risks of iodine excess are far outweighed by the substantial risks of iodine deficiency.

PMS: Natural Approaches

PMS always worsens this time of year - so I thought I'd post the latest data from a favorite database: Natural Medicines Comprehensive Database. Short version of what is proven to be helpful:
  • calcium 1200 mg/day
  • Chasteberry
  • Ginkgo
  • Magnesium
  • Pyridoxine
  • Vitamin E
While I agree with what they say about the glories of calcium, magnesium and chastetree, I disagree with their comments on natural progesterone. Here's what they say....

The cluster of symptoms called "premenstrual syndrome" got its official name in 1931, but it has been recognized since antiquity. Up to 85% of women are affected by PMS to varying degrees. It often starts with development of menstruation in young women and tends to follow a consistent pattern until menopause.

Over 150 symptoms associated with PMS have been catalogued. The most common are irritability, agitation, headache, depression, breast tenderness, fluid retention, and weight gain. These symptoms typically show up in the second half of the menstrual cycle, about 7-10 days before the start of the next period.

Minerals / Vitamins

ACOG guidelines suggest that several nutrition supplements are worth trying as a first step in treating PMS.

Calcium is one of the more interesting minerals used for PMS. Researchers began to suspect a calcium-PMS connection when they noticed that calcium deficiency and PMS share similar symptoms. In addition, women who have PMS tend to have abnormally low levels of calcium at the time of ovulation, compared to women without PMS.13776 Low calcium levels stimulate overproduction of parathyroid hormone. Too much parathyroid hormone can affect mood, possibly by interacting with serotonin.13777,13778

Some evidence suggests that women who consume an average of 1283 mg/day of calcium from the diet have about a 30% lower risk of developing PMS, compared to women who consume 529 mg/day.13094

What really makes the case for calcium is that clinical trials show giving 1000-1200 mg of elemental calcium daily for a few months to women with PMS significantly improves mood and decreases bloating, food cravings, and pain.1822,1823,1824

Calcium makes sense for most women with PMS...especially if they don't already get enough calcium in their diet.

Magnesium deficiency might be another factor that contributes to symptoms of PMS. Women with PMS tend to have lower magnesium levels than other women.6847 Women with PMS who take 360 mg/day of magnesium supplements seem to have improved mood and less fluid retention.1187,1188,6847 Taking magnesium might also reduce premenstrual migraine.1186,6847

Magnesium might be beneficial because it is involved in the activity of serotonin and other neurotransmitters. Magnesium also has a role in vascular contraction and cell membrane stability.

There is less evidence for magnesium than calcium. It's too soon to recommend magnesium for most women, but it might be worth considering for women with premenstrual migraine, fluid retention, and poor mood, despite other treatments.
Vitamin E is sometimes suggested for PMS. There is some evidence that women with PMS who take vitamin E 400 IU/day for three cycles have improved mood, reduced PMS-related anxiety and food cravings.4719,4720 Women with PMS do NOT seem to have reduced vitamin E levels. It is not known how vitamin E might work to improve symptoms of PMS. The evidence isn't strong enough to recommend vitamin E for most patients just yet.

Practice Pearl - Advise women with diabetes or heart disease NOT to use vitamin E supplements in doses of 400 IU/day or more. There is some concern that these doses of vitamin E could increase the risk of heart failure in patients with diabetes or heart disease. More evidence is needed to verify this potential risk. In the meantime, explain to these patients that the potential benefit of using vitamin E doesn't outweigh the potential risks.
Vitamin D is now being studied for prevention of PMS. There is some evidence that increasing total or dietary intake of vitamin D is associated with a decreased risk of developing PMS. Women with an average vitamin D intake of 706 mg/day seem to have about a 40% lower risk of developing PMS compared to women with an average vitamin D intake of 112 mg/day;13094 however, taking vitamin D supplements does not appear to reduce the risk of developing PMS. And there is no evidence that vitamin D can decrease symptoms in women with existing PMS. Advise patients to make sure they get adequate amounts of vitamin D in their diet.

Pyridoxine (vitamin B6) is another vitamin that is recommended for PMS. One theory is that PMS might be related to low dopamine levels. Pyridoxine is a co-factor needed for dopamine production. Another theory is that pyridoxine and other B vitamins might prevent fat accumulation in the liver. This could improve estrogen metabolism and potentially affect PMS symptoms.
There is not much scientific support for these theories. But there is some evidence from clinical studies that pyridoxine might help. Taking 100 mg/day of pyridoxine supplements seems to decrease overall symptoms of PMS as well as depression.3093

Practice Pearl: Advise patients to be careful with pyridoxine. High doses can cause peripheral neuropathy. Recommend not using doses over 100 mg/day. This is generally there's no evidence that doses over 100 mg/day are any more effective.
Manganese is a lesser known mineral. It's in most multivitamins, but in very small amounts. Low intake of dietary manganese has been linked with increased symptoms of PMS.7135 There is some evidence that taking manganese in combination with calcium might improve symptoms of PMS...irritability, depression, anxiety, tension, restlessness, etc.2004 But its not known if this benefit is due to the calcium or the manganese. For now, don't recommend manganese for PMS. Instead, let patients know that if they take a multivitamin, they're probably getting enough manganese.

Supportive Treatment: Analgesics, NSAIDs, Diuretics

Supportive treatment is also recommended as a first step in treating PMS. These treatments generally target specific symptoms.

For relief of headache, backache, or cramping, acetaminophen (Tylenol) or NSAIDs (ibuprofen, naproxen, etc) are typically used. For bloating and fluid retention, spironolactone (Aldactone) is often used. It works as a diuretic to decrease fluid retention, and it has the added benefit of having an antiandrogen effect. This might further contribute to symptom relief in women with PMS.

Women with PMS also often turn to natural products for supportive treatment.
Ginkgo (Ginkgo biloba) is sometimes tried. We don't usually think of it as a traditional "woman's herb," but there is some evidence ginkgo leaf extract can relieve PMS fluid retention and its consequences...breast swelling and tenderness, pelvic pain and swelling, and swollen hands and feet.6229 Investigators started looking into ginkgo because women who were taking it for memory reported relief from fluid retention associated with PMS. No one is quite sure why ginkgo seems to work for this indication, but one theory is that it INHIBITS platelet activating factor (PAF).5719,9760 PAF normally triggers inflammation, leading to vascular congestion, edema, and breast swelling. Therefore, it is thought that ginkgo might have an anti-inflammatory effect.
Evening primrose oil (Oenothera biennis) is often recommended for PMS. Evening primrose oil contains the omega-6 fatty acid, gamma-linolenic acid (GLA). It is thought that some women with PMS are deficient in gamma-linolenic acid, possibly due to a defect in their ability to convert linoleic acid to gamma-linolenic acid.6034 This could be important because GLA and its metabolites are precursors to the anti-inflammatory prostaglandin E1.6036,12470

In theory, by taking evening primrose oil, women could boost GLA levels, decrease inflammation, and possibly relieve some symptoms of PMS. But the clinical evidence says otherwise. Several small-scale studies suggest that evening primrose does NOT relieve symptoms of PMS.1105,1106,6847,8219 Don't recommend it.

Selective serotonin reuptake inhibitors (SSRIs) are now being used more for PMS. In fact, fluoxetine, under a different brand name Sarafem (to distinguish it from Prozac), and sertraline (Zoloft) are approved for the more severe symptoms of premenstrual dysphoric disorder (PMDD). Fluoxetine and sertraline primarily help severe mood changes, including depression and anxiety, but can also improve breast tenderness, bloating, irritability, and headache.12337,13779,13780

The ACOG guidelines suggest considering antidepressants in Step 2, for women who don't respond to supportive treatment and lifestyle changes. Fluoxetine or sertraline are considered the first line antidepressants for PMS or PMDD.12337,12349

Some women are reluctant to use conventional antidepressants. Many turn to "natural" alternatives.

St. John's wort (Hypericum perforatum) is the most popular herbal antidepressant...and the best studied. Numerous studies show that it can be beneficial for mild to moderate depression. But there is only very preliminary evidence that it can help for PMS symptoms.6429
Before patients try St. John's wort, remind them of its downside...St. John's wort causes LOTS of drug interactions. It is a potent INDUCER of cytochrome P450 3A4. It can decrease levels and the effectiveness of lots of drugs. Some of these include the HIV protease inhibitors, non-nucleoside reverse transcriptase inhibitors, oral contraceptives, cyclosporin, some statins, and many others.

Practice Pearl - Tell women who take St. John's wort that if they use oral contraceptives for birth control they should use a back up method of contraception. St. John's wort can decrease the effectiveness of oral contraceptives, which could result in unexpected pregnancy.11886,11887

SAMe (S-adenosyl-L-methionine) is another well-known natural antidepressant. SAMe works by donating methyl groups to various physiological processes, including synthesis of neurotransmitters. SAMe increases levels of serotonin, norepinephrine, and dopamine.5196,5231,5232,9110 It does seem to help for depression and seems to be safe. But there is no reliable evidence that it works for symptoms of PMS. Don't recommend it.

Advise patients to avoid supplements containing L-tryptophan or 5-HTP. These products are precursors to serotonin. They are often marketed for depression, anxiety, and sometimes for PMS. There's actually some evidence that L-tryptophan might improve some symptoms of PMS.6246 But there are lots of questions about the safety of these products. Years ago these products were linked to several cases of eosinophilia myalgia syndrome (EMS).902,919,7067,8053,10084,10085,11474,11478 Until more is known about the safety of 5-HTP and L-tryptophan, tell patients not to use them.

Practice Pearl - Tell women who take St. John's wort that if they use oral contraceptives for birth control they should use a back up method of contraception. St. John's wort can decrease the effectiveness of oral contraceptives, which could result in unexpected pregnancy.11886,11887
SAMe (S-adenosyl-L-methionine) is another well-known natural antidepressant. SAMe works by donating methyl groups to various physiological processes, including synthesis of neurotransmitters. SAMe increases levels of serotonin, norepinephrine, and dopamine.5196,5231,5232,9110 It does seem to help for depression and seems to be safe. But there is no reliable evidence that it works for symptoms of PMS. Don't recommend it.

Advise patients to avoid supplements containing L-tryptophan or 5-HTP. These products are precursors to serotonin. They are often marketed for depression, anxiety, and sometimes for PMS. There's actually some evidence that L-tryptophan might improve some symptoms of PMS.6246 But there are lots of questions about the safety of these products. Years ago these products were linked to several cases of eosinophilia myalgia syndrome (EMS).902,919,7067,8053,10084,10085,11474,11478 Until more is known about the safety of 5-HTP and L-tryptophan, tell patients not to use them.

Hormonal Agents

Lots of theories about PMS are based on hormone imbalances. Some investigators attribute PMS anxiety and depression to high estrogen and low progesterone. They think food cravings, headache, fatigue, and palpitations might be related to increased insulin resistance, low anti-inflammatory prostaglandin E1, and high levels of pro-inflammatory prostaglandin 2. And they attribute PMS fluid retention to high aldosterone levels.
Some clinicians try to adjust a woman's hormonal balance in an effort to address this potential underlying cause. Hormone therapy is usually directed toward suppressing ovulation. Oral contraceptives or gonadotropin-releasing hormones (leuprolide, goserelin) are tried. Oral contraceptives are most popular and make sense if the symptoms are mainly physical...breast tenderness, headache, etc. But when they are initiated, they can sometimes make these symptoms worse. And they're usually not helpful for mood changes. Many clinicians are reluctant to use gonadotropin-releasing hormone because they produce a "chemical menopause" that can lead to bone loss.

ACOG guidelines consider these hormonal options as the third step in treating PMS symptoms.

Lots of natural products are promoted for their hormone-like effects. Many women turn to these products with the hope of symptom relief, without the downside of conventional drugs.

Chasteberry (Vitex agnus-castus) is a very popular "woman's herb" evaluated in several studies for PMS. Chasteberry seems to be best for physical symptoms such as breast tenderness, edema, and constipation. It also seems to improve irritability, mood, anger, and headache.7055,7076,7078,7079 In some women, chasteberry improves symptoms by as much as 50%.7055 But chasteberry does not appear to be very helpful for symptoms of bloating.7055

There is also some evidence that chasteberry might help for the more severe symptoms of PMDD. One study found chasteberry to be comparable to fluoxetine 20-40 mg/day; however, chasteberry tended to be more effective for physical symptoms, while fluoxetine was more effective for psychological symptoms.12207

Exactly how chasteberry works for PMS is not known. But chasteberry has a variety of pharmacological effects that might be beneficial. Chasteberry might affect dopamine, acetylcholine and opioid receptors.7014,7015,10122 Chasteberry might also have estrogen and progestin activity.10979,11456

Chasteberry is very promising based on the evidence so far. But the evidence is somewhat limited due small sample sizes or inadequate study designs. Due to these limitations, chasteberry shouldn't be recommended just yet to most patients.

Natural progesterone is another product that is promoted for PMS...often over the Internet. But it doesn't work any better than placebo.1220,10332 Urge your patients to save their money and steer clear.

Black cohosh (Actaea racemosa), red clover (Trifolium pratense), and soy (Glycine max) are widely known as "women's herbs." They may be helpful for menopausal symptoms, but there isn't much evidence they work for PMS symptoms. Don't recommend them.
Also, steer patients away from dong quai (Angelica sinensis) for PMS. There is no reliable evidence that it is effective...and not enough is known about its safety.

The Bottom Line

If your patient wants to take a natural approach to relieving PMS symptoms, suggest 1200 mg of calcium daily. Be sure she understands that benefits would not appear for at least a few months. Even if she doesn't see an improvement in PMS symptoms, she will at least be getting some protection against osteoporosis.
Other minerals and vitamins might be helpful...magnesium, vitamin E, and pyridoxine. But there is not as much evidence for these as there is for calcium. If patients want to try pyridoxine, remind them not to exceed 100 mg/day due to risk of neuropathy.

Chasteberry is the herb with the most evidence in support of efficacy for PMS. But it is still not enough to recommend to most women.

A few other natural products have some preliminary evidence, but more research is needed before these can be recommended...ginkgo, St. John's wort, and manganese.

Tell women that using evening primrose oil, progesterone, black cohosh, red clover, soy, or dong quai is unlikely to improve PMS symptoms.

902 Michelson D, Page SW, Casey R, et al. An eosinophilia-myalgia syndrome related disorder associated with exposure to L-5-hydroxytryptophan. J Rheumatol 1994;21:2261-5.

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1186 Facchinetti F, Sances G, Borella P, et al. Magnesium prophylaxis of menstrual migraine: effects on intracellular magnesium. Headache 1991;31:298-301.

1187 Facchinetti F, Borella P, Sances G, et al. Oral magnesium successfully relieves premenstrual mood changes. Obstet Gynecol 1991;78:177-81.

1188 Walker AF, De Souza MC, Vickers MF, et al. Magnesium supplementation alleviates premenstrual symptoms of fluid retention. J Womens Health 1998;7:1157-65.

1220 Freeman EW, Rickels K, Sondheimer SJ, et al. A double-blind trial of oral progesterone, alprazolam, and placebo in treatment of severe premenstrual syndrome. JAMA 1995;274:51-7.

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5719 Kudolo GB. The effect of 3-month ingestion of Ginkgo biloba extract on pancreatic beta-cell function in response to glucose loading in normal glucose tolerant individuals. J Clin Pharmacol 2000;40:647-54.

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6246 Steinberg S, Annable L, Young SN, Liyanage N. A placebo-controlled study of the effects of L-tryptophan in patients with premenstrual dysphoria. Adv Exp Med Biol 1999;467:85-8.

6429 Stevinson C, Ernst E. A pilot study of Hypericum perforatum for the treatment of premenstrual syndrome. BJOG 2000;107:870-6.

6847 Bendich A. The potential for dietary supplements to reduce premenstrual syndrome (PMS) symptoms. J Am Coll Nutrition 2000;19:3-12.

7014 Wuttke W. Dopaminergic action of extracts of Agnus Castus. Forschende Komplementarmedizen 1996;3:329-30.

7015 Jarry H, Leonhardt S., Gorkow C, Wuttke W. In vitro prolactin but not LH and FSH release is inhibited by compounds in extracts of Agnus Castus: direct evidence for a dopaminergic principle by the dopamine receptor assay. Exp Clin Endocrinol 1994;102:448-54.

7055 Schellenberg R. Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomized, placebo-controlled study. Br Med J 2001;322:134-7.

7067 FDA. Information paper on L-tryptophan and 5-hydroxy-L-tryptophan. Office of Nutritional Products, Labeling, Dietary Supplements. Center for Food Safety and Applied Nutrition. February 2001.

7076 Lauritzen CH, Reuter HD, Repges R, et al. Treatment of premenstrual tension syndrome with Vitex agnus castus: Controlled-double blind versus pyridoxine. Phytomedicine 1997;4:183-9.

7078 Berger D. Schaffner W, Schrader E, et al. Efficacy of Vitex agnus castus L. extract Ze 440 in patients with premenstrual syndrome (PMS). Arch Gynecol Obstet 2000;264:150-3.

7079 Loch EG, Selle H, Boblitz N. Treatment of premenstrual syndrome with a phytopharmaceutical formulation containing Vitex agnus castus. J Womens Health Gend Based Med 2000;9:315-20.

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8219 Paasonen MK, Penttila O, Himberg JJ, et al. Platelet taurine in patients with arterial hypertension, myocardial failure or infarction. Acta Med Scand Suppl 1980;642:79-84.

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10084 Johnson KL, Klarskov K, Benson LM, et al. Presence of peak X and related compounds: the reported contaminant in case related 5-hydroxy-L-tryptophan associated with eosinophilia-myalgia syndrome. J Rheumatol 1999;26:2714-7.

10085 Greenberg AS, Takagi H, Hill RH, et al. Delayed onset of skin fibrosis after the ingestion of eosinophilia-myalgia syndrome-associated L-tryptophan. J Am Acad Dermatol 1996;35:264-6.

10122 Meier B, Berger D, Hoberg E, et al. Pharmacological activities of Vitex agnuscastus extracts in vitro. Phytomedicine 2000;7:373-81.

10332 Wyatt K, Dimmock P, Jones P, et al. Efficacy of progesterone and progestogens in management of premenstrual syndrome: systematic review. BMJ 2001;323:776-80.

10979 Liu J, Burdette JE, Xu H, et al. Evaluation of estrogenic activity of plant extracts for the potential treatment of menopausal symptoms. J Agric Food Chem 2001;49:2472-9.

11456 Wuttke W, Jarry H, Christoffel V, et al. Chaste tree (Vitex agnus-castus)--pharmacology and clinical indications. Phytomedicine 2003;10:348-57.

11474 Kilbourne EM, Philen RM, Kamb ML, Falk H. Tryptophan produced by Showa Denko and epidemic eosinophilia-myalgia syndrome. J Rheumatol Suppl 1996;46:81-8.

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I'm an organic gynecologist, yoga teacher + writer. I earn a living partnering with women to get them vital and self-realized again. We're born that way, but often fall off the path. Let's take your lousy mood and fatigue, and transform it into something sacred and useful.